324 results on '"Victor W.M. Van Hinsbergh"'
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2. Cardiac Microvascular Endothelial Enhancement of Cardiomyocyte Function Is Impaired by Inflammation and Restored by Empagliflozin
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Rio P. Juni, PhD, Diederik W.D. Kuster, PhD, Max Goebel, MSc, Michiel Helmes, PhD, René J.P. Musters, PhD, Jolanda van der Velden, PhD, Pieter Koolwijk, PhD, Walter J. Paulus, MD, PhD, and Victor W.M. van Hinsbergh, PhD
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Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Summary: The positive findings of the EMPA-REG OUTCOME trial (Randomized, Placebo-Controlled Cardiovascular Outcome Trial of Empagliflozin) on heart failure (HF) outcome in patients with type 2 diabetes mellitus suggest a direct effect of empagliflozin on the heart. These patients frequently have HF with preserved ejection fraction (HFpEF), in which a metabolic risk-related pro-inflammatory state induces cardiac microvascular endothelial cell (CMEC) dysfunction with subsequent cardiomyocyte (CM) contractility impairment. This study showed that CMECs confer a direct positive effect on contraction and relaxation of CMs, an effect that requires nitric oxide, is diminished after CMEC stimulation with tumor necrosis factor-α, and is restored by empagliflozin. Our findings on the effect of empagliflozin on CMEC-mediated preservation of CM function suggests that empagliflozin can be used to treat the cardiac mechanical implications of microvascular dysfunction in HFpEF. Key Words: contraction and relaxation, endothelial cell–derived nitric oxide, empagliflozin, heart failure, oxidative stress
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- 2019
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3. Supplementary Figures 1-3 from Proximal Fluid Proteome Profiling of Mouse Colon Tumors Reveals Biomarkers for Early Diagnosis of Human Colorectal Cancer
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Connie R. Jimenez, Gerrit A. Meijer, Victor W.M. van Hinsbergh, Riccardo Fodde, Ron Smits, Els C. Robanus-Maandag, Marinus A. Blankenstein, Chris J.J. Mulder, Jochim S. Terhaar sive Droste, Sietze T. van Turenhout, Pien M. Delis-van Diemen, Fiona Smit, Chloe Piso, Mehrdad Lavaei, Marc O. Warmoes, Thang V. Pham, Sander R. Piersma, Maral Pourghiasian, Meike de Wit, and Remond J.A. Fijneman
- Abstract
PDF file - 397K
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- 2023
4. Data from Proximal Fluid Proteome Profiling of Mouse Colon Tumors Reveals Biomarkers for Early Diagnosis of Human Colorectal Cancer
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Connie R. Jimenez, Gerrit A. Meijer, Victor W.M. van Hinsbergh, Riccardo Fodde, Ron Smits, Els C. Robanus-Maandag, Marinus A. Blankenstein, Chris J.J. Mulder, Jochim S. Terhaar sive Droste, Sietze T. van Turenhout, Pien M. Delis-van Diemen, Fiona Smit, Chloe Piso, Mehrdad Lavaei, Marc O. Warmoes, Thang V. Pham, Sander R. Piersma, Maral Pourghiasian, Meike de Wit, and Remond J.A. Fijneman
- Abstract
Purpose: Early detection of colorectal cancer (CRC) and its precursor lesions is an effective approach to reduce CRC mortality rates. This study aimed to identify novel protein biomarkers for the early diagnosis of CRC.Experimental Design: Proximal fluids are a rich source of candidate biomarkers as they contain high concentrations of tissue-derived proteins. The FabplCre;Apc15lox/+ mouse model represents early-stage development of human sporadic CRC. Proximal fluids were collected from normal colon and colon tumors and subjected to in-depth proteome profiling by tandem mass spectrometry. Carcinoembryonic antigen (CEA) and CHI3L1 human serum protein levels were determined by ELISA.Results: Of the 2,172 proteins identified, quantitative comparison revealed 192 proteins that were significantly (P < 0.05) and abundantly (>5-fold) more excreted by tumors than by controls. Further selection for biomarkers with highest specificity and sensitivity yielded 52 candidates, including S100A9, MCM4, and four other proteins that have been proposed as candidate biomarkers for human CRC screening or surveillance, supporting the validity of our approach. For CHI3L1, we verified that protein levels were significantly increased in sera from patients with adenomas and advanced adenomas compared with control individuals, in contrast to the CRC biomarker CEA.Conclusion: These data show that proximal fluid proteome profiling with a mouse tumor model is a powerful approach to identify candidate biomarkers for early diagnosis of human cancer, exemplified by increased CHI3L1 protein levels in sera from patients with CRC precursor lesions. Clin Cancer Res; 18(9); 2613–24. ©2012 AACR.
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- 2023
5. Supplementary Table 1 from Proximal Fluid Proteome Profiling of Mouse Colon Tumors Reveals Biomarkers for Early Diagnosis of Human Colorectal Cancer
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Connie R. Jimenez, Gerrit A. Meijer, Victor W.M. van Hinsbergh, Riccardo Fodde, Ron Smits, Els C. Robanus-Maandag, Marinus A. Blankenstein, Chris J.J. Mulder, Jochim S. Terhaar sive Droste, Sietze T. van Turenhout, Pien M. Delis-van Diemen, Fiona Smit, Chloe Piso, Mehrdad Lavaei, Marc O. Warmoes, Thang V. Pham, Sander R. Piersma, Maral Pourghiasian, Meike de Wit, and Remond J.A. Fijneman
- Abstract
XLS file - 37K
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- 2023
6. Supplementary Table 2 from Proximal Fluid Proteome Profiling of Mouse Colon Tumors Reveals Biomarkers for Early Diagnosis of Human Colorectal Cancer
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Connie R. Jimenez, Gerrit A. Meijer, Victor W.M. van Hinsbergh, Riccardo Fodde, Ron Smits, Els C. Robanus-Maandag, Marinus A. Blankenstein, Chris J.J. Mulder, Jochim S. Terhaar sive Droste, Sietze T. van Turenhout, Pien M. Delis-van Diemen, Fiona Smit, Chloe Piso, Mehrdad Lavaei, Marc O. Warmoes, Thang V. Pham, Sander R. Piersma, Maral Pourghiasian, Meike de Wit, and Remond J.A. Fijneman
- Abstract
XLS file - 1.2MB
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- 2023
7. Supplementary Figure Legends 1-3 from Proximal Fluid Proteome Profiling of Mouse Colon Tumors Reveals Biomarkers for Early Diagnosis of Human Colorectal Cancer
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Connie R. Jimenez, Gerrit A. Meijer, Victor W.M. van Hinsbergh, Riccardo Fodde, Ron Smits, Els C. Robanus-Maandag, Marinus A. Blankenstein, Chris J.J. Mulder, Jochim S. Terhaar sive Droste, Sietze T. van Turenhout, Pien M. Delis-van Diemen, Fiona Smit, Chloe Piso, Mehrdad Lavaei, Marc O. Warmoes, Thang V. Pham, Sander R. Piersma, Maral Pourghiasian, Meike de Wit, and Remond J.A. Fijneman
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PDF file - 53K
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- 2023
8. Empagliflozin restores chronic kidney disease-induced impairment of endothelial regulation of cardiomyocyte relaxation and contraction
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Pieter Koolwijk, Diederik W. D. Kuster, Rushd Al-Shama, Etto C. Eringa, Jolanda van der Velden, Victor W.M. van Hinsbergh, Rio P. Juni, Marc G. Vervloet, Henrike M Hamer, Fysiologie, RS: Carim - H08 Experimental atrial fibrillation, Physiology, ACS - Heart failure & arrhythmias, Laboratory Medicine, Nephrology, ACS - Diabetes & metabolism, and ACS - Microcirculation
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0301 basic medicine ,MITOCHONDRIAL FRAGMENTATION ,STRESS ,endothelium-to-cardiomyocyte crosstalk ,mitochondrial oxidative damage ,030232 urology & nephrology ,heart failure ,cardiomyocyte relaxation and contraction ,chemistry.chemical_compound ,0302 clinical medicine ,Glucosides ,Myocytes, Cardiac ,Endothelial dysfunction ,chemistry.chemical_classification ,RISK ,OUTCOMES ,Ejection fraction ,Endothelial stem cell ,PRESERVED EJECTION FRACTION ,Nephrology ,HEART-FAILURE ,medicine.medical_specialty ,empagliflozin ,INHIBITION ,RENAL DYSFUNCTION ,Nitric Oxide ,Nitric oxide ,03 medical and health sciences ,Internal medicine ,medicine ,Empagliflozin ,Animals ,Humans ,Endothelium ,Benzhydryl Compounds ,Renal Insufficiency, Chronic ,Reactive oxygen species ,ADVANCED GLYCATION ENDPRODUCTS ,NITRIC-OXIDE ,business.industry ,Endothelial Cells ,medicine.disease ,Rats ,030104 developmental biology ,Endocrinology ,chemistry ,Heart failure ,Endothelium, Vascular ,business ,Heart failure with preserved ejection fraction ,chronic kidney disease - Abstract
Chronic kidney disease (CKD) promotes development of cardiac abnormalities and is highly prevalent in patients with heart failure, particularly in those with preserved ejection fraction. CKD is associated with endothelial dysfunction, however, whether CKD can induce impairment of endothelium-to-cardiomyocyte crosstalk leading to impairment of cardiomyocyte function is not known. The sodium-glucose co-transporter 2 inhibitor, empagliflozin, reduced cardiovascular events in diabetic patients with or without CKD, suggesting its potential as a new treatment for heart failure with preserved ejection fraction. We hypothesized that uremic serum from patients with CKD would impair endothelial control of cardiomyocyte relaxation and contraction, and that empagliflozin would protect against this effect. Using a co-culture system of human cardiac microvascular endothelial cells with adult rat ventricular cardiomyocytes to measure cardiomyocyte relaxation and contraction, we showed that serum from patients with CKD impaired endothelial enhancement of cardiomyocyte function which was rescued by empagliflozin. Exposure to uremic serum reduced human cardiac microvascular endothelial cell nitric oxide bioavailability, and increased mitochondrial reactive oxygen species and 3-nitrotyrosine levels, indicating nitric oxide scavenging by reactive oxygen species. Empagliflozin attenuated uremic serum-induced generation of endothelial mitochondrial reactive oxygen species, leading to restoration of nitric oxide production and endothelium-mediated enhancement of nitric oxide levels in cardiomyocytes, an effect largely independent of sodium-hydrogen exchanger-1. Thus, empagliflozin restores the beneficial effect of cardiac microvascular endothelial cells on cardiomyocyte function by reducing mitochondrial oxidative damage, leading to reduced reactive oxygen species accumulation and increased endothelial nitric oxide bioavailability.
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- 2021
9. Zanclean and Piacenzian otolith-based fish faunas of Estepona (Málaga, Spain)
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Victor W.M. van Hinsbergh, Kristiaan Hoedemakers, Victor W.M. van Hinsbergh, and Kristiaan Hoedemakers
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Sediments of Zanclean and Piacenzian age are exposed along hill slopes near the community of Estepona (prov. Málaga, Spain) on the shores of the NW Alborán Sea (Mediterranean). Molluscs from these sediments are well known and here we present data on teleost fish otoliths. Our study reveals the presence of 209 taxa, including 17 new to science, all from the Piacenzian and 4 of them also from the Zanclean: Pythonichthys gibbosus nov. sp., Saurenchelys silex nov. sp., Paraconger pinguis nov. sp., Gnathophis henkmulderi nov. sp., Diaphus mermuysi nov. sp., Diaphus postcavallonis nov. sp., Kryptophanaron nolfi nov. sp., Bidenichhys mediterraneus nov. sp., Fowleria velerinensis nov. sp., Buenia pulvinus nov. sp., Gobius alboranensis nov. sp., Gobius lombartei nov. sp., Thorogobius mirbachae nov. sp., ‘Gobius’ pterois nov. sp., Snyderina stillaformis nov. sp., Prionotus arenarius nov. sp. and Pristigenys adrianae nov. sp. An additional 23 are recorded for the first time as fossil species and several are left in open nomenclature. The most frequent taxa (myctophids, macrourids, Gadiculus argenteus Guichenot, 1850, Micromesistius poutassou (Risso, 1827), Verilus mutinensis (Bassoli, 1906) and Deltentosteus quadrimaculatus (Valenciennes, 1837) point to a habitat at an estimated depth of 200 to 400 m. Further bathymetric comparisons of four major sites (one Zanclean and three Piacenzian) based on a distribution model of the extant taxa in our samples indicate marked differences in their depositional environments, with habitats ranging from bathyal to mixed bathyal/ neritic. Comparison of the palaeobiogeography of the nominal species with known Neogene assemblages from the Mediterranean and the adjacent NE Atlantic adds 25 nominal otolith-based teleost species for the Zanclean and 95 for the Piacenzian of the Mediterranean, and to the conclusion, that during the Zanclean the Mediterranean ichthyofauna probably was replenished from the Lusitania Province. Furthermore, the possib
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- 2022
10. Perivascular Adipose Tissue Controls Insulin-Stimulated Perfusion, Mitochondrial Protein Expression, and Glucose Uptake in Muscle Through Adipomuscular Arterioles
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Carla F. M. Molthoff, John S Yudkin, Erik M. van Poelgeest, Marie-José Goumans, Etto C. Eringa, Alexander H. Turaihi, E.H. Serné, Victor W.M. van Hinsbergh, Jasper J. Koning, Hans W.M. Niessen, Yvo M. Smulders, Jaco C. Knol, Connie R. Jimenez, ACS - Diabetes & metabolism, Physiology, Internal medicine, Radiology and nuclear medicine, Molecular cell biology and Immunology, Medical oncology laboratory, Pathology, AGEM - Re-generation and cancer of the digestive system, ACS - Microcirculation, ACS - Atherosclerosis & ischemic syndromes, and ACS - Heart failure & arrhythmias
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0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Glucose uptake ,Adipose tissue ,030209 endocrinology & metabolism ,Microcirculation ,Mitochondrial Proteins ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Insulin ,Muscle, Skeletal ,Chemistry ,Glucose clamp technique ,Mitochondria ,Arterioles ,Glucose ,030104 developmental biology ,Endocrinology ,Adipose Tissue ,Glucose Clamp Technique ,Insulin Resistance ,Perfusion ,Intravital microscopy - Abstract
Insulin-mediated microvascular recruitment (IMVR) regulates delivery of insulin and glucose to insulin-sensitive tissues. We have previously proposed that perivascular adipose tissue (PVAT) controls vascular function through outside-to-inside communication and through vessel-to-vessel, or "vasocrine" signaling. However, direct experimental evidence supporting a role of local PVAT in regulating IMVR and insulin sensitivity in vivo is lacking. Here, we studied muscles with and without PVAT in mice using combined contrast-enhanced ultrasonography and intravital microscopy to measure IMVR and gracilis artery (GA) diameter at baseline and during the hyperinsulinemic-euglycemic clamp. We show, using microsurgical removal of PVAT from the muscle microcirculation, that local PVAT depots regulate insulin-stimulated muscle perfusion and glucose uptake in vivo We discovered direct microvascular connections between PVAT and the distal muscle microcirculation, or adipomuscular arterioles, removal of which abolished IMVR. Local removal of intramuscular PVAT altered protein clusters in the connected muscle, including upregulation of a cluster featuring heat shock proteins 90ab1 and 70 and downregulation of a cluster of mitochondrial protein components of complexes III, IV and V. These data highlight the importance of PVAT in vascular and metabolic physiology, and are likely relevant for obesity and diabetes.
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- 2020
11. Depletion of Arg/Abl2 improves endothelial cell adhesion and prevents vascular leak during inflammation
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Femke P. M. Hoevenaars, Geerten P van Nieuw Amerongen, Jan van Bezu, Anne-Marieke D. van Stalborch, Iris M. De Cuyper, Coert Margadant, Etto C. Eringa, Jurjan Aman, Erik T. Valent, Kalim Nawaz, Victor W.M. van Hinsbergh, Peter L. Hordijk, Joana Amado-Azevedo, AII - Inflammatory diseases, ACS - Atherosclerosis & ischemic syndromes, Physiology, ACS - Microcirculation, ACS - Diabetes & metabolism, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and Medical oncology laboratory
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0301 basic medicine ,Cancer Research ,Integrins ,RHOA ,Endothelium ,Physiology ,Angiogenesis ,Clinical Biochemistry ,Integrin ,Inflammation ,Adherens junction ,Extracellular matrix ,03 medical and health sciences ,Mice ,0302 clinical medicine ,VE-cadherin ,Arg/Abl2 ,medicine ,Cell Adhesion ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,Mice, Knockout ,Original Paper ,Vascular leak ,biology ,Chemistry ,Gap Junctions ,Endothelial barrier function ,Protein-Tyrosine Kinases ,Cell biology ,Extracellular Matrix ,Endothelial stem cell ,Enzyme Activation ,Pulmonary Alveoli ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,biology.protein ,medicine.symptom - Abstract
Endothelial barrier disruption and vascular leak importantly contribute to organ dysfunction and mortality during inflammatory conditions like sepsis and acute respiratory distress syndrome. We identified the kinase Arg/Abl2 as a mediator of endothelial barrier disruption, but the role of Arg in endothelial monolayer regulation and its relevance in vivo remain poorly understood. Here we show that depletion of Arg in endothelial cells results in the activation of both RhoA and Rac1, increased cell spreading and elongation, redistribution of integrin-dependent cell-matrix adhesions to the cell periphery, and improved adhesion to the extracellular matrix. We further show that Arg is activated in the endothelium during inflammation, both in murine lungs exposed to barrier-disruptive agents, and in pulmonary microvessels of septic patients. Importantly, Arg-depleted endothelial cells were less sensitive to barrier-disruptive agents. Despite the formation of F-actin stress fibers and myosin light chain phosphorylation, Arg depletion diminished adherens junction disruption and intercellular gap formation, by reducing the disassembly of cell-matrix adhesions and cell retraction. In vivo, genetic deletion of Arg diminished vascular leak in the skin and lungs, in the presence of a normal immune response. Together, our data indicate that Arg is a central and non-redundant regulator of endothelial barrier integrity, which contributes to cell retraction and gap formation by increasing the dynamics of adherens junctions and cell-matrix adhesions in a Rho GTPase-dependent fashion. Therapeutic inhibition of Arg may provide a suitable strategy for the treatment of a variety of clinical conditions characterized by vascular leak. Supplementary Information The online version contains supplementary material available at 10.1007/s10456-021-09781-x.
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- 2021
12. Cardiac Microvascular Endothelial Enhancement of Cardiomyocyte Function Is Impaired by Inflammation and Restored by Empagliflozin
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Michiel Helmes, Walter Paulus, Diederik W. D. Kuster, René J. P. Musters, Victor W.M. van Hinsbergh, Pieter Koolwijk, Rio P. Juni, Jolanda van der Velden, Max Goebel, ACS - Heart failure & arrhythmias, Physiology, and ACS - Microcirculation
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0301 basic medicine ,lcsh:Diseases of the circulatory (Cardiovascular) system ,heart failure ,cardiomyocyte ,030204 cardiovascular system & hematology ,Ca, calcium ,HF, heart failure ,NK-κB, nuclear factor-κB ,PRECLINICAL RESEARCH ,chemistry.chemical_compound ,0302 clinical medicine ,DM, diabetes mellitus ,L-NAME, N(ω)-nitro-L-arginine methyl ester ,oxidative stress ,CM, cardiomyocyte ,DPPH, 1,1-diphenyl-picrylhydrazyl ,Ejection fraction ,eNOS, endothelial nitric oxide synthase ,Endothelial stem cell ,JNK, Jun N-terminal kinase ,endothelial cell ,Cardiology ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Editorial Comment ,SGLT2, sodium glucose transporter 2 ,microvasculature ,medicine.medical_specialty ,empagliflozin ,HFpEF, heart failure with preserved ejection fraction ,Inflammation ,Nitric oxide ,Contractility ,03 medical and health sciences ,ROS, reactive oxygen species ,Internal medicine ,medicine ,Empagliflozin ,contraction and relaxation ,HFrEF, heart failure with reduced ejection fraction ,LV, left ventricular ,NO, nitric oxide ,EC, endothelial cell ,business.industry ,Type 2 Diabetes Mellitus ,medicine.disease ,CMEC, cardiac microvascular endothelial cell ,030104 developmental biology ,chemistry ,lcsh:RC666-701 ,Heart failure ,endothelial cell–derived nitric oxide ,business - Abstract
Visual Abstract, Highlights • CMECs exert a direct positive effect on cardiomyocyte contraction and relaxation, which is mainly mediated by endothelial-derived NO. • Pro-inflammatory stimulation of CMECs by pre-incubation with TNF-α or interleukin-1β abrogates the positive regulatory function of these cells on cardiomyocyte contractile property. • Mechanistically, pro-inflammatory activation of CMECs leads to mitochondrial and cytoplasmic ROS accumulation that results in the scavenging of NO. • Empagliflozin directly restores the beneficial effect of CMECs on cardiomyocyte contraction and relaxation by reducing TNF-α-induced mitochondrial and cytoplasmic ROS accumulation, which leads to reinstatement of CMEC-derived NO delivery., Summary The positive findings of the EMPA-REG OUTCOME trial (Randomized, Placebo-Controlled Cardiovascular Outcome Trial of Empagliflozin) on heart failure (HF) outcome in patients with type 2 diabetes mellitus suggest a direct effect of empagliflozin on the heart. These patients frequently have HF with preserved ejection fraction (HFpEF), in which a metabolic risk-related pro-inflammatory state induces cardiac microvascular endothelial cell (CMEC) dysfunction with subsequent cardiomyocyte (CM) contractility impairment. This study showed that CMECs confer a direct positive effect on contraction and relaxation of CMs, an effect that requires nitric oxide, is diminished after CMEC stimulation with tumor necrosis factor-α, and is restored by empagliflozin. Our findings on the effect of empagliflozin on CMEC-mediated preservation of CM function suggests that empagliflozin can be used to treat the cardiac mechanical implications of microvascular dysfunction in HFpEF.
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- 2019
13. JNK2 in myeloid cells impairs insulin's vasodilator effects in muscle during early obesity development through perivascular adipose tissue dysfunction
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Etto C. Eringa, Tom J. A. Kokhuis, Rick I. Meijer, John S Yudkin, Yvo M. Smulders, Femke P. M. Hoevenaars, Victor W.M. van Hinsbergh, Ester M Weijers, E.H. Serné, Cardiology, Internal medicine, ACS - Diabetes & metabolism, Physiology, ACS - Microcirculation, and ACS - Atherosclerosis & ischemic syndromes
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0301 basic medicine ,Male ,medicine.medical_specialty ,Time Factors ,Physiology ,Adipose tissue ,Vasodilation ,Inflammation ,030204 cardiovascular system & hematology ,Diet, High-Fat ,Weight Gain ,Microcirculation ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,Physiology (medical) ,Internal medicine ,Medicine ,Animals ,Insulin ,Mitogen-Activated Protein Kinase 9 ,Myeloid Cells ,Obesity ,Muscle, Skeletal ,Bone Marrow Transplantation ,Mice, Knockout ,business.industry ,Skeletal muscle ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Adipose Tissue ,Regional Blood Flow ,Microvessels ,Bone marrow ,medicine.symptom ,Insulin Resistance ,Cardiology and Cardiovascular Medicine ,business ,Perfusion ,Ex vivo - Abstract
Reduced vasodilator properties of insulin in obesity are caused by changes in perivascular adipose tissue and contribute to microvascular dysfunction in skeletal muscle. The causes of this dysfunction are unknown. The effects of a short-term Western diet on JNK2-expressing cells in perivascular adipose tissue (PVAT) on insulin-induced vasodilation and perfusion of skeletal muscle were assessed. In vivo, 2 wk of Western diet (WD) reduced whole body insulin sensitivity and insulin-stimulated muscle perfusion, determined using contrast ultrasonography during the hyperinsulinemic clamp. Ex vivo, WD triggered accumulation of PVAT in skeletal muscle and blunted its ability to facilitate insulin-induced vasodilation. Labeling of myeloid cells with green fluorescent protein identified bone marrow as a source of PVAT in muscle. To study whether JNK2-expressing inflammatory cells from bone marrow were involved, we transplanted JNK2−/− bone marrow to WT mice. Deletion of JNK2 in bone marrow rescued the vasodilator phenotype of PVAT during WD exposure. JNK2 deletion in myeloid cells prevented the WD-induced increase in F4/80 expression. Even though WD and JNK2 deletion resulted in specific changes in gene expression of PVAT; epididymal and subcutaneous adipose tissue; expression of tumor necrosis factor-α, interleukin-1β, interleukin-6, or protein inhibitor of STAT1 was not affected. In conclusion, short-term Western diet triggers infiltration of JNK2-positive myeloid cells into PVAT, resulting in PVAT dysfunction, nonclassical inflammation, and loss of insulin-induced vasodilatation in vivo and ex vivo. NEW & NOTEWORTHY We demonstrate that in the earliest phase of weight gain, changes in perivascular adipose tissue in muscle impair insulin-stimulated muscle perfusion. The hallmark of these changes is infiltration by inflammatory cells. Deletion of JNK2 from the bone marrow restores the function of perivascular adipose tissue to enhance insulin’s vasodilator effects in muscle, showing that the bone marrow contributes to regulation of muscle perfusion.
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- 2019
14. 493-P: Cardiac Microvascular Endothelial Enhancement of Cardiomyocyte Function Is Impaired by Uremic Serum and Restored by Empagliflozin
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Rushd Al-Shama, Pieter Koolwijk, Victor W.M. van Hinsbergh, Etto C. Eringa, Rio P. Juni, Walter Paulus, Jolanda van der Velden, Marc G. Vervloet, and Diederik W. D. Kuster
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medicine.medical_specialty ,Contraction (grammar) ,business.industry ,Endocrinology, Diabetes and Metabolism ,Inflammation ,medicine.disease ,Endocrinology ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Empagliflozin ,Endothelial dysfunction ,medicine.symptom ,business ,Heart failure with preserved ejection fraction ,Intracellular ,Kidney disease - Abstract
Background: It has been proposed that diabetes and chronic kidney disease cause heart failure with preserved ejection fraction (HFpEF) through low-grade inflammation and microvascular endothelial dysfunction. We have previously shown that endothelial enhancement of cardiomyocyte contraction and relaxation is mediated by NO, impaired by cytokines, and restored upon treatment with the SGLT2 inhibitor Empagliflozin. Chronic kidney disease (CKD) is linked to diabetes and HFpEF and causes systemic endothelial dysfunction. Objective: To test the hypothesis that uremic serum from patients with CKD impairs endothelial control of cardiomyocyte contraction and relaxation, and that Empagliflozin protects against this effect. Methods and Results: Co-culture of rat cardiomyocytes (CM) with human cardiac microvascular endothelial cells (CMECs) enhanced their contraction and relaxation. Pre-treatment with serum from patients with CKD abrogated these effects of CMEC, and treatment of CMECs with Empagliflozin restored the effects of CMECs on CM function. Exposure of CMECs to the uremic serum reduced endothelial NO bioavailability and increased intracellular reactive oxygen species ROS by increasing ROS generation by mitochondria. Uremic serum also increased 3-nitrotyrosine (3-NT) level, indicating scavenging of NO by ROS. Empagliflozin attenuated uremic serum-induced mitochondrial and intracellular ROS, leading to restoration of endothelial NO bioavailability. Conclusions: Exposure of CMECs to serum from CKD patients impairs CMEC-mediated enhancement of CM contraction and relaxation. Empagliflozin restores the beneficial effect of CMECs on CM function by reducing mitochondrial oxidative damage, leading to a decrease in intracellular ROS accumulation and increased endothelial NO bioavailability. Disclosure R. Juni: None. R. Al-Shama: None. D. Kuster: None. J. van der Velden: None. M. Vervloet: None. W. Paulus: None. E.C. Eringa: None. P. Koolwijk: None. V.W. van Hinsbergh: None. Funding Netherlands Heart Foundation
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- 2020
15. Bosutinib prevents vascular leakage by reducing focal adhesion turnover and reinforcing junctional integrity
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Jurjan Aman, Jan van Bezu, Manon C. A. Pronk, Stephan Huveneers, Sofia K. H. Morsing, Pieter R. Tuinman, Peter L. Hordijk, Robert H. Bates, Jenny Juschten, Victor W.M. van Hinsbergh, Jaap D. van Buul, Harm Jan Bogaard, Liza Botros, John Liddle, Graduate School, AII - Inflammatory diseases, Landsteiner Laboratory, Medical Biochemistry, ACS - Atherosclerosis & ischemic syndromes, ACS - Microcirculation, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Physiology, Anesthesiology, Intensive care medicine, and ACS - Diabetes & metabolism
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Moesin ,Vascular permeability ,Biology ,Lung injury ,Capillary Permeability ,Adherens junction ,Focal adhesion ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Radixin ,Nitriles ,medicine ,Animals ,030304 developmental biology ,Tyrosine kinase inhibitors ,Focal Adhesions ,0303 health sciences ,Aniline Compounds ,Endothelial barrier function ,Adherens Junctions ,Cell Biology ,Extravasation ,Pharmaceutical Preparations ,030220 oncology & carcinogenesis ,Quinolines ,Cancer research ,Bosutinib ,medicine.drug ,MAP4K4 - Abstract
Aims: Endothelial barrier dysfunction leads to edema and vascular leak, carrying high morbidity and mortality. Previously, Abl kinase inhibition was shown to protect against vascular leak. Using the distinct inhibitory profiles of clinically available Abl kinase inhibitors, we aimed to provide a mechanistic basis for novel treatment strategies against vascular leakage syndromes. Methods & Results: Bosutinib most potently protected against inflammation-induced endothelial barrier disruption. In vivo, bosutinib prevented LPS-induced alveolar protein extravasation in an acute lung injury mice model. Mechanistically, Mitogen-activated Protein 4 Kinase 4 (MAP4K4) was identified as important novel mediator of endothelial permeability, which signals via ezrin, radixin and moesin proteins to increase turnover of integrin-based focal adhesions. The combined inhibition of MAP4K4 and Arg by bosutinib preserved adherens junction integrity and reduced turnover of focal adhesions, which synergistically act to stabilize the endothelial barrier during inflammation. Conclusion: MAP4K4 was identified as important regulator of endothelial barrier integrity, increasing focal adhesion turnover and disruption of cell-cell junctions during inflammation. Inhibiting both Arg and MAP4K4, the clinically available drug bosutinib may form a viable strategy against vascular leakage syndromes.
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- 2020
16. Consensus guidelines for the use and interpretation of angiogenesis assays
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Marcus Fruttiger, Mark J. Post, Andrey Anisimov, Robert S. Kerbel, Jan Kitajewski, Federico Bussolino, Sarah-Maria Fendt, Neil Dufton, Dai Fukumura, Agnès Noël, Raghu Kalluri, Johannes Waltenberger, Roberto Pili, Anna Dimberg, David O. Bates, Koen Marien, Victor W.M. van Hinsbergh, Peter Carmeliet, Andreas Bikfalvi, Curzio Rüegg, Hong Xin, Rakesh K. Jain, Hellmut G. Augustin, Robert Auerbach, Anna M. Randi, Jimmy Stalin, Bahar Yetkin-Arik, Gabriele Bergers, Stefan Schulte-Merker, Napoleone Ferrara, Paul H.A. Quax, Elisabeth Kuczynski, M. Luisa Iruela-Arispe, Judy R. van Beijnum, R. Hugh F. Bender, Elizabeth Allen, Ruud P.M. Dings, Anca Maria Cimpean, Joanna Kalucka, Andrew C. Dudley, Brant M. Weinstein, Lance L. Munn, Barbara C. Böck, Yan Gong, Jonathan W. Song, Lois E.H. Smith, Alfred C. Aplin, Steven A. Stacker, Jussi Nurro, Nan W. Hultgren, Anna-Karin Olsson, Bart Ghesquière, Peter C. Brooks, Adrian L. Harris, Joyce Bischoff, Juan M. Melero-Martin, Reinier O. Schlingemann, Hynda K. Kleinmann, Amber N. Stratman, Gabriel A. Rabinovich, Pieter Koolwijk, Patrycja Nowak-Sliwinska, Robert J. Griffin, Marius Raica, Mervin C. Yoder, Daniel Castranova, Roberto F. Nicosia, Seppo Ylä-Herttuala, Bertan Cakir, Peter B. Vermeulen, George E. Davis, Christopher C.W. Hughes, Tatiana V. Petrova, Maureen Van de Velde, George Coukos, Jeffrey W. Pollard, Kari Alitalo, Valentin Djonov, Kristian Pietras, Ondine Cleaver, Domenico Ribatti, Melita Irving, Brenda R. Kwak, Arjan W. Griffioen, Michele De Palma, Ingeborg Klaassen, British Heart Foundation, Imperial College Healthcare Charity, Rosetrees Trust, and Kwak, Brenda
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0301 basic medicine ,Tumor angiogenesis ,Cancer Research ,Physiology ,Angiogenesis ,Computer science ,Cell- och molekylärbiologi ,Clinical Biochemistry ,Proliferation ,ddc:616.07 ,Regenerative Medicine ,Neovascularization ,Mice ,Plug assay ,Blood vessels ,ENDOTHELIAL CELLS ,Neoplasms ,AORTIC RING MODEL ,Intussusceptive angiogenesis ,Zebrafish ,Recombinant proteins ,ddc:615 ,Neovascularization, Pathologic ,Angiogenesis assays ,purl.org/becyt/ford/3.1 [https] ,Pharmacology and Pharmaceutical Sciences ,TUBULAR NETWORKS ,Bioquímica y Biología Molecular ,3. Good health ,Medicina Básica ,Retinal vasculature ,purl.org/becyt/ford/3 [https] ,Biological Assay ,Tip cells ,medicine.symptom ,1115 Pharmacology and Pharmaceutical Sciences ,Life Sciences & Biomedicine ,Hindlimb ischemia ,VASCULAR-PERMEABILITY FACTOR ,CIENCIAS MÉDICAS Y DE LA SALUD ,EMBRYO CHORIOALLANTOIC MEMBRANE ,Clinical Sciences ,Guidelines as Topic ,Chorioallantoic membrane ,Endothelial cell migration ,Computational biology ,Aortic ring ,Guidelines ,Article ,ENDOTHELIAL-GROWTH-FACTOR ,03 medical and health sciences ,In vivo ,LIVING CAPILLARY NETWORKS ,medicine ,VASCULAR BIOLOGY METHODS ,Animals ,Humans ,Oncology & Carcinogenesis ,Chorioallantoic membrane (CAM) ,ETS TRANSCRIPTION FACTORS ,Organ regeneration ,Pathologic ,OXYGEN-INDUCED RETINOPATHY ,Science & Technology ,PERIPHERAL ARTERIAL-DISEASE ,1103 Clinical Sciences ,030104 developmental biology ,Corneal angiogenesis ,Vascular network ,Peripheral Vascular Disease ,Microfluidic ,Myocardial angiogenesis ,Vessel co-option ,Cardiovascular System & Cardiology ,Human medicine ,PANCREATIC NEUROENDOCRINE TUMORS ,Biological Assay/instrumentation ,Biological Assay/methods ,Neoplasms/blood supply ,Neoplasms/metabolism ,Neoplasms/pathology ,Neovascularization, Pathologic/metabolism ,Neovascularization, Pathologic/pathology ,Ex vivo ,Cell and Molecular Biology - Abstract
The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference. Fil: Nowak Sliwinska, Patrycja. Université of Lausanne; Suiza. Univeristé of Geneve; Suiza Fil: Alitalo, Kari. Katholikie Universiteit Leuven; Bélgica Fil: Allen, Elizabeth. Katholikie Universiteit Leuven; Bélgica Fil: Anisimov, Andrey. Katholikie Universiteit Leuven; Bélgica Fil: Aplin, Alfred C.. University of Washington; Estados Unidos Fil: Auerbach, Robert. University of Wisconsin; Estados Unidos Fil: Augustin, Hellmut G.. Heidelberg University; Alemania. German Cancer Consortium; Alemania Fil: Bates, David O.. University of Nottingham; Reino Unido Fil: Beijnum, Judy R. van. Cancer Center Amsterdam; Países Bajos Fil: Bender, R. Hugh F.. University of California; Estados Unidos Fil: Bergers, Gabriele. Katholikie Universiteit Leuven; Bélgica Fil: Bikfalvi, Andreas. Universite de Bordeaux; Francia Fil: Bischoff, Joyce. Harvard Medical School; Estados Unidos Fil: Böck, Barbara C.. Heidelberg University; Alemania. German Cancer Consortium; Alemania Fil: Brooks, Peter C.. Maine Medical Center Research Institute; Estados Unidos Fil: Bussolino, Federico. Università di Torino; Italia. Candiolo Cancer Institute; Italia Fil: Cakir, Bertan. Harvard Medical School; Estados Unidos Fil: Carmeliet, Peter. Katholikie Universiteit Leuven; Bélgica Fil: Castranova, Daniel. Harvard Medical School; Estados Unidos Fil: Cimpean, Anca M.. Victor Babes University of Medicine and Pharmacy; Rumania Fil: Cleaver, Ondine. University Of Texas At Brownsville; Estados Unidos Fil: Coukos, George. Universida de Lausanne; Suiza Fil: Davis, George E.. University of Missouri; Estados Unidos Fil: De Palma, Michele. Swiss Federal Institute of Technology; Suiza Fil: Dimberg, Anna. Uppsala University; Suiza Fil: Dings, Ruud P. M.. University of Arkansas for Medical Sciences; Estados Unidos Fil: Djonov, Valentin. University of Bern; Suiza Fil: Dudley, Andrew C.. University of Virginia; Estados Unidos Fil: Dufton, Neil P.. Imperial College London; Reino Unido Fil: Fendt, Sarah-Maria. VIB Center for Cancer Biology; Bélgica Fil: Ferrara, Napoleone. University of California at San Diego; Estados Unidos Fil: Fruttiger, Marcus. University College London; Estados Unidos Fil: Fukumura, Dai. Harvard Medical School; Estados Unidos Fil: Ghesquière, Bart. Harvard Medical School; Estados Unidos Fil: Gong, Yan. Harvard Medical School; Estados Unidos Fil: Griffin, Robert J.. VIB Center for Cancer Biology; Bélgica Fil: Harris, Adrian L.. University of Oxford; Reino Unido Fil: Hughes, Christopher C. W.. University of California at Irvine; Estados Unidos Fil: Hultgren, Nan W.. University of California at Irvine; Estados Unidos Fil: Iruela-Arispe, M. Luisa. University of California at Los Angeles; Estados Unidos Fil: Irving, Melita. Universida de Lausanne; Suiza Fil: Maidana, Agostina Jainen. Harvard Medical School; Estados Unidos Fil: Kalluri, Raghu. Texas A&M University; Estados Unidos Fil: Kalucka, Joanna. Katholikie Universiteit Leuven; Bélgica Fil: Kerbel, Robert S.. University of Toronto; Canadá Fil: Kitajewski, Jan. University of Illinois; Estados Unidos Fil: Klaassen, Ingeborg. University of Amsterdam; Países Bajos Fil: Kleinmann, Hynda K.. The George Washington University; Estados Unidos Fil: Koolwijk, Pieter. Fondation Asile des Aveugles; Suiza. Universida de Lausanne; Suiza Fil: Kuczynski, Elisabeth. University of Toronto; Canadá Fil: Kwak, Brenda R.. University of Geneva; Suiza Fil: Koen, Marien. HistoGeneX; Bélgica Fil: Melero Martin, Juan M.. University of Liège; Bélgica Fil: Munn, Lance L.. Harvard Medical School; Estados Unidos Fil: Nicosia, Roberto F.. VA Puget Sound Health Care System; Estados Unidos Fil: Noel, Agnes. University of Liège; Bélgica Fil: Nurro, Jussi. University of Eastern Finland; Finlandia Fil: Olsson, Anna-Karin. Uppsala University; Suiza Fil: Petrova, Tatiana V.. Ludwig Institute for Cancer Research Lausanne; Suiza Fil: Pietras, Kristian. Division of Translational Cancer Research; Suecia Fil: Pili, Roberto. Indiana University Simon Cancer Center; Estados Unidos Fil: Pollard, Jeffrey W.. University of Edinburgh; Reino Unido Fil: Post, Mark J.. Maastricht University; Países Bajos Fil: Quax, Paul H. A.. Einthoven Laboratory for Experimental Vascular Medicine; Países Bajos Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Raica, Marius. Victor Babes University of Medicine and Pharmacy; Rumania Fil: Randi, Anna M.. Imperial College London; Reino Unido Fil: Ribatti, Domenico. Università degli Studi di Bari; Italia Fil: Ruegg, Curzio. University of Fribourg; Suiza Fil: Schlingemann, Reinier O.. University of Amsterdam; Países Bajos Fil: Schulte Merker, Stefan. Institute of Cardiovascular Organogenesis and Regeneration; Alemania Fil: Smith, Lois E. H.. Harvard Medical School; Estados Unidos Fil: Song, Jonathan W.. Ohio State University; Estados Unidos Fil: Stacker, Steven A.. University of Melbourne; Australia Fil: Stalin, Jimmy. Institute of Cardiovascular Organogenesis and Regeneration; Alemania Fil: Stratman, Amber N.. National Institutes of Health; Estados Unidos Fil: Van de Velde, Maureen. University of Liège; Bélgica Fil: van Hinsbergh, Victor W. M.. Universida de Lausanne; Suiza Fil: Vermeulen, Peter B.. HistoGeneX; Bélgica. University of Antwerp; Bélgica Fil: Waltenberger, Johannes. University of Münster; Alemania Fil: Weinstein, Brant M.. National Institutes of Health; Estados Unidos Fil: Xin, Hong. University of California at San Diego; Estados Unidos Fil: Yetkin Arik, Bahar. University of Amsterdam; Países Bajos Fil: Yla Herttuala, Seppo. University of Eastern Finland; Finlandia Fil: Yoder, Mervin C.. Indiana University; Estados Unidos Fil: Griffioen, Arjan W.. VU University Medical Center; Países Bajos
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- 2018
17. Effects of TNF-α on Endothelial Control of Hemostasis
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Victor W.M. van Hinsbergh
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- 2019
18. The minor histocompatibility antigen 1 (HMHA1)/ArhGAP45 is a RacGAP and a novel regulator of endothelial integrity
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Joana Amado-Azevedo, Nathalie R. Reinhard, G.P. van Nieuw Amerongen, Peter L. Hordijk, Victor W.M. van Hinsbergh, J. van Bezu, Physiology, and ACS - Microcirculation
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rac1 GTP-Binding Protein ,0301 basic medicine ,Time Factors ,Endothelium ,Physiology ,Regulator ,Neovascularization, Physiologic ,RAC1 ,Matrix (biology) ,Transfection ,Mechanotransduction, Cellular ,Capillary Permeability ,Minor Histocompatibility Antigens ,03 medical and health sciences ,Interstitial space ,Cell Movement ,Electric Impedance ,Fluorescence Resonance Energy Transfer ,Human Umbilical Vein Endothelial Cells ,medicine ,Minor histocompatibility antigen ,Humans ,Gene silencing ,Cells, Cultured ,Endothelial Progenitor Cells ,Pharmacology ,Chemistry ,GTPase-Activating Proteins ,Endothelial Cells ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Molecular Medicine ,RNA Interference ,Stress, Mechanical ,Function (biology) ,Protein Binding - Abstract
Endothelial cells line the vasculature and act as gatekeepers that control the passage of plasma, macromolecules and cells from the circulation to the interstitial space. Dysfunction of the endothelial barrier can lead to uncontrolled leak or edema. Vascular leakage is a hallmark of a range of diseases and despite its large impact no specialized therapies are available to prevent or reduce it. RhoGTPases are known key regulators of cellular behavior that are directly involved in the regulation of the endothelial barrier. We recently performed a comprehensive analysis of the effect of all RhoGTPases and their regulators on basal endothelial integrity. In addition to novel positive regulators of endothelial barrier function, we also identified novel negative regulators, of which the ArhGAP45 (also known as HMHA1) was the most significant. We now demonstrate that ArhGAP45 acts as a Rac-GAP (GTPase-Activating Protein) in endothelial cells, which explains its negative effect on endothelial barrier function. Silencing ArhGAP45 not only promotes basal endothelial barrier function, but also increases cellular surface area and induces sprout formation in a 3D-fibrin matrix. Our data further shows that loss of ArhGAP45 promotes migration and shear stress adaptation. In conclusion, we identify ArhGAP45 (HMHA1) as a novel regulator, which contributes to the fine-tuning of the regulation of basal endothelial integrity.
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- 2018
19. Endothelial permeability, LDL deposition, and cardiovascular risk factors—a review
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Egeria Scoditti, S. Mundi, Victor W.M. van Hinsbergh, Marial Luisa Iruela-Arispe, Maria Annunziata Carluccio, Marika Massaro, and Raffaele De Caterina
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0301 basic medicine ,Physiology ,Vascular permeability ,Comorbidity ,Cardiorespiratory Medicine and Haematology ,Cardiovascular ,medicine.disease_cause ,Risk Factors ,2.1 Biological and endogenous factors ,Cardiovascular risk factors ,Plaque ,Atherosclerotic ,chemistry.chemical_classification ,Cardiovascular Medicine And Haematology ,Chemistry ,Smoking ,Arteries ,Prognosis ,Plaque, Atherosclerotic ,Lipoproteins, LDL ,Heart Disease ,medicine.anatomical_structure ,Inflammation Mediators ,Cardiology and Cardiovascular Medicine ,Infiltration (medical) ,Signal Transduction ,medicine.medical_specialty ,Endothelial permeability ,Endothelium ,Lipoproteins ,Reviews ,Permeability ,LDL ,03 medical and health sciences ,Vascular ,Physiology (medical) ,Internal medicine ,Diabetes mellitus ,Genetics ,medicine ,Animals ,Humans ,Reactive oxygen species ,Prevention ,Biological Transport ,Atherosclerosis ,medicine.disease ,Oxidative Stress ,030104 developmental biology ,Endocrinology ,Cardiovascular System & Hematology ,Endothelium, Vascular ,sense organs ,Reactive Oxygen Species ,Oxidative stress - Abstract
Early atherosclerosis features functional and structural changes in the endothelial barrier function that affect the traffic of molecules and solutes between the vessel lumen and the vascular wall. Such changes are mechanistically related to the development of atherosclerosis. Proatherogenic stimuli and cardiovascular risk factors, such as dyslipidaemias, diabetes, obesity, and smoking, all increase endothelial permeability sharing a common signalling denominator: an imbalance in the production/disposal of reactive oxygen species (ROS), broadly termed oxidative stress. Mostly as a consequence of the activation of enzymatic systems leading to ROS overproduction, proatherogenic factors lead to a pro-inflammatory status that translates in changes in gene expression and functional rearrangements, including changes in the transendothelial transport of molecules, leading to the deposition of low-density lipoproteins (LDL) and the subsequent infiltration of circulating leucocytes in the intima. In this review, we focus on such early changes in atherogenesis and on the concept that proatherogenic stimuli and risk factors for cardiovascular disease, by altering the endothelial barrier properties, co-ordinately trigger the accumulation of LDL in the intima and ultimately plaque formation.
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- 2017
20. Correction to: Depletion of Arg/Abl2 improves endothelial cell adhesion and prevents vascular leak during inflammation
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Geerten P van Nieuw Amerongen, Jurjan Aman, Kalim Nawaz, Coert Margadant, Jan van Bezu, Femke P. M. Hoevenaars, Peter L. Hordijk, Victor W.M. van Hinsbergh, Iris M. De Cuyper, Erik T. Valent, Joana Amado-Azevedo, Anne-Marieke D. van Stalborch, and Etto C. Eringa
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Cancer Research ,medicine.medical_specialty ,Physiology ,Angiogenesis ,business.industry ,Clinical Biochemistry ,Inflammation ,Adhesion ,ABL2 ,Vascular leakage ,Endothelial stem cell ,Internal medicine ,medicine ,Cardiology ,medicine.symptom ,business - Abstract
In the original article, due to an XML tagging error the equal contribution statement “Joana Amado-Azevedo, Anne-Marieke D. van Stalborch, Erik T. Valent have contributed equally to this work (shared first author), Jurjan Aman and Coert Margadant have contributed equally to this work (shared last author).” was not correctly reflected in the PubMed. The original article has been corrected.
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- 2021
21. RhoA, RhoB and RhoC differentially regulate endothelial barrier function
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Jan van Bezu, Victor W.M. van Hinsbergh, Geerten P. van Nieuw Amerongen, Manon C. A. Pronk, Peter L. Hordijk, Landsteiner Laboratory, ACS - Amsterdam Cardiovascular Sciences, Physiology, and ACS - Microcirculation
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rac1 GTP-Binding Protein ,Myosin light-chain kinase ,RHOA ,Endothelium ,RHOB ,RhoC ,Regulator ,Cell Communication ,RhoGTPases ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,VE-cadherin ,Antigens, CD ,medicine ,Human Umbilical Vein Endothelial Cells ,Humans ,RNA, Small Interfering ,rhoB GTP-Binding Protein ,Barrier function ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,biology ,Thrombin ,cytoskeleton ,Endothelial barrier function ,RhoA ,Cell Biology ,RhoB ,Cadherins ,Actins ,Cell biology ,medicine.anatomical_structure ,rhoC GTP-Binding Protein ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,rhoA GTP-Binding Protein ,Research Paper - Abstract
RhoGTPases are known regulators of intracellular actin dynamics that are important for maintaining endothelial barrier function. RhoA is most extensively studied as a key regulator of endothelial barrier function, however the function of the 2 highly homologous family-members (> 88%) RhoB and RhoC in endothelial barrier function is still poorly understood. This study aimed to determine whether RhoA, RhoB and RhoC have overlapping or distinct roles in barrier function and permeability in resting and activated endothelium. By using primary endothelial cells in combination with siRNA transfection to establish individual, double or triple knockdown of the RhoA/B/C RhoGTPases, we found that RhoB, but not RhoA or RhoC, is in resting endothelium a negative regulator of permeability. Loss of RhoB accounted for an accumulation of VE-cadherin at cell-cell contacts. Thrombin-induced loss of endothelial integrity is mediated primarily by RhoA and RhoB. Combined loss of RhoA/B showed decreased phosphorylation of Myosin Light Chain and increased expression of VE-cadherin at cell-cell contacts after thrombin stimulation. RhoC contributes to the Rac1-dependent restoration of endothelial barrier function. In summary, this study shows that these highly homologous RhoGTPases differentially control the dynamics of endothelial barrier function.
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- 2017
22. Exercise effects on perivascular adipose tissue: endocrine and paracrine determinants of vascular function
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B C S Boa, Etto C. Eringa, John S Yudkin, Victor W.M. van Hinsbergh, and Eliete Bouskela
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0301 basic medicine ,Pharmacology ,medicine.medical_specialty ,FGF21 ,Skeletal muscle ,Adipokine ,Adipose tissue ,Inflammation ,030204 cardiovascular system & hematology ,Biology ,Muscle hypertrophy ,03 medical and health sciences ,Paracrine signalling ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Endocrinology ,Internal medicine ,Myokine ,medicine ,medicine.symptom - Abstract
Obesity is a global epidemic, accompanied by increased risk of type 2 diabetes and cardiovascular disease. Adipose tissue hypertrophy is associated with adipose tissue inflammation, which alters secretion of adipose tissue-derived bioactive products, known as adipokines. Adipokines determine vessel wall properties such as smooth muscle tone and vessel wall inflammation. Exercise is a mainstay of prevention of chronic, non-communicable diseases, type 2 diabetes and cardiovascular disease in particular. Aside from reducing adipose tissue mass, exercise has been shown to reduce inflammatory activity in this tissue. Mechanistically, contracting muscles release bioactive molecules known as myokines, which have been shown to alter adipose tissue metabolic phenotype. In adipose tissue, myokines induce browning, enhance fatty acid oxidation and improve insulin sensitivity. In the past years, so-called perivascular adipose tissue surrounding the vasculature (PVAT) has been shown to control vascular tone and inflammation through local release of adipokines. In obesity, an increase in mass and inflammation of PVAT culminate in dysregulation of adipokine secretion, which contributes to vascular dysfunction. This review describes our current understanding of the mechanisms by which active muscles interact with adipose tissue and improve vascular function. Aside from the exercise-dependent regulation of canonical adipose tissue function, we will focus on interaction between skeletal muscle and PVAT and the role of novel myokines, such as interleukin-15, fibroblast growth factor 21 and irisin, in this cross talk.
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- 2017
23. Mast cells are increased in the media of coronary lesions in patients with myocardial infarction and may favor atherosclerotic plaque instability
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Paul A.J. Krijnen, Yvo M. Smulders, Koba Kupreishvili, Victor W.M. van Hinsbergh, Wim Stooker, Alexander B.A. Vonk, Hans W.M. Niessen, Wessel W. Fuijkschot, Pathology, Internal medicine, ICaR - Circulation and metabolism, Cardio-thoracic surgery, Physiology, ICaR - Ischemia and repair, ACS - Microcirculation, ACS - Atherosclerosis & ischemic syndromes, ACS - Heart failure & arrhythmias, and ACS - Diabetes & metabolism
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Plaque instability ,Myocardial Infarction ,Autopsy ,030204 cardiovascular system & hematology ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,In patient ,Mast Cells ,Myocardial infarction ,Acute mi ,Aged ,Aged, 80 and over ,business.industry ,Middle Aged ,medicine.disease ,Coronary Vessels ,Plaque, Atherosclerotic ,humanities ,Coronary arteries ,030104 developmental biology ,medicine.anatomical_structure ,Cardiology ,Female ,Tunica Intima ,Tunica Media ,Cardiology and Cardiovascular Medicine ,business - Abstract
Objectives Mast cells (MCs) may play an important role in plaque destabilization and atherosclerotic coronary complications. Here, we have studied the presence of MCs in the intima and media of unstable and stable coronary lesions at different time points after myocardial infarction (MI). Methods Coronary arteries were obtained at autopsy from patients with acute MI (up to 5 days old; n = 27) and with chronic MI (5–14 days old; n = 18), as well as sections from controls without cardiac disease ( n = 10). Herein, tryptase-positive MCs were quantified in the intima and media of both unstable and stable atherosclerotic plaques in infarct-related and non-infarct-related coronary arteries. Results In the media of both acute and chronic MI patients, the number of MCs was significantly higher than in controls. This was also found when evaluating unstable and stable plaques separately. In patients with chronic MI, the number of MCs in unstable lesions was significantly higher than in stable lesions. This coincided with a significant increase in the relative number of unstable plaques in patients with chronic MI compared with control and acute MI. No differences in MC density were found between infarct-related and non-infarct-related coronary arteries in patients with MI. Conclusion The presence of MCs in the media of both stable and unstable atherosclerotic coronary lesions after MI suggests that MCs may be involved in the onset of MI and, on the other hand, that MI triggers intra-plaque infiltration of MCs especially in unstable plaques, possibly increasing the risk of re-infarction.
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- 2017
24. Transdifferentiation of Human Dermal Fibroblasts to Smooth Muscle-Like Cells to Study the Effect of MYH11 and ACTA2 Mutations in Aortic Aneurysms
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Willem Wisselink, Kim van der Kuij, René J. P. Musters, Niels Keekstra, Kak K. Yeung, Jan D. Blankensteijn, Dimitra Micha, Natalija Bogunovic, Behrouz Zandieh-Doulabi, Jorrit Pals, Gerard Pals, Adriaan A M Beunders, Victor W.M. van Hinsbergh, Eline Overwater, Oral Cell Biology, Surgery, ICaR - Ischemia and repair, Amsterdam Reproduction & Development (AR&D), Physiology, Human genetics, Amsterdam Movement Sciences - Restoration and Development, Amsterdam Gastroenterology Endocrinology Metabolism, ACS - Microcirculation, ACS - Atherosclerosis & ischemic syndromes, Orale Celbiologie (ORM, ACTA), Human Genetics, and ACS - Heart failure & arrhythmias
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Adult ,Male ,0301 basic medicine ,Myocytes, Smooth Muscle ,Gene Expression ,030204 cardiovascular system & hematology ,Extracellular matrix ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,Transforming Growth Factor beta ,Myosin ,Genetics ,Humans ,RNA, Messenger ,Cells, Cultured ,Genetics (clinical) ,Actin ,Aged ,Extracellular Matrix Proteins ,Myosin Heavy Chains ,biology ,Transdifferentiation ,Dermis ,Anatomy ,Transforming growth factor beta ,Fibroblasts ,Middle Aged ,musculoskeletal system ,Molecular biology ,Actins ,Aortic Aneurysm ,Blot ,030104 developmental biology ,Cell Transdifferentiation ,Mutation ,biology.protein ,cardiovascular system ,Female ,RNA Interference ,ACTA2 ,Elastin ,tissues - Abstract
Mutations in genes encoding proteins of the smooth muscle cell (SMC) contractile apparatus contribute to familial aortic aneurysms. To investigate the pathogenicity of these mutations, SMC are required. We demonstrate a novel method to generate SMC-like cells from human dermal fibroblasts by transdifferentiation to study the effect of variants in genes encoding proteins of the SMC contractile apparatus (ACTA2 and MYH11) in patients with aortic aneurysms. Dermal fibroblasts from seven healthy donors and cells from seven patients with MYH11 or ACTA2 variants were transdifferentiated into SMC-like cells within a 2-week duration using 5 ng/ml TGFβ1 on a scaffold containing collagen and elastin. The induced SMC were comparable to primary human aortic SMC in mRNA expression of SMC markers which was confirmed on the protein level by immunofluorescence quantification analysis and Western blotting. In patients with MYH11 or ACTA2 variants, the effect of intronic variants on splicing was demonstrated on the mRNA level in the induced SMC, allowing classification into pathogenic or nonpathogenic variants. In conclusion, direct conversion of human dermal fibroblasts into SMC-like cells is a highly efficient method to investigate the pathogenicity of variants in proteins of the SMC contractile apparatus.
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- 2017
25. Bosutinib protects against pulmonary vascular leakage by improving endothelial cell-matrix adhesion
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Peter L. Hordijk, Victor W.M. van Hinsbergh, Stephan Huveneers, Jurjan Aman, Harm Jan Bogaard, Jenny Juschten, Liza Botros, John Liddle, Pieter R. Tuinman, and Manon C. A. Pronk
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Adherens junction ,Focal adhesion ,business.industry ,Cancer research ,Endothelial cell-matrix adhesion ,Medicine ,Lung injury ,business ,Protein kinase A ,Bosutinib ,Extravasation ,Barrier function ,medicine.drug - Abstract
Dysfunction of the endothelial barrier leads to uncontrolled fluid extravasation and vascular leak, yielding high morbidity and mortality. We previously demonstrated that Abl kinase inhibition protects against vascular leak. Since then, next generation AKIs were developed with broader kinase inhibition and better safety profiles. The current study aims to evaluate whether combined kinase inhibition as provided by next generation AKIs, provides novel therapy strategies against vascular leakage. A screen on second and third generation AKIs revealed that bosutinib (Bosulif®) has better protective effects on endothelial barrier, as compared to imatinib and other AKIs. Materials and results: Upon exposure to various inflammatory mediators, bosutinib reinforced vascular integrity through enhanced focal adhesion formation and adherens junction stabilization in primary human lung endothelial cells. Bosutinib treatment attenuated alveolar protein leakage and pulmonary edema in an acute lung injury mice model. We demonstrate that these protective effects of bosutinib resulted from combined inhibition of mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) and Arg. MAP4K4 was identified as important novel regulator of focal adhesion turnover and combined inhibition of Arg and MAP4K4 completely mimicked the protective effect of bosutinib on barrier function. In conclusion, bosutinib shows a robust protective effect against inflammation-induced endothelial barrier disruption via combined inhibition of Arg and MAP4K4. Because bosutinib is a clinically available drug, reinforcement of cell-matrix adhesions by bosutinib may be a viable strategy against pulmonary vascular leakage syndromes.
- Published
- 2019
26. Indoxyl Sulfate Stimulates Angiogenesis by Regulating Reactive Oxygen Species Production via CYP1B1
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Pieter Koolwijk, Rio Juni, Folkert W. Asselbergs, Michal Mokry, Jiayi Pei, Marianne C. Verhaar, Victor W.M. van Hinsbergh, Magdalena Harakalova, Dirk J. Duncker, Caroline Cheng, ACS - Heart failure & arrhythmias, Physiology, ACS - Microcirculation, and Cardiology
- Subjects
Senescence ,Angiogenesis ,Health, Toxicology and Mutagenesis ,CYP1B1 ,Cell ,030232 urology & nephrology ,lcsh:Medicine ,Neovascularization, Physiologic ,Toxicology ,Umbilical vein ,Article ,Transcriptome ,03 medical and health sciences ,angiogenesis ,0302 clinical medicine ,Downregulation and upregulation ,medicine ,Human Umbilical Vein Endothelial Cells ,Journal Article ,Humans ,indoxyl sulfate ,030304 developmental biology ,chemistry.chemical_classification ,reactive oxygen species ,0303 health sciences ,Reactive oxygen species ,Chemistry ,Sequence Analysis, RNA ,Gene Expression Profiling ,lcsh:R ,Cell biology ,medicine.anatomical_structure ,Cytochrome P-450 CYP1B1 ,Endothelium, Vascular ,Indican ,chronic kidney disease - Abstract
Indoxyl sulfate (IS) is an accumulative protein-bound uremic toxin found in patients with kidney disease. It is reported that IS impairs the vascular endothelium, but a comprehensive overview of all mechanisms active in IS-injury currently remains lacking. Here we performed RNA sequencing in human umbilical vein endothelial cells (HUVECs) after IS or control medium treatment and identified 1293 genes that were affected in a IS-induced response. Gene enrichment analysis highlighted pathways involved in altered vascular formation and cell metabolism. We confirmed these transcriptome profiles at the functional level by demonstrating decreased viability and increased cell senescence in response to IS treatment. In line with the additional pathways highlighted by the transcriptome analysis, we further could demonstrate that IS exposure of HUVECs promoted tubule formation as shown by the increase in total tubule length in a 3D HUVECs/pericytes co-culture assay. Notably, the pro-angiogenic response of IS and increased ROS production were abolished when CYP1B1, one of the main target genes that was highly upregulated by IS, was silenced. This observation indicates IS-induced ROS in endothelial cells is CYP1B1-dependent. Taken together, our findings demonstrate that IS promotes angiogenesis and CYP1B1 is an important factor in IS-activated angiogenic response.
- Published
- 2019
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27. Fish Otoliths from the Cabarruyan Piacenzian-Gelasian fauna found in the Philippines
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Victor W.M. Van Hinsbergh and Renate A. Helwerda
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Piacenzian ,Congridae ,Philippines ,Fauna ,Bythitidae ,Bregmacerotidae ,Carangidae ,Cepolidae ,Chordata ,Macrouridae ,Acropomatidae ,Fossils ,Ecology ,Gadiformes ,Fishes ,Champsodontidae ,Biodiversity ,Gempylidae ,Paraulopidae ,Gonorynchidae ,Apogonidae ,Bathyclupeidae ,Argentinidae ,Osmeriformes ,Benthosema ,Caproidae ,Myctophiformes ,food.ingredient ,Sternoptychidae ,Pteropsaron ,Stomiiformes ,Biology ,Gonorynchiformes ,Opisthoproctidae ,Otolithic Membrane ,food ,Ophidiidae ,Animalia ,Animals ,Ophidiiformes ,Sparidae ,Ecology, Evolution, Behavior and Systematics ,Taxonomy ,Actinopterygii ,Percophidae ,Aulopiformes ,Maurolicus ,biology.organism_classification ,Anguilliformes ,Carapidae ,Perciformes ,Myctophidae ,Animal Science and Zoology ,Gobiidae ,Serranidae - Abstract
We studied fish otoliths from twelve sediment samples of a well-preserved late Pliocene to early Pleistocene fauna originally from the northwest Philippines that were originally deposited in relatively deepwater marine environment. The fish fauna is systematically described, its paleoenvironmental character is explored, and its diversity is analyzed. Four unknown species have been encountered: Parascombrops schwarzhansi n. sp., Maurolicus sp., Pteropsaron sp., and Priolepis sp., of which one is described as new species and three were left in open nomenclature as their local recent counterparts are not well known yet. In addition, a variant Benthosema, Benthosema aff. fibulatum, is described. Overall, fifty-three taxa of fish otoliths were found, of which eighteen were identified at the species level and an additional twenty-seven at the genus level. Most extant species nowadays occur around the Philippines in relatively deep water (about 200 m depth), which is congruent with earlier studies on mollusks and echinoderms from the same deposits. This is the first study on a fossil fish otolith assemblage from the Philippines. Its diversity is very high and analysis by rarefaction curves suggests that additional sampling would add more fish species to the presented fauna list.
- Published
- 2019
28. Empagliflozin and Dapagliflozin Reduce ROS Generation and Restore NO Bioavailability in Tumor Necrosis Factor α-Stimulated Human Coronary Arterial Endothelial Cells
- Author
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Coert J. Zuurbier, Anna Homayr, Benedikt Preckel, Laween Uthman, Martin Albrecht, Pieter Koolwijk, Rio P Juni, Marleen Boomsma, Nina C. Weber, Eva L Spin, Markus W. Hollmann, Victor W.M. van Hinsbergh, Raphaela P. Kerindongo, Physiology, ACS - Heart failure & arrhythmias, ACS - Microcirculation, Anesthesiology, Graduate School, ACS - Atherosclerosis & ischemic syndromes, ACS - Diabetes & metabolism, ANS - Neuroinfection & -inflammation, and APH - Quality of Care
- Subjects
0301 basic medicine ,Endothelium ,Nitric Oxide Synthase Type III ,Physiology ,Down-Regulation ,Vascular Cell Adhesion Molecule-1 ,Inflammation ,Pharmacology ,Nitric Oxide ,Permeability ,lcsh:Physiology ,Nitric oxide ,lcsh:Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Glucosides ,Sodium-Glucose Transporter 2 ,Enos ,medicine ,Human Umbilical Vein Endothelial Cells ,Humans ,lcsh:QD415-436 ,Endothelial dysfunction ,Benzhydryl Compounds ,biology ,lcsh:QP1-981 ,Cell adhesion molecule ,Tumor Necrosis Factor-alpha ,Endothelial Cells ,biology.organism_classification ,medicine.disease ,Intercellular Adhesion Molecule-1 ,Coronary Vessels ,Endothelial stem cell ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Tumor necrosis factor alpha ,medicine.symptom ,Reactive Oxygen Species ,Signal Transduction - Abstract
BACKGROUND/AIMS: Heart failure is characterized by chronic low-grade vascular inflammation, which in itself can lead to endothelial dysfunction. Clinical trials showed reductions in heart failure-related hospitalizations of type 2 diabetic patients using sodium glucose co-transporter 2 inhibitors (SGLT2i's). Whether and how SGLT2i's directly affect the endothelium under inflammatory conditions is not completely understood. The aim of the study was to investigate whether the SGLT2i Empagliflozin (EMPA) and Dapagliflozin (DAPA) reduce tumor necrosis factor α (TNFα) induced endothelial inflammation in vitro. METHODS: Human coronary arterial endothelial cells (HCAECs) and human umbilical vein endothelial cells (HUVECs) were (pre-)incubated with 1 µM EMPA or DAPA and subsequently exposed to 10 ng/ml TNFα. ROS and NO were measured using live cell imaging. Target proteins were either determined by infrared western blotting or fluorescence activated cell sorting (FACS). The connection between Cav-1 and eNOS was determined by co-immunoprecipitation. RESULTS: Nitric oxide (NO) bioavailability was reduced by TNFα and both EMPA and DAPA restored NO levels in TNFα-stimulated HCAECs. Intracellular ROS was increased by TNFα, and this increase was completely abolished by EMPA and DAPA in HCAECs by means of live cell imaging. eNOS signaling was significantly disturbed after 24 h when cells were exposed to TNFα for 24h, yet the presence of both SGLT2is did not prevent this disruption. TNFα-induced enhanced permeability at t=24h was unaffected in HUVECs by EMPA. Similarly, adhesion molecule expression (VCAM-1 and ICAM-1) was elevated after 4h TNFα (1.5-5.5 fold increase of VCAM-1 and 4-12 fold increase of ICAM-1) but were unaffected by EMPA and DAPA in both cell types. Although we detected expression of SGLT2 protein levels, the fact that we could not silence this expression by means of siRNA and the mRNA levels of SGLT2 were not detectable in HCAECs, suggests aspecificity or our SGLT2 antibody and absence of SGLT2 in our cells. CONCLUSION: These data suggest that EMPA and DAPA rather restore NO bioavailability by inhibiting ROS generation than by affecting eNOS expression or signaling, barrier function and adhesion molecules expression in TNFα-induced endothelial cells. Furthermore, the observed effects cannot be ascribed to the inhibition of SGLT2 in endothelial cells.
- Published
- 2019
29. Hypoxia Impairs Initial Outgrowth of Endothelial Colony Forming Cells and Reduces Their Proliferative and Sprouting Potential
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Michiel van Wijhe, Henk J. Broxterman, Victor W.M. van Hinsbergh, Dimitar Tasev, Pieter Koolwijk, Laura Dekker-Vroling, Physiology, Medical oncology, Medical oncology laboratory, ACS - Microcirculation, and ACS - Atherosclerosis & ischemic syndromes
- Subjects
0301 basic medicine ,Angiogenesis ,proliferation ,Peripheral blood mononuclear cell ,Neovascularization ,03 medical and health sciences ,angiogenesis ,0302 clinical medicine ,ECFCs ,medicine ,tissue repair ,Progenitor cell ,colony growth ,Original Research ,Tube formation ,lcsh:R5-920 ,Chemistry ,hypoxia ,General Medicine ,Hypoxia (medical) ,Cell cycle ,Cell biology ,030104 developmental biology ,Cell culture ,030220 oncology & carcinogenesis ,Medicine ,medicine.symptom ,lcsh:Medicine (General) - Abstract
Vascular homeostasis and regeneration in ischemic tissue relies on intrinsic competence of the tissue to rapidly recruit endothelial cells for vascularization. The mononuclear cell (MNC) fraction of blood contains circulating progenitors committed to endothelial lineage. These progenitors give rise to endothelial colony-forming cells (ECFCs) that actively participate in neovascularization of ischemic tissue. To evaluate if the initial clonal outgrowth of ECFCs from cord (CB) and peripheral blood (PB) was stimulated by hypoxic conditions, MNCs obtained from CB and PB were subjected at 20% and 1% O2 cell culture conditions. Clonal outgrowth was followed during a 30 days incubation period. Hypoxia impaired the initial outgrowth of ECFC colonies from CB and also reduced their number that were developing from PB MNCs. Three days of oxygenation (20% O2) prior to hypoxia could overcome the initial CB-ECFC outgrowth. Once proliferating and subcultured the CB-ECFCs growth was only modestly affected by hypoxia (18±2% reduction); proliferation of PB-ECFCs was reduced to a similar extent. Early passages of subcultured CB- and PB-ECFCs contained only viable cells and few if any senescent cells, but the clonal ability of subcultured PB-ECFCs was reduced by 30% for PB-ECFCs. Tube formation by subcultured PB-ECFCs was also markedly inhibited by continuous exposure to 1% O2. Gene expression profiles point to regulation of the cell cycle and metabolism as major altered gene clusters. Finally we discuss our counterintuitive observations in the context of the important role that hypoxia has in promoting neovascularization.
- Published
- 2018
30. Traction force dynamics predict gap formation in activated endothelium
- Author
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Peter L. Hordijk, Victor W.M. van Hinsbergh, Erik T. Valent, Geerten P. van Nieuw Amerongen, Physiology, and ICaR - Ischemia and repair
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0301 basic medicine ,Endothelium ,medicine.medical_treatment ,Biology ,Traction force microscopy ,Adherens junction ,03 medical and health sciences ,0302 clinical medicine ,Human Umbilical Vein Endothelial Cells ,medicine ,Humans ,Cytoskeleton ,Actin ,Cell Nucleus ,Tractive force ,Cell Membrane ,Thrombin ,Gap Junctions ,Cell Biology ,Traction (orthopedics) ,Actins ,Biomechanical Phenomena ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Endothelium, Vascular ,Filopodia ,030217 neurology & neurosurgery - Abstract
In many pathological conditions the endothelium becomes activated and dysfunctional, resulting in hyperpermeability and plasma leakage. No specific therapies are available yet to control endothelial barrier function, which is regulated by inter-endothelial junctions and the generation of acto-myosin-based contractile forces in the context of cell-cell and cell-matrix interactions. However, the spatiotemporal distribution and stimulus-induced reorganization of these integral forces remain largely unknown. Traction force microscopy of human endothelial monolayers was used to visualize contractile forces in resting cells and during thrombin-induced hyperpermeability. Simultaneously, information about endothelial monolayer integrity, adherens junctions and cytoskeletal proteins (F-actin) were captured. This revealed a heterogeneous distribution of traction forces, with nuclear areas showing lower and cell-cell junctions higher traction forces than the whole-monolayer average. Moreover, junctional forces were asymmetrically distributed among neighboring cells. Force vector orientation analysis showed a good correlation with the alignment of F-actin and revealed contractile forces in newly formed filopodia and lamellipodia-like protrusions within the monolayer. Finally, unstable areas, showing high force fluctuations within the monolayer were prone to form inter-endothelial gaps upon stimulation with thrombin. To conclude, contractile traction forces are heterogeneously distributed within endothelial monolayers and force instability, rather than force magnitude, predicts the stimulus-induced formation of intercellular gaps.
- Published
- 2016
31. Globular adiponectin controls insulin-mediated vasoreactivity in muscle through AMPK alpha 2
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Geerten P. van Nieuw Amerongen, Jurjan Aman, Tom J. A. Kokhuis, Erik M. van Poelgeest, Yvo M. Smulders, Michiel P. de Boer, Victor W.M. van Hinsbergh, Pieter Koolwijk, Etto C. Eringa, Pieter Sipkema, Erik A. Richter, Erik H. Serné, Rick I. Meijer, Cardiology, Internal medicine, ICaR - Circulation and metabolism, Physiology, and ICaR - Ischemia and repair
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Physiology ,medicine.medical_treatment ,Vasodilation ,AMP-Activated Protein Kinases ,Nitric Oxide ,Mice ,03 medical and health sciences ,Insulin resistance ,AMP-activated protein kinase ,Enos ,Internal medicine ,medicine ,Hyperinsulinemia ,Animals ,Humans ,Insulin ,Obesity ,Rats, Wistar ,Pharmacology ,Endothelin-1 ,biology ,Adiponectin ,business.industry ,Endothelial Cells ,AMPK ,Middle Aged ,medicine.disease ,biology.organism_classification ,Rats ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,biology.protein ,Molecular Medicine ,Female ,Insulin Resistance ,business ,Signal Transduction - Abstract
Decreased tissue perfusion increases the risk of developing insulin resistance and cardiovascular disease in obesity, and decreased levels of globular adiponectin (gAdn) have been proposed to contribute to this risk. We hypothesized that gAdn controls insulin's vasoactive effects through AMP-activated protein kinase (AMPK), specifically its α2 subunit, and studied the mechanisms involved. In healthy volunteers, we found that decreased plasma gAdn levels in obese subjects associate with insulin resistance and reduced capillary perfusion during hyperinsulinemia. In cultured human microvascular endothelial cells (HMEC), gAdn increased AMPK activity. In isolated muscle resistance arteries gAdn uncovered insulin-induced vasodilation by selectively inhibiting insulin-induced activation of ERK1/2, and the AMPK inhibitor compound C as well as genetic deletion of AMPKα2 blunted insulin-induced vasodilation. In HMEC deletion of AMPKα2 abolished insulin-induced Ser(1177) phosphorylation of eNOS. In mice we confirmed that AMPKα2 deficiency decreases insulin sensitivity, and this was accompanied by decreased muscle microvascular blood volume during hyperinsulinemia in vivo. This impairment was accompanied by a decrease in arterial Ser(1177) phosphorylation of eNOS, which closely related to AMPK activity. In conclusion, globular adiponectin controls muscle perfusion during hyperinsulinemia through AMPKα2, which determines the balance between NO and ET-1 activity in muscle resistance arteries. Our findings provide a novel mechanism linking reduced gAdn-AMPK signaling to insulin resistance and impaired organ perfusion.
- Published
- 2016
32. Osteoglycin’s embracement of VEGF receptor-2 limits angiogenesis and collateralization
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Victor W.M. van Hinsbergh, Physiology, and ACS - Microcirculation
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Vascular Endothelial Growth Factor A ,0301 basic medicine ,Physiology ,Angiogenesis ,030204 cardiovascular system & hematology ,Biology ,Neovascularization ,Extracellular matrix ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Ischemia ,Physiology (medical) ,medicine ,Animals ,Sprouting angiogenesis ,Thrombospondin ,Neovascularization, Pathologic ,Kinase insert domain receptor ,Vascular Endothelial Growth Factor Receptor-2 ,Cell biology ,Vascular endothelial growth factor ,Vascular endothelial growth factor A ,030104 developmental biology ,chemistry ,Immunology ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Signal Transduction - Abstract
This editorial refers to ‘Loss of osteoglycin promotes angiogenesis in limb ischaemia mouse models via modulation of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 signalling pathway’ by Gao et al. , pp. 70–80. The circulatory system regulates adequate distribution of blood and delivery of oxygen and nutrients to the tissues. When arterial blood flow is interrupted a rapid neovascularization response occurs by expansion of collateral blood vessels and angiogenic sprouting in the hypoxic tissue. VEGF-A plays a central role in hypoxia-induced angiogenesis.1 According to insight obtained from developing tissues, VEGF-A binds to VEGF receptor-2 dimers on the protruding filopodia of sprouting endothelial tips. The receptor is subsequently internalized, after which intracellular signalling evokes a proper sprouting response.2 However, clinical studies in which VEGF was used to induce angiogenesis in chronically ischemic heart or limb have been unsuccessful.3,4 Apparently these tissues are refractory to VEGF stimulation. It is generally assumed that the extracellular matrix harbours information that regulates and guides endothelial sprouting. Matrix association of VEGF-A via its heparin-binding domain can direct the invading sprout, while angiogenesis inhibitors such as thrombospondin and matrikines (proteolytically generated matrix fragments that modulate angiogenesis) do the opposite. In this issue of Cardiovascular Research , Wu et al .5 report on a potentially important role of osteoglycin in limiting the cellular response to VEGF. Osteoglycin inhibits the VEGF-VEGFR2 interaction in healthy tissue, while its absence in the ischemic mouse hindleg enhances both sprouting angiogenesis and collateralization. Osteoglycin (gene symbol: OGN), also called mimecan (UniProt entry name: MIME), is a member of the small leucine-rich proteoglycans (SLRPs) and is expressed in most cells of the body.6 Many SLRPs including osteoglycin can bind to matrix proteins, can expose a binding site to collagen fibrils, and can act …
- Published
- 2017
33. Perivascular Adipose Tissue Controls Insulin-Stimulated Perfusion and Glucose Uptake in Muscle through Adipomuscular Microvascular Anastomoses
- Author
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Victor W.M. van Hinsbergh, John Yudkin, Connie J. Jimenez, Etto C. Eringa, Erik H. Serné, Marie-Jose T. Goumans, Carla F. M. Molthoff, Alexander H. Turaihi, and Yvo M. Smulders
- Subjects
medicine.medical_specialty ,biology ,Chemistry ,Endocrinology, Diabetes and Metabolism ,Glucose uptake ,Insulin ,medicine.medical_treatment ,Adipose tissue ,Carbohydrate metabolism ,Microcirculation ,Endocrinology ,Internal medicine ,Internal Medicine ,biology.protein ,medicine ,Perfusion ,GLUT4 ,Intravital microscopy - Abstract
Insulin-mediated microvascular recruitment (IMVR) regulates delivery of insulin and glucose to insulin-sensitive tissues. We have previously proposed that perivascular adipose tissue (PVAT) controls glucose metabolism and vascular function through outside-to-inside communication and through vessel-to-vessel, or “vasocrine” signaling. Here, we studied this hypothesis in mice by examining effects of removal of local intramuscular PVAT on muscle blood flow and glucose metabolism. Using the hyperinsulinemic, euglycemic clamp (HEC) in combination with positron emission tomography, we found that local PVAT removal transiently reduces muscle glucose uptake by ±50 percent. Contrast-enhanced ultrasonography and intravital microscopy of the gracilis artery (GA) during the HEC showed that PVAT removal abolishes insulin-induced increases in GA diameter and abrogated insulin-stimulated muscle blood volume (microvascular recruitment or IMVR). The effect of PVAT on IMVR was mediated by distinct microvessels or anastomoses, which we showed using lightsheet microscopy of mice expressing mCherry in endothelial cells. Proteomics analysis revealed that PVAT removal significantly alters expression of 109 of 1719 detected proteins in muscle. Observed changes in protein expression included reduction of a mitochondrial protein cluster and of vesicle-associated membrane protein 5 (Vamp5), involved in Glut4 trafficking. In conclusion, we have found that PVAT within muscle regulates muscle perfusion, glucose uptake and muscle protein expression, communicating with the distal microcirculation via microvascular anastomoses. These data highlight the importance of PVAT in vascular and metabolic physiology, and are relevant for type 2 diabetes and associated muscle dysfunction. Disclosure A.H. Turaihi: None. E.H. Serne: None. C. Molthoff: None. M.T. Goumans: None. C.J. Jimenez: None. J.S. Yudkin: None. Y.M. Smulders: None. V.W. van Hinsbergh: None. E.C. Eringa: None.
- Published
- 2018
34. Exercise Prevents High-Fat Diet–Induced Impairment of Insulin-Induced Vasodilatation of Muscle Arterioles in Mice by Browning Perivascular Adipose Tissue of Mice
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Etto C. Eringa, Beatriz C.S. Boa, Luis Felipe Ribeiro Pinto, Fernanda M. Ferrão, Victor W.M. van Hinsbergh, and Isabela Martins Gonzaga
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medicine.medical_specialty ,Induced vasodilatation ,business.industry ,Endocrinology, Diabetes and Metabolism ,Insulin ,medicine.medical_treatment ,digestive, oral, and skin physiology ,nutritional and metabolic diseases ,food and beverages ,Adipose tissue ,Adipokine ,Vasodilation ,High fat diet ,Microcirculation ,Endocrinology ,Internal medicine ,Internal Medicine ,Browning ,medicine ,lipids (amino acids, peptides, and proteins) ,business ,hormones, hormone substitutes, and hormone antagonists - Abstract
Perivascular adipose tissue (PVAT) surrounds most arteries and enhances insulin-induced vasodilatation through local release of adipokines. Obesity impairs the vasoregulatory function of PVAT on insulin-induced vasodilation, thus contributing to cardiovascular risk. Exercise enhances insulin-induced vasodilatation, and we evaluated whether exercise preconditions the muscle microcirculation against HFD-induced impairment of insulin-induced vasodilatation. C57BL/6 mice were exercised for 4 weeks (EX), or fed a high fat diet (HFD) for 2 weeks. Exercise preconditioning was performed by exercising mice for 4 weeks prior to HFD treatment (EX+HFD) or before and during HFD (EX+HFD/EX). HFD increased femoral PVAT and exercise attenuated this effect [(Control (C) 9±1mg vs. HFD 64±7mg - p In conclusion, exercise reduces the HFD-induced increase in PVAT and preserves insulin-induced vasodilatation by increasing mitochondrial uncoupling and improving adipokine expression in PVAT. Disclosure B.C.S. Boa: None. F.M. Ferr o: None. I.M. Gonzaga: None. L.R. Pinto: None. V.W.M. van Hinsbergh: None. E.C. Eringa: None.
- Published
- 2018
35. Insulin Receptor Substrate 2 Controls Insulin-Mediated Vasoreactivity and Perivascular Adipose Tissue Function in Muscle
- Author
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Erik H. Serné, Yvo M. Smulders, Victor W.M. van Hinsbergh, Hans W.M. Niessen, Wineke Bakker, Etto C. Eringa, Alexander H. Turaihi, Neurosurgery, Physiology, Internal medicine, ACS - Diabetes & metabolism, ACS - Microcirculation, ACS - Atherosclerosis & ischemic syndromes, Cardio-thoracic surgery, Pathology, ACS - Heart failure & arrhythmias, AGEM - Digestive immunity, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, and CCA - Cancer biology and immunology
- Subjects
0301 basic medicine ,medicine.medical_specialty ,endothelium ,Physiology ,medicine.medical_treatment ,Adipose tissue ,Adipokine ,microcirculation ,030204 cardiovascular system & hematology ,lcsh:Physiology ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,Insulin receptor substrate ,perivascular adipose tissue ,medicine ,insulin sensitivity ,Adiponectin secretion ,Original Research ,Adiponectin ,biology ,lcsh:QP1-981 ,Chemistry ,Insulin ,insulin receptor substrate 2 ,IRS2 ,Insulin receptor ,030104 developmental biology ,Endocrinology ,biology.protein - Abstract
Introduction: Insulin signaling in adipose tissue has been shown to regulate insulin's effects in muscle. In muscle, perivascular adipose tissue (PVAT) and vascular insulin signaling regulate muscle perfusion. Insulin receptor substrate (IRS) 2 has been shown to control adipose tissue function and glucose metabolism, and here we tested the hypothesis that IRS2 mediates insulin's actions on the vessel wall as well as the vasoactive properties of PVAT. Methods: We studied PVAT and muscle resistance arteries (RA) from littermate IRS2+/+ and IRS2-/- mice and vasoreactivity by pressure myography, vascular insulin signaling, adipokine expression, and release and PVAT morphology. As insulin induced constriction of IRS2+/+ RA in our mouse model, we also exposed RA's of C57/Bl6 mice to PVAT from IRS2+/+ and IRS2-/- littermates to evaluate vasodilator properties of PVAT. Results: IRS2-/- RA exhibited normal vasomotor function, yet a decreased maximal diameter compared to IRS2+/+ RA. IRS2+/+ vessels unexpectedly constricted endothelin-dependently in response to insulin, and this effect was absent in IRS2-/- RA due to reduced ERK1/2activation. For evaluation of PVAT function, we also used C57/Bl6 vessels with a neutral basal effect of insulin. In these experiments insulin (10.0 nM) increased diameter in the presence of IRS2+/+ PVAT (17 ± 4.8, p = 0.014), yet induced a 10 ± 7.6% decrease in diameter in the presence of IRS2-/- PVAT. Adipocytes in IRS2-/- PVAT (1314 ± 161 μm2) were larger (p = 0.0013) than of IRS2+/+ PVAT (915 ± 63 μm2). Adiponectin, IL-6, PAI-1 secretion were similar between IRS2+/+ and IRS2-/- PVAT, as were expression of pro-inflammatory genes (TNF-α, CCL2) and adipokines (adiponectin, leptin, endothelin-1). Insulin-induced AKT phosphorylation in RA was similar in the presence of IRS2-/- and IRS2+/+ PVAT. Conclusion: In muscle, IRS2 regulates both insulin's vasoconstrictor effects, mediating ERK1/2-ET-1 activation, and its vasodilator effects, by mediating the vasodilator effect of PVAT. The regulatory role of IRS2 in PVAT is independent from adiponectin secretion.
- Published
- 2018
36. A functional siRNA screen identifies RhoGTPase-associated genes involved in thrombin-induced endothelial permeability
- Author
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Renee X. de Menezes, Peter L. Hordijk, Victor W.M. van Hinsbergh, Geerten P. van Nieuw Amerongen, Joana Amado-Azevedo, VU University medical center, APH - Methodology, Epidemiology and Data Science, ACS - Microcirculation, and Physiology
- Subjects
0301 basic medicine ,rho GTP-Binding Proteins ,Small interfering RNA ,Genetic Screens ,Hydrolases ,Gene Identification and Analysis ,Thrombin Signaling ,lcsh:Medicine ,Vascular permeability ,Biochemistry ,Epithelium ,Signaling Molecules ,0302 clinical medicine ,Cell Signaling ,Animal Cells ,Medicine and Health Sciences ,Electric Impedance ,Guanine Nucleotide Exchange Factors ,Small interfering RNAs ,RNA, Small Interfering ,lcsh:Science ,Barrier function ,Cells, Cultured ,Multidisciplinary ,Chemistry ,Thrombin ,Cell biology ,Enzymes ,Nucleic acids ,Genetic Techniques ,030220 oncology & carcinogenesis ,RNA Interference ,Cellular Types ,Anatomy ,medicine.drug ,Research Article ,Signal Transduction ,SEPT2 ,Adherens junction ,Capillary Permeability ,03 medical and health sciences ,Gene Types ,medicine ,Genetics ,Human Umbilical Vein Endothelial Cells ,Gene silencing ,Humans ,Endothelium ,Non-coding RNA ,lcsh:R ,Biology and Life Sciences ,Proteins ,Endothelial Cells ,Epithelial Cells ,Cell Biology ,Gene regulation ,Guanosine Triphosphatase ,030104 developmental biology ,Biological Tissue ,Enzymology ,RNA ,Regulator Genes ,lcsh:Q ,Gene expression ,Genetic screen - Abstract
Thrombin and other inflammatory mediators may induce vascular permeability through the disruption of adherens junctions between adjacent endothelial cells. If uncontrolled, hyperpermeability leads to an impaired barrier, fluid leakage and edema, which can contribute to multi-organ failure and death. RhoGTPases control cytoskeletal dynamics, adhesion and migration and are known regulators of endothelial integrity. Knowledge of the precise role of each RhoGTPase, and their associated regulatory and effector genes, in endothelial integrity is incomplete. Using a combination of a RNAi screen with electrical impedance measurements, we quantified the effect of individually silencing 270 Rho-associated genes on the barrier function of thrombin-activated, primary endothelial cells. Known and novel RhoGTPase-associated regulators that modulate the response to thrombin were identified (RTKN, TIAM2, MLC1, ARPC1B, SEPT2, SLC9A3R1, RACGAP1, RAPGEF2, RHOD, PREX1, ARHGEF7, PLXNB2, ARHGAP45, SRGAP2, ARHGEF5). In conclusion, with this siRNA screen, we confirmed the roles of known regulators of endothelial integrity but also identified new, potential key players in thrombin-induced endothelial signaling.
- Published
- 2018
37. A CDC42-centered signaling unit is a dominant positive regulator of endothelial integrity
- Author
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Victor W.M. van Hinsbergh, G.P. van Nieuw Amerongen, Victor W. van Beusechem, Nathalie R. Reinhard, Joana Amado-Azevedo, Peter L. Hordijk, Rene X. Menezes, J. van Bezu, CCA - Cancer biology and immunology, Medical oncology laboratory, Physiology, and ACS - Microcirculation
- Subjects
0301 basic medicine ,Regulator ,Down-Regulation ,lcsh:Medicine ,RAC1 ,CDC42 ,Biology ,Bioinformatics ,Article ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,RNA interference ,Human Umbilical Vein Endothelial Cells ,Guanine Nucleotide Exchange Factors ,Humans ,cdc42 GTP-Binding Protein ,lcsh:Science ,Barrier function ,Multidisciplinary ,Effector ,GTPase-Activating Proteins ,lcsh:R ,Cell biology ,030104 developmental biology ,p21-Activated Kinases ,lcsh:Q ,Guanine nucleotide exchange factor ,Rho Guanine Nucleotide Exchange Factors ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Endothelial barrier function is carefully controlled to protect tissues from edema and damage inflicted by extravasated leukocytes. RhoGTPases, in conjunction with myriad regulatory proteins, exert both positive and negative effects on the endothelial barrier integrity. Precise knowledge about the relevant mechanisms is currently fragmented and we therefore performed a comprehensive analysis of endothelial barrier regulation by RhoGTPases and their regulators. Combining RNAi with electrical impedance measurements we quantified the relevance of 270 Rho-associated genes for endothelial barrier function. Statistical analysis identified 10 targets of which six promoted- and four reduced endothelial barrier function upon downregulation. We analyzed in more detail two of these which were not previously identified as regulators of endothelial integrity. We found that the Rac1-GEF (Guanine nucleotide Exchange Factor) TIAM2 is a positive regulator and the Cdc42(Rac1)-GAP (GTPase-Activating Protein) SYDE1 is a negative regulator of the endothelial barrier function. Finally, we found that the GAP SYDE1 is part of a Cdc42-centered signaling unit, also comprising the Cdc42-GEF FARP1 and the Cdc42 effector PAK7 which controls the integrity of the endothelial barrier. In conclusion, using a siRNA-based screen, we identified new regulators of barrier function and found that Cdc42 is a dominant positive regulator of endothelial integrity.
- Published
- 2017
38. Neovascularization of the atherosclerotic plaque
- Author
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Etto C. Eringa, Victor W.M. van Hinsbergh, Mat J.A.P. Daemen, Physiology, and ICaR - Ischemia and repair
- Subjects
Adventitia ,Pathology ,medicine.medical_specialty ,Angiogenesis ,Endocrinology, Diabetes and Metabolism ,Adipose tissue ,Inflammation ,Neovascularization ,Lesion ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Nutrition and Dietetics ,Neovascularization, Pathologic ,business.industry ,Cell Biology ,Hypoxia (medical) ,Atherosclerosis ,Cell Hypoxia ,Plaque, Atherosclerotic ,eye diseases ,Lymphangiogenesis ,Oxygen ,medicine.anatomical_structure ,Adipose Tissue ,Microvessels ,Adiponectin ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
Purpose of review Neovascularization is a prominent feature in advanced human atherosclerotic plaques. This review surveys recent evidence for and remaining uncertainties regarding a role of neovascularization in atherosclerotic plaque progression. Specific emphasis is given to hypoxia, angiogenesis inhibition, and perivascular adipose tissue (PVAT). Recent findings Immunohistochemical and imaging studies showed a strong association between hypoxia, inflammation and neovascularization, and the progression of the atherosclerotic plaque both in humans and mice. Whereas in humans, a profound invasion of microvessels from the adventitia into the plaque occurs, neovascularization in mice is found mainly (peri)adventitially. Influencing neovascularization in mice affected plaque progression, possibly by improving vessel perfusion, but supportive clinical data are not available. Whereas plaque neovascularization contributes to monocyte/macrophage accumulation in the plaque, lymphangiogenesis may facilitate egress of cells and waste products. A specific role for PVAT and its secreted factors is anticipated and wait further clinical evaluation. Summary Hypoxia, inflammation, and plaque neovascularization are associated with plaque progression as underpinned by recent imaging data in humans. Recent studies provide new insights into modulation of adventitia-associated angiogenesis, PVAT, and plaque development in mice, but there is still a need for detailed information on modulating human plaque vascularization in patients.
- Published
- 2015
39. ROCK2 primes the endothelium for vascular hyperpermeability responses by raising baseline junctional tension
- Author
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Geerten P. van Nieuw Amerongen, Nebojsa Nick Knezevic, Ramaswamy Krishnan, Cora M.L. Beckers, Victor W.M. van Hinsbergh, Mohammad Tauseef, Erik T. Valent, Jurjan Aman, Jan van Bezu, C. Corey Hardin, Kavitha Rajendran, Dolly Mehta, Paul Sweetnam, Physiology, and ICaR - Ischemia and repair
- Subjects
Time Factors ,Endothelium ,Physiology ,Mice, Transgenic ,Vascular permeability ,Biology ,Transfection ,Cell junction ,Article ,Capillary Permeability ,Adherens junction ,Stress Fibers ,Electric Impedance ,Human Umbilical Vein Endothelial Cells ,medicine ,Animals ,Humans ,ROCK1 ,ROCK2 ,Protein Kinase Inhibitors ,Rho-associated protein kinase ,Cells, Cultured ,Pharmacology ,rho-Associated Kinases ,Thrombin ,Endothelial Cells ,Cell biology ,Mice, Inbred C57BL ,Intercellular Junctions ,medicine.anatomical_structure ,Molecular Medicine ,RNA Interference ,Signal transduction ,Signal Transduction - Abstract
Rho kinase mediates the effects of inflammatory permeability factors by increasing actomyosin-generated traction forces on endothelial adherens junctions, resulting in disassembly of intercellular junctions and increased vascular leakage. In vitro, this is accompanied by the Rho kinase-driven formation of prominent radial F-actin fibers, but the in vivo relevance of those F-actin fibers has been debated, suggesting other Rho kinase-mediated events to occur in vascular leak. Here, we delineated the contributions of the highly homologous isoforms of Rho kinase (ROCK1 and ROCK2) to vascular hyperpermeability responses. We show that ROCK2, rather than ROCK1 is the critical Rho kinase for regulation of thrombin receptor-mediated vascular permeability. Novel traction force mapping in endothelial monolayers, however, shows that ROCK2 is not required for the thrombin-induced force enhancements. Rather, ROCK2 is pivotal to baseline junctional tension as a novel mechanism by which Rho kinase primes the endothelium for hyperpermeability responses, independent from subsequent ROCK1-mediated contractile stress-fiber formation during the late phase of the permeability response.
- Published
- 2015
40. C1q/TNF-related protein 1: a novel link between visceral fat and athero-inflammation
- Author
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Etto C. Eringa, Victor W.M. van Hinsbergh, Physiology, ICaR - Ischemia and repair, and ICaR - Circulation and metabolism
- Subjects
Inflammation ,0301 basic medicine ,medicine.medical_specialty ,Necrosis ,Adiponectin ,business.industry ,Adipose tissue macrophages ,Leptin ,Adipokine ,Adipose tissue ,Intra-Abdominal Fat ,030204 cardiovascular system & hematology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Humans ,Medicine ,Tumor necrosis factor alpha ,Obesity ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
This editorial refers to ‘C1q/tumour necrosis factor-related protein 1: an adipokine marking and promoting atherosclerosis’, by L. Lu et al ., doi:10.1093/eurheartj/ehv649. Approximately 30% of the global population are overweight or obese, posing a major threat to healthcare in developed and developing countries. Obesity decreases life expectancy, mainly by increasing the risk of type 2 diabetes and cardiovascular disease. A mechanistic explanation for these intertwined metabolic and cardiovascular risks has been offered by adipokines, a large and diverse group of molecules secreted by adipose tissue that affect both glucose metabolism and cardiovascular function. Importantly, the perivascular depot of adipose tissue is situated around the majority of the arterial tree, and a large number of studies have shown that local adipokine expression controls vascular function and dysfunction.1 Well-known adipokines include cytokines such as interleukin-1β and tumour necrosis factor α (TNFα) (resulting in the term adipose tissue-derived cytokines), leptin, and fatty acids. Among the most intriguing adipokines are the 16-member family of C1q/TNF-related proteins (CTRPs) that includes the intensively studied adiponectin,2 also synthesized in arterial perivascular adipose tissue (PVAT).3 The CTRPs share the globular adiponectin domain in their molecular structure, which binds and activates the adiponectin receptors AdipoR1 and AdipoR2, widely expressed in the cardiovascular system.4 CTRPs circulate as monomers but also as heterotrimers, enabling diverse biological effects.2 Figure 1 The adipokine CTRP1 (C1q/tumour necrosis factor-related protein 1) is produced in adipose tissue (yellow area) as well by oxidized LDL (OxLDL)- or interleukin-1β (IL-1β)-stimulated macrophages and endothelial cells in the atherosclerotic plaque (purple area). In the plaque, CTRP1 activates endothelial cells and macrophages themselves to produce leucocyte adhesion molecules and tumour necrosis factor α (TNFα), …
- Published
- 2016
41. Arterial Blood Pressure Induces Transient C4b-Binding Protein in Human Saphenous Vein Grafts
- Author
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Hans W. M. Niessen, Koba Kupreishvili, Paul H.A. Quax, Anna M. Blom, Paul A.J. Krijnen, Christof Meischl, Alexander B.A. Vonk, Victor W.M. van Hinsbergh, Leon Eijsman, Wim Stooker, Pathology, Cardio-thoracic surgery, ACS - Microcirculation, AGEM - Digestive immunity, ACS - Atherosclerosis & ischemic syndromes, and ACS - Heart failure & arrhythmias
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Time Factors ,Inflammation ,In Vitro Techniques ,030204 cardiovascular system & hematology ,Antioxidants ,03 medical and health sciences ,Complement inhibitor ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Arterial Pressure ,Saphenous Vein ,Coronary Artery Bypass ,Vein ,business.industry ,Complement C4b-Binding Protein ,General Medicine ,Up-Regulation ,Complement system ,Surgery ,030104 developmental biology ,Blood pressure ,medicine.anatomical_structure ,Complement C3d ,Cardiology ,Arterial blood ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Perfusion ,Artery - Abstract
BACKGROUND: Complement is an important mediator in arterial blood pressure-induced vein graft failure. Previously, we noted activation of cell protective mechanisms in human saphenous veins too. Here we have analyzed whether C4b-binding protein (C4bp), an endogenous complement inhibitor, is present in the vein wall.METHODS: Human saphenous vein segments obtained from patients undergoing coronary artery bypass grafting (n = 55) were perfused in vitro at arterial blood pressure with either autologous blood for 1, 2, 4, or 6 hr or with autologous blood supplemented with reactive oxygen species scavenger N-acetylcysteine. The segments were subsequently analyzed quantitatively for presence of C4bp and complement activation product C3d using immunohistochemistry.RESULTS: Perfusion induced deposition of C3d and C4bp within the media of the vessel wall, which increased reproducibly and significantly over a period of 4 hr up to 3.8% for C3d and 81% for C4bp of the total vessel area. Remarkably after 6 hr of perfusion, the C3d-positive area decreased significantly to 1.3% and the C4bp-positive area to 19% of the total area of the vein. The areas positive for both C4bp and C3d were increased in the presence of N-acetylcysteine.CONCLUSIONS: Exposure to arterial blood pressure leads to a transient presence of C4bp in the vein wall. This may be part of a cell-protective mechanism to counteract arterial blood pressure-induced cellular stress and inflammation in grafted veins.
- Published
- 2017
42. Combined Intravital Microscopy and Contrast-enhanced Ultrasonography of the Mouse Hindlimb to Study Insulin-induced Vasodilation and Muscle Perfusion
- Author
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Yvo M. Smulders, Alexander H. Turaihi, Erik H. Serné, Erik M. van Poelgeest, Victor W.M. van Hinsbergh, Etto C. Eringa, Physiology, ACS - Diabetes & metabolism, Internal medicine, ACS - Microcirculation, and ACS - Atherosclerosis & ischemic syndromes
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Intravital Microscopy ,endothelium ,General Chemical Engineering ,medicine.medical_treatment ,Contrast Media ,Vasodilation ,Hindlimb ,General Biochemistry, Genetics and Molecular Biology ,Microcirculation ,Mice ,03 medical and health sciences ,medicine ,Animals ,Hypoglycemic Agents ,Insulin ,insulin sensitivity ,Muscle, Skeletal ,Ultrasonography ,contrast-enhanced ultrasonography ,Microbubbles ,General Immunology and Microbiology ,business.industry ,General Neuroscience ,microsurgery ,Glucose clamp technique ,Arterial tree ,Femoral Artery ,Issue 121 ,030104 developmental biology ,Glucose Clamp Technique ,Medicine ,vascular responsiveness ,business ,Perfusion ,Intravital microscopy - Abstract
It has been demonstrated that insulin’s vascular actions contribute to regulation of insulin sensitivity. Insulin’s effects on muscle perfusion regulate postprandial delivery of nutrients and hormones to insulin-sensitive tissues. We here describe a technique for combining intravital microscopy (IVM) and contrast-enhanced ultrasonography (CEUS) of the adductor compartment of the mouse hindlimb to simultaneously visualize muscle resistance arteries and perfusion of the microcirculation in vivo. Simultaneously assessing insulin’s effect at multiple levels of the vascular tree is important to study relationships between insulin’s multiple vasoactive effects and muscle perfusion. Experiments in this study were performed in mice. First, the tail vein cannula is inserted for the infusion of anesthesia, vasoactive compounds and ultrasound contrast agent (lipid-encapsulated microbubbles). Second, a small incision is made in the groin area to expose the arterial tree of the adductor muscle compartment. The ultrasound probe is then positioned at the contralateral upper hindlimb to view the muscles in cross-section. To assess baseline parameters, the arterial diameter is assessed and microbubbles are subsequently infused at a constant rate to estimate muscle blood flow and microvascular blood volume (MBV). When applied before and during a hyperinsulinemic-euglycemic clamp, combined IVM and CEUS allow assessment of insulin-induced changes of arterial diameter, microvascular muscle perfusion and whole-body insulin sensitivity. Moreover, the temporal relationship between responses of the microcirculation and the resistance arteries to insulin can be quantified. It is also possible to follow-up the mice longitudinally in time, making it a valuable tool to study changes in vascular and whole-body insulin sensitivity.
- Published
- 2017
43. Physiology of blood vessels
- Author
-
Victor W.M. van Hinsbergh
- Abstract
This chapter covers two major fields of the blood circulation: ‘distribution’ and ‘exchange’. After a short survey of the types of vessels, which form the circulation system together with the heart, the chapter describes how hydrostatic pressure derived from the heartbeat and vascular resistance determine the volume of blood that is locally delivered per time unit. The vascular resistance depends on the length of the vessel, blood viscosity, and, in particular, on the diameter of the vessel, as formulated in the Poiseuille-Hagen equation. Blood flow can be determined in vivo by different imaging modalities. A summary is provided of how smooth muscle cell contraction is regulated at the cellular level, and how neuronal, humoral, and paracrine factors affect smooth muscle contraction and thereby blood pressure and blood volume distribution among tissues. Subsequently the exchange of solutes and macromolecules over the capillary endothelium and the contribution of its surface layer, the glycocalyx, are discussed. After a description of the Starling equation for capillary exchange, new insights are summarized(in the so-called glycocalyx cleft model) that led to a new view on exchange along the capillary and on the contribution of oncotic pressure. Finally mechanisms are indicated in brief that play a role in keeping the blood volume constant, as a constant volume is a prerequisite for adequate functioning of the circulatory system.
- Published
- 2017
44. Identification of HIF-2α-regulated genes that play a role in human microvascular endothelial sprouting during prolonged hypoxia in vitro
- Author
-
Susan Gibbs, Victor W.M. van Hinsbergh, Tineke C. T. M. van der Pouw-Kraan, Marloes van den Broek, Tessa D. Nauta, Pieter Koolwijk, Cees B.M. Oudejans, Academic Centre for Dentistry Amsterdam, Oral Cell Biology, Dental Material Sciences, Physiology, Dermatology, AMS - Trauma and Reconstruction, Molecular cell biology and Immunology, ICaR - Ischemia and repair, Clinical chemistry, CCA - Cancer biology and immunology, ACTA, Orale Celbiologie (ORM, ACTA), and Tandheelkundige Materiaalwetenschappen (ORM, ACTA)
- Subjects
0301 basic medicine ,Cancer Research ,Physiology ,Angiogenesis ,Clinical Biochemistry ,Neovascularization, Physiologic ,Biology ,Transfection ,Neovascularization ,03 medical and health sciences ,Genome-wide RNA-sequencing ,Downregulation and upregulation ,SDG 3 - Good Health and Well-being ,Gene expression ,medicine ,Basic Helix-Loop-Helix Transcription Factors ,Gene silencing ,Humans ,Gene Silencing ,RNA, Messenger ,Hypoxia ,Gene ,Original Paper ,Cell Cycle ,Endothelial Cells ,HIF-2α ,Hypoxia (medical) ,Molecular biology ,In vitro ,Cell Hypoxia ,Cell biology ,Oxygen ,030104 developmental biology ,Gene Expression Regulation ,Microvessels ,medicine.symptom ,Signal Transduction - Abstract
During prolonged hypoxic conditions, endothelial cells change their gene expression to adjust to the low oxygen environment. This process is mainly regulated by the hypoxia-inducible factors, HIF-1α and HIF-2α. Although endothelial cells do not form sprouts during prolonged hypoxic culturing, silencing of HIF-2α partially restores sprout formation. The present study identifies novel HIF-2α-target genes that may regulate endothelial sprouting during prolonged hypoxia. The gene expression profile of primary human microvascular endothelial cells (hMVECs) that were cultured at 20 % oxygen was compared to hMVECs that were cultured at 1 % oxygen for 14 days by using genome-wide RNA-sequencing. The differentially regulated genes in hypoxia were compared to the genes that were differentially regulated upon silencing of HIF-2α in hypoxia. Surprisingly, KEGG pathway analysis showed that metabolic pathways were enriched within genes upregulated in response to hypoxia and enriched within genes downregulated upon HIF-2α silencing. Moreover, 51 HIF-2α-regulated genes were screened for their role in endothelial sprouting in hypoxia, of which four genes ARRDC3, MME, PPARG and RALGPS2 directly influenced endothelial sprouting during prolonged hypoxic culturing. The manipulation of specific downstream targets of HIF-2α provides a new, but to be further evaluated, perspective for restoring reduced neovascularization in several pathological conditions, such as diabetic ulcers or other chronic wounds, for improvement of vascularization of implanted tissue-engineered scaffolds. Electronic supplementary material The online version of this article (doi:10.1007/s10456-016-9527-4) contains supplementary material, which is available to authorized users.
- Published
- 2017
45. Hypoxic Signaling During Tissue Repair and Regenerative Medicine
- Author
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Pieter Koolwijk, Victor W.M. van Hinsbergh, Tessa D. Nauta, Physiology, and ICaR - Ischemia and repair
- Subjects
medicine.medical_specialty ,Scaffold ,Angiogenesis ,HIF-1α ,Neovascularization, Physiologic ,Review ,Biology ,Bioinformatics ,Regenerative Medicine ,Regenerative medicine ,Catalysis ,Hypoxia-Inducible Factor-Proline Dioxygenases ,Inorganic Chemistry ,lcsh:Chemistry ,angiogenesis ,Tissue engineering ,medicine ,Basic Helix-Loop-Helix Transcription Factors ,Humans ,Physical and Theoretical Chemistry ,Molecular Biology ,Transcription factor ,lcsh:QH301-705.5 ,Spectroscopy ,Wound Healing ,integumentary system ,Tissue Engineering ,hypoxia ,Organic Chemistry ,HIF-2α ,General Medicine ,Tissue repair ,Hypoxia (medical) ,Computer Science Applications ,Surgery ,lcsh:Biology (General) ,lcsh:QD1-999 ,medicine.symptom ,Wound healing ,Signal Transduction - Abstract
In patients with chronic wounds, autologous tissue repair is often not sufficient to heal the wound. These patients might benefit from regenerative medicine or the implantation of a tissue-engineered scaffold. Both wound healing and tissue engineering is dependent on the formation of a microvascular network. This process is highly regulated by hypoxia and the transcription factors hypoxia-inducible factors-1α (HIF-1α) and -2α (HIF-2α). Even though much is known about the function of HIF-1α in wound healing, knowledge about the function of HIF-2α in wound healing is lacking. This review focuses on the function of HIF-1α and HIF-2α in microvascular network formation, wound healing, and therapy strategies.
- Published
- 2014
46. Endothelial Progenitors: A Consensus Statement on Nomenclature
- Author
-
Osamu Ohneda, Teruhide Yamaguchi, Mervin C. Yoder, Victor W.M. van Hinsbergh, Juan M. Melero-Martin, Chad L. Barber, Reinhold J. Medina, Kiarash Khosrotehrani, Alan W. Stitt, Anna M. Randi, Jerry Kok Yen Chan, Françoise Dignat-George, Florence Sabatier, Queen's University [Belfast] (QUB), California Lutheran University, Vascular research center of Marseille (VRCM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Molecular and Developmental Biology, Université de Tsukuba = University of Tsukuba, Imperial College for Translational and Experimental Medicine, Imperial College London, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)
- Subjects
0301 basic medicine ,Cell type ,Angiogenesis ,Cellular therapy ,Cell- and Tissue-Based Therapy ,Neovascularization, Physiologic ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,030204 cardiovascular system & hematology ,Biology ,Endothelial progenitor cell ,Progenitor cells ,Cell therapy ,03 medical and health sciences ,IDENTITIES ,0302 clinical medicine ,Vasculogenesis ,Endothelial cell ,Cell & Tissue Engineering ,Terminology as Topic ,Animals ,Humans ,COLONY-FORMING CELLS ,Progenitor cell ,Endothelial Progenitor Cells ,NEOVASCULARIZATION ,PRECURSORS ,Science & Technology ,IDENTIFICATION ,ANGIOGENIC CELLS ,General Medicine ,Cell Biology ,STEM ,Endothelial stem cell ,Editorial ,030104 developmental biology ,VASCULOGENESIS ,Immunology ,UMBILICAL-CORD BLOOD ,Stem cell ,Neuroscience ,Life Sciences & Biomedicine ,OUTGROWTH ,Perspectives ,Developmental Biology - Abstract
Summary Endothelial progenitor cell (EPC) nomenclature remains ambiguous and there is a general lack of concordance in the stem cell field with many distinct cell subtypes continually grouped under the term “EPC.” It would be highly advantageous to agree on standards to confirm an endothelial progenitor phenotype and this should include detailed immunophenotyping, potency assays, and clear separation from hematopoietic angiogenic cells which are not endothelial progenitors. In this review, we seek to discourage the indiscriminate use of “EPCs,” and instead propose precise terminology based on defining cellular phenotype and function. Endothelial colony forming cells and myeloid angiogenic cells are examples of two distinct and well-defined cell types that have been considered EPCs because they both promote vascular repair, albeit by completely different mechanisms of action. It is acknowledged that scientific nomenclature should be a dynamic process driven by technological and conceptual advances; ergo the ongoing “EPC” nomenclature ought not to be permanent and should become more precise in the light of strong scientific evidence. This is especially important as these cells become recognized for their role in vascular repair in health and disease and, in some cases, progress toward use in cell therapy.
- Published
- 2016
47. Perivascular fat in human muscle
- Author
-
Etto C. Eringa, John Yudkin, Erik H. Serné, Rick I. Meijer, Yvo M. Smulders, Victor W.M. van Hinsbergh, Internal medicine, ICaR - Circulation and metabolism, and Physiology
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Adipose tissue ,Perivascular fat ,03 medical and health sciences ,Endocrinology ,Insulin resistance ,Internal medicine ,Internal Medicine ,medicine ,Body Fat Distribution ,Humans ,Obesity ,Muscle, Skeletal ,Adiposity ,030109 nutrition & dietetics ,Muscle biopsy ,medicine.diagnostic_test ,business.industry ,Vascular disease ,Insulin ,Middle Aged ,medicine.disease ,Adipose Tissue ,Female ,business ,Perfusion - Abstract
A 53-year-old obese, but otherwise healthy, woman, participated in a study on impaired muscle perfusion in obesity. A muscle biopsy taken from this patient shows the fi rst identifi cation of perivascular adipose tissue (PVAT) in human muscle. In the past decade, evidence has accumulated that PVAT controls various vascular functions, including infl ammation, smooth-muscle tone, and endothelial function. Perivascular fat has been proposed to control insulin sensitivity through regulation of insulin-stimulated muscle perfusion. In 2015, PVAT was shown to determine insulin’s vasoactive eff ect on muscle arterioles; this regulation is impaired in obesity. The discovery of PVAT in human muscle and its vascular functions opens new avenues for the treatment of vascular disease and insulin resistance in obesity.
- Published
- 2016
48. Empagliflozin for heart failure with preserved ejection fraction: targeting cardiac endothelial cell-cardiomyocyte interaction
- Author
-
Victor W.M. van Hinsbergh, J. van der Velden, Max Goebel, Diederik W. D. Kuster, P. Koolwijk, Walter Paulus, R.J.P. Musters, Rio P. Juni, and Michiel Helmes
- Subjects
Endothelial stem cell ,medicine.medical_specialty ,business.industry ,Internal medicine ,Cardiology ,Empagliflozin ,Medicine ,Cardiology and Cardiovascular Medicine ,business ,Heart failure with preserved ejection fraction ,Molecular Biology - Published
- 2018
49. Platelets and thromboxane receptors: pivotal players in arteriogenesis: Figure 1
- Author
-
Dimitar Tasev and Victor W.M. van Hinsbergh
- Subjects
Sprouting angiogenesis ,medicine.medical_specialty ,Endothelium ,Physiology ,Angiogenesis ,Microvascular Density ,Anatomy ,Biology ,Collateral circulation ,Thromboxane A2 ,chemistry.chemical_compound ,medicine.anatomical_structure ,Vasculogenesis ,chemistry ,Physiology (medical) ,Internal medicine ,medicine ,Cardiology ,Arteriogenesis ,Cardiology and Cardiovascular Medicine - Abstract
This editorial refers to ‘Thromboxane A2 induces blood flow recovery via platelet adhesion to ischaemic regions’ by H. Amano et al. , doi:10.1093/cvr/cvv139. The reconstitution of oxygen and nutrient supply in cases of disturbed blood flow caused by tissue damage or vascular occlusion is driven by sprouting angiogenesis, arteriogenesis as an adaptation of pre-collateral vessels into collateral conduit vessels, and vasculogenesis characterized by invasion of circulating monocytic and endothelial progenitor cells.1 To study these mechanisms, a mouse model is often used, in which ligation of the femoral artery causes interruption of blood flow in the hind leg and hypoxia in the distal tissue.2 To save the hind leg tissue, the body responds immediately by the stimulation of a collateral circulation that starts proximal to the ligation. In a healthy C57/BL6 mouse, the transformation of pre-existing narrow collaterals into arterial conduit vessels with a many-fold wider diameter restores the blood supply and tissue perfusion to the hind leg within 7–10 days. In the occluded hind leg model, arteriogenesis is usually accompanied by angiogenesis in the ischaemic muscle, which results in an increase in local microvascular density. This further facilitates blood distribution and oxygen diffusion to meet the increased oxygen demand of the injured tissue. Figure 1 Involvement of platelets and TPs in arteriogenesis in mice.6,7 After femoral occlusion, altered shear forces and oxygen availability modulate endothelial functioning, after which platelets start adhering the endothelium of pre-existing collaterals and vessels that became ischaemic distal of the occlusion. These …
- Published
- 2015
50. Endothelial dysfunction in (pre)diabetes: Characteristics, causative mechanisms and pathogenic role in type 2 diabetes
- Author
-
Rick I. Meijer, Etto C. Eringa, Victor W.M. van Hinsbergh, Yvo M. Smulders, Casper G. Schalkwijk, Erik H. Serné, Alfons J.H.M. Houben, Coen D.A. Stehouwer, Interne Geneeskunde, MUMC+: MA Interne Geneeskunde (3), RS: CARIM School for Cardiovascular Diseases, Physiology, Internal medicine, and ICaR - Circulation and metabolism
- Subjects
medicine.medical_specialty ,Endothelium ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Adipokine ,Adipose tissue ,Type 2 diabetes ,Prediabetic State ,Endocrinology ,Internal medicine ,Diabetes mellitus ,medicine ,Animals ,Humans ,Insulin ,Obesity ,Endothelial dysfunction ,biology ,Diabetes ,nutritional and metabolic diseases ,medicine.disease ,Insulin receptor ,medicine.anatomical_structure ,Diabetes Mellitus, Type 2 ,Intracellular signaling ,Immunology ,biology.protein ,Endothelium, Vascular - Abstract
Endothelial dysfunction associated with diabetes and cardiovascular disease is characterized by changes in vasoregulation, enhanced generation of reactive oxygen intermediates, inflammatory activation, and altered barrier function. These endothelial alterations contribute to excess cardiovascular disease in diabetes, but may also play a role in the pathogenesis of diabetes, especially type 2. The mechanisms underlying endothelial dysfunction in diabetes differ between type 1 (T1D) and type 2 diabetes (T2D): hyperglycemia contributes to endothelial dysfunction in all individuals with diabetes, whereas the causative mechanisms in T2D also include impaired insulin signaling in endothelial cells, dyslipidemia and altered secretion of bioactive substances (adipokines) by adipose tissue. The close association of so-called perivascular adipose tissue with arteries and arterioles facilitates the exposure of vascular endothelium to adipokines, particularly if inflammation activates the adipose tissue. Glucose and adipokines activate specific intracellular signaling pathways in endothelium, which in concert result in endothelial dysfunction in diabetes. Here, we review the characteristics of endothelial dysfunction in diabetes, the causative mechanisms involved and the role of endothelial dysfunction(s) in the pathogenesis of T2D. Finally, we will discuss the therapeutic potential of endothelial dysfunction in T2D.
- Published
- 2013
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