324 results on '"Victor W.M. Van Hinsbergh"'
Search Results
152. Substrate stiffening promotes endothelial monolayer disruption through enhanced physical forces
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Jan van Bezu, Christopher V. Carman, Joseph D. Brain, Kavitha Rajendran, Geerten P. van Nieuw Amerongen, Ramaswamy Krishnan, James P. Butler, Darinka D. Klumpers, Xavier Trepat, Chan Young Park, Jeffrey J. Fredberg, Victor W.M. van Hinsbergh, Orthopedic Surgery and Sports Medicine, Physiology, and ICaR - Ischemia and repair
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Endothelium ,Physiology ,Acrylic Resins ,Biology ,Traction force microscopy ,Thrombin ,Antigens, CD ,Vascular Biology ,Monolayer ,Cell Adhesion ,medicine ,Humans ,Cell adhesion ,Rho-associated protein kinase ,Cells, Cultured ,Microscopy ,rho-Associated Kinases ,Endothelial Cells ,Membranes, Artificial ,Cell Biology ,Cadherins ,Biomechanical Phenomena ,Culture Media ,Endothelial stem cell ,medicine.anatomical_structure ,Biochemistry ,Biophysics ,VE-cadherin ,medicine.drug - Abstract
A hallmark of many, sometimes life-threatening, inflammatory diseases and disorders is vascular leakage. The extent and severity of vascular leakage is broadly mediated by the integrity of the endothelial cell (EC) monolayer, which is in turn governed by three major interactions: cell-cell and cell-substrate contacts, soluble mediators, and biomechanical forces. A potentially critical but essentially uninvestigated component mediating these interactions is the stiffness of the substrate to which the endothelial monolayer is adherent. Accordingly, we investigated the extent to which substrate stiffening influences endothelial monolayer disruption and the role of cell-cell and cell-substrate contacts, soluble mediators, and physical forces in that process. Traction force microscopy showed that forces between cell and cell and between cell and substrate were greater on stiffer substrates. On stiffer substrates, these forces were substantially enhanced by a hyperpermeability stimulus (thrombin, 1 U/ml), and gaps formed between cells. On softer substrates, by contrast, these forces were increased far less by thrombin, and gaps did not form between cells. This stiffness-dependent force enhancement was associated with increased Rho kinase activity, whereas inhibition of Rho kinase attenuated baseline forces and lessened thrombin-induced inter-EC gap formation. Our findings demonstrate a central role of physical forces in EC gap formation and highlight a novel physiological mechanism. Integrity of the endothelial monolayer is governed by its physical microenvironment, which in normal circumstances is compliant but during pathology becomes stiffer.
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- 2011
153. Homocysteine induces phosphatidylserine exposure in cardiomyocytes through inhibition of Rho kinase and flippase activity
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Victor W.M. van Hinsbergh, Geerten P van Nieuw-Amerongen, Nynke E. Hahn, Coen D.A. Stehouwer, Jessica A. Sipkens, Hans W.M. Niessen, Paul A.J. Krijnen, Jan A. Rauwerda, Pathology, Physiology, Surgery, ICaR - Heartfailure and pulmonary arterial hypertension, Interne Geneeskunde, RS: NUTRIM - R1 - Metabolic Syndrome, and RS: CARIM School for Cardiovascular Diseases
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RHOA ,GTP' ,Physiology ,Pyridines ,Inflammation ,Phosphatidylserines ,chemistry.chemical_compound ,Adenosine Triphosphate ,medicine ,Myocyte ,Animals ,Myocytes, Cardiac ,Phospholipid Transfer Proteins ,Rho-associated protein kinase ,Homocysteine ,Protein Kinase Inhibitors ,Cells, Cultured ,rho-Associated Kinases ,biology ,Phosphatidylserine ,Flippase ,Amides ,Cell biology ,Rats ,Biochemistry ,chemistry ,biology.protein ,Guanosine Triphosphate ,medicine.symptom ,rhoA GTP-Binding Protein ,Adenosine triphosphate - Abstract
AIMS: Increased levels of homocysteine (Hcy) form an independent risk factor for cardiovascular disease. In a previous study we have shown that Hcy induced phosphatidylserine (PS) exposure to the outer leaflet of the plasma membrane in cardiomyocytes, inducing a pro-inflammatory phenotype. In the present study the mechanism(s) involved in Hcy-induced PS exposure were analyzed.METHODS: H9c2 rat cardiomyoblasts were subjected to 2.5 mM D,L-Hcy and analyzed for RhoA translocation and activity, Rho Kinase (ROCK) activity and expression and flippase activity. In addition, the effect of ROCK inhibition with Y27632 on Hcy-induced PS exposure and flippase activity was analyzed. Furthermore, GTP and ATP levels were determined.RESULTS: Incubation of H9c2 cells with 2.5 mM D,L-Hcy did not inhibit RhoA translocation to the plasma membrane. Neither did it inhibit activation of RhoA, even though GTP levels were significantly decreased. Hcy did significantly inhibit ROCK activation, but not its expression, and did inhibit flippase activity, in advance of a significant decrease in ATP levels. ROCK inhibition via Y27632 did not have significant added effects on this.CONCLUSION: Hcy induced PS exposure in the outer leaflet of the plasma membrane in cardiomyocytes via inhibition of ROCK and flippase activity. As such Hcy may induce cardiomyocytes vulnerable to inflammation in vivo in hyperhomocysteinaemia patients.
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- 2011
154. Opposing Effects of the Angiopoietins on the Thrombin-Induced Permeability of Human Pulmonary Microvascular Endothelial Cells
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Melanie van der Heijden, A. B. Johan Groeneveld, Marinus A. Paul, Victor W.M. van Hinsbergh, Jan van Bezu, Geerten P. van Nieuw Amerongen, Intensive care medicine, Physiology, Surgery, and ICaR - Ischemia and repair
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rac1 GTP-Binding Protein ,RHOA ,Cell Membrane Permeability ,Time Factors ,Critical Care and Emergency Medicine ,lcsh:Medicine ,Vascular permeability ,Cardiovascular ,Biochemistry ,Molecular Cell Biology ,Electric Impedance ,Phosphorylation ,lcsh:Science ,Lung ,Cells, Cultured ,Multidisciplinary ,biology ,Chemistry ,Thrombin ,Cadherins ,Receptor, TIE-2 ,Recombinant Proteins ,Cell biology ,Medicine ,Cellular Types ,Coagulation Factors ,medicine.drug ,Research Article ,Immunoblotting ,RAC1 ,Lung injury ,Endothelial activation ,Angiopoietin-2 ,Respiratory Failure ,Antigens, CD ,Vascular Biology ,Sepsis ,medicine ,Angiopoietin-1 ,Humans ,Pulmonary Vascular Diseases ,Biology ,Cadherin ,Coagulants ,lcsh:R ,Endothelial Cells ,Proteins ,Permeability (electromagnetism) ,biology.protein ,lcsh:Q ,rhoA GTP-Binding Protein ,Angiopoietins - Abstract
Background Angiopoietin-2 (Ang-2) is associated with lung injury in ALI/ARDS. As endothelial activation by thrombin plays a role in the permeability of acute lung injury and Ang-2 may modulate the kinetics of thrombin-induced permeability by impairing the organization of vascular endothelial (VE-)cadherin, and affecting small Rho GTPases in human pulmonary microvascular endothelial cells (HPMVECs), we hypothesized that Ang-2 acts as a sensitizer of thrombin-induced hyperpermeability of HPMVECs, opposed by Ang-1. Methodology/Principal Findings Permeability was assessed by measuring macromolecule passage and transendothelial electrical resistance (TEER). Angiopoietins did not affect basal permeability. Nevertheless, they had opposing effects on the thrombin-induced permeability, in particular in the initial phase. Ang-2 enhanced the initial permeability increase (passage, P = 0.010; TEER, P = 0.021) in parallel with impairment of VE-cadherin organization without affecting VE-cadherin Tyr685 phosphorylation or increasing RhoA activity. Ang-2 also increased intercellular gap formation. Ang-1 preincubation increased Rac1 activity, enforced the VE-cadherin organization, reduced the initial thrombin-induced permeability (TEER, P = 0.027), while Rac1 activity simultaneously normalized, and reduced RhoA activity at 15 min thrombin exposure (P = 0.039), but not at earlier time points. The simultaneous presence of Ang-2 largely prevented the effect of Ang-1 on TEER and macromolecule passage. Conclusions/Significance Ang-1 attenuated thrombin-induced permeability, which involved initial Rac1 activation-enforced cell-cell junctions, and later RhoA inhibition. In addition to antagonizing Ang-1, Ang-2 had also a direct effect itself. Ang-2 sensitized the initial thrombin-induced permeability accompanied by destabilization of VE-cadherin junctions and increased gap formation, in the absence of increased RhoA activity.
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- 2011
155. Plasma protein levels are markers of pulmonary vascular permeability and degree of lung injury in critically ill patients with or at risk for acute lung injury/acute respiratory distress syndrome
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Jurjan Aman, Melanie van der Heijden, Arthur van Lingen, Armand R. J. Girbes, A. B. Johan Groeneveld, Victor W.M. van Hinsbergh, Geerten P. van Nieuw Amerongen, Physiology, Intensive care medicine, Radiology and nuclear medicine, and ICaR - Ischemia and repair
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Male ,medicine.medical_specialty ,Critical Care ,Acute Lung Injury ,Vascular permeability ,Pulmonary Edema ,Lung injury ,Critical Care and Intensive Care Medicine ,Risk Assessment ,Capillary Permeability ,Cohort Studies ,Predictive Value of Tests ,Internal medicine ,Sepsis ,Medicine ,Humans ,Hospital Mortality ,Prospective Studies ,Diffuse alveolar damage ,Prospective cohort study ,Lung ,Survival analysis ,Serum Albumin ,Aged ,Respiratory Distress Syndrome ,business.industry ,Transferrin ,Blood Proteins ,Middle Aged ,Prognosis ,Blood proteins ,Respiration, Artificial ,Survival Analysis ,Extravasation ,Intensive Care Units ,Treatment Outcome ,Anesthesia ,Predictive value of tests ,Cardiology ,Female ,business ,Biomarkers - Abstract
To evaluate the diagnostic value of plasma protein levels for pulmonary vascular permeability and acute respiratory distress syndrome. During acute lung injury and acute respiratory distress syndrome, increased vascular permeability induces protein-rich fluid extravasation. We hypothesized that plasma protein levels predict increased vascular permeability and acute respiratory distress syndrome.A prospective, observational study.Eighty-three consecutive, mechanically ventilated patients with or at risk for acute lung injury/acute respiratory distress syndrome, of whom 18 had sepsis. Patients with increased pulmonary capillary wedge pressures or central venous pressures were excluded.Patients were subjected to pulmonary capillary wedge pressure/central venous pressure-guided fluid loading with saline or colloid fluids.We measured plasma albumin and transferrin levels and determined the Gallium-transferrin pulmonary leak index, the American European Consensus Conference criteria, and the lung injury score. Measurements were performed before and after fluid loading to evaluate effects of fluid loading. Plasma albumin and transferrin levels were approximately 30% lower in acute respiratory distress syndrome than patients with acute lung injury (p.01) and patients without lung injury (p.05). Protein levels inversely related to the pulmonary leak index (standardized regression coefficient -0.28, p.001 for albumin; standardized regression coefficient -0.30, p = .003 for transferrin) and the lung injury score (standardized regression coefficient -0.19, p = .01 for albumin), independently of presence of sepsis, severity of disease, and fluid loading. Albumin and transferrin levels had a high sensitivity (77-93%) and negative predictive value (80-98%) for elevated pulmonary vascular permeability and acute respiratory distress syndrome (American European Consensus Conference criteria and lung injury score). The addition of hypoalbuminemia (17.5 g/L) and hypotransferrinemia (0.98 g/L) as criteria to the American European Consensus Conference criteria or the lung injury score increased their predictive values for elevated pulmonary vascular permeability.In critically ill patients, decreased plasma albumin and transferrin levels parallel increased pulmonary vascular permeability irrespective of underlying disease and fluid status. While normal levels help to exclude acute respiratory distress syndrome, hypoalbuminemia and hypotransferrinemia increase the diagnostic accuracy of the American European Consensus Conference criteria and lung injury score for elevated pulmonary vascular permeability.
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- 2011
156. Proteases and receptors in the recruitment of endothelial progenitor cells in neovascularization
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Anton Jan van Zonneveld, Victor W.M. van Hinsbergh, Pieter Koolwijk, R. E. Verloop, Anatomy and neurosciences, Physiology, and ICaR - Ischemia and repair
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Angiogenesis ,Clinical Biochemistry ,Immunology ,Population ,CD34 ,Neovascularization, Physiologic ,Receptors, Cell Surface ,Biology ,Endothelial progenitor cell ,Neovascularization ,Vasculogenesis ,Cell Movement ,medicine ,Immunology and Allergy ,Animals ,Humans ,Progenitor cell ,education ,education.field_of_study ,Stem Cells ,Endothelial Cells ,Cell biology ,Endothelial stem cell ,medicine.symptom ,Peptide Hydrolases - Abstract
Since the initial discovery of endothelial progenitor cells (EPC), and their promise in increasing angiogenesis and vasculogenesis, a myriad of papers have highlighted their potential application in experimental and clinical neovascularization and in tissue engineering. However, promising reports are contrasted by other studies that could not find a role for EPC in neovascularization. Presently, two types of endothelial progenitor cell populations are recognized. The first population provides early-outgrowth CD34 +/VEGFR-2 + cells, or colony-forming unit endothelial cells (CFU-EC), which represent myeloid cells with some endothelial properties, but no ability to form endothelial colonies. They can stimulate neovascularization by paracrine means, but are not incorporated in the endothelial lining themselves. The second population generates the late-outgrowth endothelial colony-forming cells (ECFC) from a very scant blood-derived cell population. ECFC have a very high proliferative potential, can insert into the endothelial lining of new blood vessels, and can also form endothelial tubes by themselves after stimulation with the proper angiogenic stimulus. This review surveys the mobilization of progenitor cells from the bone marrow, the homing of EPC (CFU-EC) to areas of neovascularization, and the participation of EPC (ECFC) in the endothelial lining of newly formed blood vessels. Specific emphasis has been placed on the role of proteases, which include serine proteases, including urokinase, L-cathepsin, and several ADAM- and matrix metalloproteinases. The specific properties of ECFC make them a potential source of cells for tissue engineering applications, but much has to be learned about their nature, origin and properties.
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- 2010
157. The Interaction of Soluble Tie2 with Angiopoietins and Pulmonary Vascular Permeability in Septic and Nonseptic Critically Ill Patients
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Geerten P. van Nieuw Amerongen, Victor W.M. van Hinsbergh, A. B. Johan Groeneveld, Melanie van der Heijden, Intensive care medicine, Physiology, and ICaR - Ischemia and repair
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Male ,Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,Critical Illness ,Acute Lung Injury ,Vascular permeability ,Gallium Radioisotopes ,Lung injury ,Critical Care and Intensive Care Medicine ,Angiopoietin ,Angiopoietin-2 ,Capillary Permeability ,chemistry.chemical_compound ,In vivo ,Internal medicine ,Sepsis ,Angiopoietin-1 ,Organometallic Compounds ,Medicine ,Humans ,Prospective Studies ,Receptor ,Lung ,Aged ,chemistry.chemical_classification ,Respiratory Distress Syndrome ,biology ,business.industry ,Transferrin ,Middle Aged ,Angiopoietin receptor ,Receptor, TIE-2 ,Vascular endothelial growth factor ,Endocrinology ,chemistry ,Immunology ,cardiovascular system ,Emergency Medicine ,biology.protein ,Female ,business - Abstract
Circulating angiopoietin (Ang) 1 may inhibit and Ang-2 may enhance pulmonary vascular permeability in septic and nonseptic patients with or at risk for acute lung injury or acute respiratory distress syndrome. We hypothesized that the soluble form of the Ang-binding Tie2 receptor (sTie2), whose shedding may be induced by vascular endothelial growth factor (VEGF) levels, may bind circulating Angs and thereby inhibit their effects on pulmonary vascular permeability. In 24 septic and 40 nonseptic mechanically ventilated patients, sTie2, Ang-1, Ang-2, and VEGF plasma levels were measured together with the pulmonary leak index (PLI) for (67)Gallium-labeled transferrin as a measure of pulmonary vascular permeability. Soluble Tie2 and VEGF levels correlated (r = 0.53, P = 0.001). Soluble Tie2 was higher in septic than in nonseptic patients (7.43 [6.57 - 8.40] vs. 5.03 [4.57 - 5.54] ng/mL; P < 0.001). Soluble Tie2 was associated with the PLI (standardized regression coefficient [beta] = 0.26; P = 0.006) but lost its association with the PLI when the Angs were included in a multivariate model. Soluble Tie2 did not affect the association between Ang-1 or Ang-2 and the PLI (beta = -0.39, P < 0.001; beta = 0.52, P < 0.001, respectively), independently of underlying disease. Although limited to correlations and associations, the clinical data support in vivo shedding of sTie2 through VEGF signaling upon pulmonary vascular injury. However, this shedding may not prevent a direct role of Angs in pulmonary vascular permeability.
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- 2010
158. Fasudil reduces monocrotaline-induced pulmonary arterial hypertension: comparison with bosentan and sildenafil
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Koen T. B. Mouchaers, Ingrid Schalij, Victor W.M. van Hinsbergh, M A de Boer, G.P. van Nieuw Amerongen, W. J. Van Der Laarse, P E Postmus, A. Vonk Noordegraaf, Pulmonary medicine, Physiology, and ICaR - Heartfailure and pulmonary arterial hypertension
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,medicine.drug_mechanism_of_action ,Sildenafil ,Heart Ventricles ,Hypertension, Pulmonary ,Vasodilator Agents ,Administration, Oral ,Blood Pressure ,Pulmonary Artery ,Piperazines ,Sildenafil Citrate ,chemistry.chemical_compound ,1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine ,Internal medicine ,medicine ,Animals ,Familial Primary Pulmonary Hypertension ,Sulfones ,Antihypertensive Agents ,Sulfonamides ,Monocrotaline ,Hypertrophy, Right Ventricular ,business.industry ,Hemodynamics ,Fasudil ,Bosentan ,medicine.disease ,Pulmonary hypertension ,Rats ,respiratory tract diseases ,Blood pressure ,medicine.anatomical_structure ,chemistry ,Purines ,Anesthesia ,cardiovascular system ,Cardiology ,Vascular resistance ,business ,Phosphodiesterase 5 inhibitor ,medicine.drug ,Artery - Abstract
Pulmonary arterial hypertension (PAH) still cannot be cured, warranting the search for novel treatments. Fasudil (a Rho kinase inhibitor) was compared with bosentan (an endothelin receptor blocker) and sildenafil (a phosphodiesterase 5 inhibitor), with emphasis on right ventricular (RV) function, in a reversal rat model of monocrotaline (MCT)-induced PAH. In addition, the effects of combining bosentan or sildenafil with fasudil were studied. MCT (40 mg·kg body weight(-1)) induced clear PAH in male Wistar rats (n = 9). After 28 days, echocardiography, RV catheterisation and histochemistry showed that cardiac frequency, stroke volume and RV contractility had deteriorated, accompanied by RV dilatation and hypertrophy, and marked pulmonary arterial wall thickening. Mean pulmonary arterial pressure and pulmonary vascular resistance increased significantly compared to healthy rats (n = 9). After 14 days, MCT-treated rats received a 14-day oral treatment with bosentan, sildenafil, fasudil or a combination of fasudil with either bosentan or sildenafil (all n = 9). All treatments preserved cardiac frequency, stroke volume and RV contractility, and reduced pulmonary vascular resistance and RV dilatation. Fasudil lowered RV systolic pressure and mean pulmonary arterial pressure significantly, by reducing pulmonary arterial remodelling, which reduced RV hypertrophy. Combining bosentan or sildenafil with fasudil had no synergistic effect. Fasudil significantly improved PAH, to a greater degree than did bosentan and sildenafil.
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- 2010
159. Driving Rho GTPase activity in endothelial cells regulates barrier integrity
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Victor W.M. van Hinsbergh, Cora M.L. Beckers, Geerten P. van Nieuw Amerongen, Physiology, and ICaR - Ischemia and repair
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Vascular Endothelial Growth Factor A ,rac1 GTP-Binding Protein ,rho GTP-Binding Proteins ,RHOA ,biology ,Thrombin ,Endothelial Cells ,RAC1 ,Hematology ,CDC42 ,GTPase ,Cell biology ,Capillary Permeability ,Intercellular Junctions ,biology.protein ,Animals ,Humans ,Signal transduction ,Lamellipodium ,cdc42 GTP-Binding Protein ,rhoA GTP-Binding Protein ,Cytoskeleton ,Filopodia ,Signal Transduction - Abstract
SummaryIn the past decade understanding of the role of the Rho GTPases RhoA, Rac1 and Cdc42 has been developed from regulatory proteins that regulate specific actin cytoskeletal structures – stress fibers, lamellipodia and filopodia – to complex integrators of cytoskeletal structures that can exert multiple functions depending on the cellular context. Fundamental to these functions are three-dimensional complexes between the individual Rho GTPases, their specific activators (GEFs) and inhibitors (GDIs and GAPs), which greatly outnumber the Rho GTPases themselves, and additional regulatory proteins. By this complexity of regulation different vasoactive mediators can induce various cytoskeletal structures that enable the endothelial cell (EC) to respond adequately. In this review we have focused on this complexity and the consequences of Rho GTPase regulation for endothelial barrier function. The permeability inducers thrombin and VEGF are presented as examples of G-protein coupled receptor- and tyrosine kinase receptormediated Rho GTPase activation, respectively. These mediators induce complex but markedly different networks of activators, inhibitors and effectors of Rho GTPases, which alter the endothelial barrier function. An interesting feature in this regulation is that Rho GTPases often have both barrier-protecting and barrier-disturbing functions. While Rac1 enforces the endothelial junctions, it becomes part of a barrier-disturbing mechanism as activator of reactive oxygen species generating NADPH oxidase. Similarly RhoA is protective under basal conditions, but becomes involved in barrier dysfunction after activation of ECs by thrombin. The challenge and promise lies in unfolding this complex regulation, as this will provide leads for new therapeutic opportunities.
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- 2010
160. Fibrin beta(15-42) domain is cryptic in intact fibrinogen: comment on the study by A. Sahni et al
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Pieter Koolwijk, Victor W.M. van Hinsbergh, Ester M. Weijers, Geerten P. van Nieuw Amerongen, Physiology, and ICaR - Ischemia and repair
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Cancer Research ,Cell membrane permeability ,biology ,Endothelium ,Chemistry ,Cell movement ,Fibrinogen ,Fibrin ,Domain (software engineering) ,Cell biology ,medicine.anatomical_structure ,Oncology ,Antigen ,Immunology ,medicine ,biology.protein ,medicine.drug - Published
- 2010
161. CD133(+) circulating haematopoietic progenitor cells predict for response to sorafenib plus erlotinib in non-small cell lung cancer patients
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Henk J. Broxterman, Laura Vroling, R R de Haas, Joline S.W. Lind, Victor W.M. van Hinsbergh, Henk M.W. Verheul, Egbert F. Smit, Medical oncology laboratory, Pulmonary medicine, Medical oncology, Physiology, CCA - Innovative therapy, and ICaR - Ischemia and repair
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Male ,Oncology ,erlotinib ,Cancer Research ,Pathology ,Lung Neoplasms ,Pyridines ,Angiogenesis ,Tyrosine-kinase inhibitor ,chemistry.chemical_compound ,HPCs ,Carcinoma, Non-Small-Cell Lung ,Antineoplastic Combined Chemotherapy Protocols ,Clinical Studies ,Medicine ,AC133 Antigen ,Benzenesulfonates ,Middle Aged ,Sorafenib ,Vascular endothelial growth factor ,Response Evaluation Criteria in Solid Tumors ,embryonic structures ,cardiovascular system ,biomarker ,Female ,Erlotinib ,medicine.drug ,Adult ,Niacinamide ,medicine.medical_specialty ,Bevacizumab ,medicine.drug_class ,CECs ,bevacizumab ,Erlotinib Hydrochloride ,Antigens, CD ,Internal medicine ,Biomarkers, Tumor ,Humans ,Lung cancer ,neoplasms ,Aged ,Glycoproteins ,business.industry ,Phenylurea Compounds ,angiogenesis inhibitors ,Hematopoietic Stem Cells ,medicine.disease ,chemistry ,Quinazolines ,Peptides ,business - Abstract
Background: Blood-based biomarkers may be particularly useful for patient selection and prediction of treatment response for angiogenesis inhibitors. Circulating endothelial cells (CECs) and haematopoietic progenitor cells (HPCs) might have a role in tumour angiogenesis and in tumour growth. Measurement of CECs and HPCs in the blood of patients could be a simple, non-invasive way to monitor or predict responses to treatment. Methods: (VEGFR2+) CECs, (CD133+) HPCs, plasma vascular endothelial growth factor (VEGF) and erythropoietin were measured in blood from 25 non-small cell lung cancer (NSCLC) patients before and during treatment with sorafenib plus erlotinib (SO/ER). In order to assess the drug specificity of changes in CECs and HPCs, 18 patients treated with bevacizumab plus erlotinib (BV/ER) and 10 patients with erlotinib (ER) monotherapy were studied. Response was measured in all patient groups by Response Evaluation Criteria in Solid Tumors (RECIST). Results: At day 7, SO/ER-treated patients showed a three-fold increase in CECs (P
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- 2010
162. Book reviews: The diversity of fish otoliths, past and present
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Victor W.M. van Hinsbergh and Victor W.M. van Hinsbergh
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In this book Dirk Nolf summarizes his half a century of study on fossil and recent fish otoliths. From the beginning of his career onwards he advocated that fossil fish otoliths cannot be interpreted well without a thorough knowledge of the otoliths of living fishes. Such knowledge not only provides information about consistent features of species and families, but also about otolith variability within species, morphological changes during development, and malformations. All this information is required for proper identification and interpretation of fossil fish otoliths. In over forty-five years Dirk Nolf built up a unique collection of Recent fish otoliths; studied fishes and their otoliths in many famous museums; and travelled around to scrutinize collections and holotypes of fossil fish otoliths. Among his many publications he reissued and extended the classical work of Chaine & Duvergier on recent fish otoliths stressing the importance of knowledge about this subject (Nolf et al., 2009).
- Published
- 2014
163. Presidential address: Society and vascular surgery[mdash ]The need for humanism and research
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Victor W.M. van Hinsbergh
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medicine.medical_specialty ,business.industry ,Presidential address ,General surgery ,medicine ,Surgery ,Humanism ,Vascular surgery ,Cardiology and Cardiovascular Medicine ,business - Published
- 1992
164. The Procoagulant Response of Cytomegalovirus Infected Endothelial Cells
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Alice Muller, Cathrien A. Bruggeman, W. Mullers, M.C.E. van Dam-Mieras, P. H. H. Bomans, and Victor W.M. van Hinsbergh
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Endothelium ,Factor X ,media_common.quotation_subject ,Hematology ,Biology ,Molecular biology ,Microbiology ,Endothelial stem cell ,chemistry.chemical_compound ,Tissue factor ,medicine.anatomical_structure ,Thrombin ,chemistry ,Plasminogen activator inhibitor-1 ,medicine ,Internalization ,Plasminogen activator ,media_common ,medicine.drug - Abstract
SummaryThe report describes the effect of an in vitro infection of human umbilical vein endothelial cells with human Cytomegalovirus (CMV). The parameters studied are cellular procoagulant activity, secretion of plasminogen activator inhibitor (PAI-1) and urokinase-type plasminogen activator (u-PA), activation and internalization of factor X and Merocyanine 540 staining.The infection does not result in an increase in PAI-1 and u-PA secretion, but it brings about a procoagulant response, which is relatively rapid compared to the tissue factor mediated response induced by inflammatory mediators. The time course and the coagulation factor dependency suggest a facilitated interaction of coagulation factors on the surface of infected cells. Chromogenic activity measurements after the addition of purified factor X and electron microscopic examination of the cells after addition of colloidal gold-factor X conjugates both point to an internalization of factor X and/or Xa after interaction with the endothelial cell surface. Merocyanine 540 staining suggests that CMV infection leads to membrane pertubations.
- Published
- 1992
165. Endothelin receptor blockade combined with phosphodiesterase-5 inhibition increases right ventricular mitochondrial capacity in pulmonary arterial hypertension
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Koen T. B. Mouchaers, Anton Vonk-Noordegraaf, Geerten P. van Nieuw Amerongen, Victor W.M. van Hinsbergh, Awal M. Hadi, Amanda M. G. Versteilen, Willem J. van der Laarse, Pieter E. Postmus, Ingrid Schalij, Pulmonary medicine, Physiology, and ICaR - Heartfailure and pulmonary arterial hypertension
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Endothelin Receptor Antagonists ,Male ,medicine.drug_mechanism_of_action ,Physiology ,Phosphodiesterase Inhibitors ,Mitochondria, Heart ,Piperazines ,Diffusion ,chemistry.chemical_compound ,Medicine ,Myocytes, Cardiac ,Sulfones ,Ultrasonography ,Sulfonamides ,Myoglobin ,Organ Size ,cGMP-specific phosphodiesterase type 5 ,cardiovascular system ,Cardiology ,Cardiology and Cardiovascular Medicine ,Endothelin receptor ,Phosphodiesterase 5 inhibitor ,medicine.drug ,medicine.medical_specialty ,Sildenafil ,Hypertension, Pulmonary ,In Vitro Techniques ,Pulmonary Artery ,Sildenafil Citrate ,Oxygen Consumption ,Physiology (medical) ,Internal medicine ,Cyclic GMP-Dependent Protein Kinases ,Animals ,Phosphodiesterase inhibitor ,Rats, Wistar ,business.industry ,Myocardium ,Body Weight ,Hemodynamics ,Bosentan ,Phosphodiesterase 5 Inhibitors ,medicine.disease ,Pulmonary hypertension ,Fibrosis ,Myocardial Contraction ,respiratory tract diseases ,Blockade ,Capillaries ,Rats ,Endocrinology ,chemistry ,Purines ,business - Abstract
Pulmonary arterial hypertension (PAH) is often treated with endothelin (ET) receptor blockade or phosphodiesterase-5 (PDE5) inhibition. Little is known about the specific effects on right ventricular (RV) function and metabolism. We determined the effects of single and combination treatment with Bosentan [an ET type A (ETA)/type B (ETB) receptor blocker] and Sildenafil (a PDE5 inhibitor) on RV function and oxidative metabolism in monocrotaline (MCT)-induced PAH. Fourteen days after MCT injection, male Wistar rats were orally treated for 10 days with Bosentan, Sildenafil, or both. RV catheterization and echocardiography showed that MCT clearly induced PAH. This was evidenced by increased RV systolic pressure, reduced cardiac output, increased pulmonary vascular resistance (PVR), and reduced RV fractional shortening. Quantitative histochemistry showed marked RV hypertrophy and fibrosis. Monotreatment with Bosentan or Sildenafil had no effect on RV systolic pressure or cardiac function, but RV fibrosis was reduced and RV capillarization increased. Combination treatment did not reduce RV systolic pressure, but significantly lowered PVR, and normalized cardiac output, RV fractional shortening, and fibrosis. Only combination treatment increased the mitochondrial capacity of the RV, as reflected by increased succinate dehydrogenase and cytochrome c oxidase activities, associated with an activation of PKG, as indicated by increased VASP phosphorylation. Moreover, significant interactions were found between Bosentan and Sildenafil on PVR, cardiac output, RV contractility, PKG activity, and mitochondrial capacity. These data indicate that the combination of Bosentan and Sildenafil may beneficially contribute to RV adaptation in PAH, not only by reducing PVR but also by acting on the mitochondria in the heart.
- Published
- 2009
166. Blood outgrowth endothelial cells from cord blood and peripheral blood: angiogenesis-related characteristics in vitro: reply to rebuttal
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P. Koolwijk, R. E. Verloop, Victor W.M. van Hinsbergh, R. T. Van Beem, J.J. Zwaginga, Anatomy and neurosciences, Physiology, ICaR - Ischemia and repair, and Landsteiner Laboratory
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Pathology ,medicine.medical_specialty ,business.industry ,Angiogenesis ,Cord blood ,Medicine ,Hematology ,business ,In vitro ,Peripheral blood - Published
- 2009
167. Role of ROCK I/II in vascular branching
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Victor W.M. van Hinsbergh, Geerten P. van Nieuw Amerongen, Physiology, and ICaR - Ischemia and repair
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medicine.medical_specialty ,Pathology ,Physiology ,business.industry ,Physiology (medical) ,Internal medicine ,Ischemic stroke ,medicine ,Cardiology ,Treatment options ,Vascular leakage ,Cardiology and Cardiovascular Medicine ,business - Abstract
the highly similar rho kinases ROCK I and II have drawn a lot of attention over the past decade as potential targets for novel treatment options for a variety of cardiovascular disorders such as (pulmonary) hypertension, ischemic stroke, and vascular leakage ([27][1]). Several previous in vivo
- Published
- 2009
168. Norepinephrine and iloprost improve barrier function of human endothelial cell monolayers: role of cAMP
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Victor W.M. van Hinsbergh and E. G. Langeler
- Subjects
medicine.medical_specialty ,Adrenergic receptor ,Physiology ,Fluorescent Antibody Technique ,Stimulation ,Umbilical Arteries ,Norepinephrine (medication) ,Norepinephrine ,1-Methyl-3-isobutylxanthine ,Internal medicine ,Cyclic AMP ,medicine ,Humans ,Iloprost ,Phentolamine ,Aorta ,Cells, Cultured ,Horseradish Peroxidase ,Barrier function ,Chemistry ,Colforsin ,Electric Conductivity ,Isoproterenol ,Cell Biology ,Propranolol ,Adenosine ,Cell biology ,Endothelial stem cell ,Kinetics ,medicine.anatomical_structure ,Endocrinology ,Endothelium, Vascular ,Venae Cavae ,Blood vessel ,medicine.drug - Abstract
The barrier function of human artery endothelial cells was improved by addition of agents that increase the cellular adenosine 3',5'-cyclic monophosphate (cAMP) concentration. Together with a decrease in the passage rate of peroxidase, an increase in the transendothelial electrical resistance was observed. A direct correlation was found between the relative increases in cellular cAMP concentration and the relative decrease in peroxidase passage after incubation of the cells with forskolin (0.25 and 2.5 microM), the beta-adrenergic agonist isoproterenol (10 microM), and the stable prostacyclin analogue iloprost (10 microM). Norepinephrine (10 microM) reduced the peroxidase passage to a much larger extent (40% reduction) than might be expected on the basis of a small increase of cAMP concentration. This small increase in cAMP (44%) was the result of interactions of norepinephrine with beta-adrenergic receptors, which increase cAMP, and alpha-adrenergic receptors, which decrease cAMP. The relatively strong reduction in permeability (also found in the presence of the alpha-adrenergic antagonist phentolamine) suggests that an additional cAMP-independent mechanism underlaid the barrier-improving effect of norepinephrine. A marked elevation of cAMP by forskolin was accompanied by a disappearance of F-actin and myosin from stress fibers. They were found diffusely spread over the cell, and F-actin in the cell periphery became prominently visible.
- Published
- 1991
169. Cells derived from omental fat tissue and used for seeding vascular prostheses are not endothelial in origin
- Author
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M.J.T. Visser, Goos N.P. van Muijen, J. Hajo van Bockel, and Victor W.M. van Hinsbergh
- Subjects
Differential centrifugation ,Pathology ,medicine.medical_specialty ,Cell type ,biology ,business.industry ,Vimentin ,Umbilical vein ,Von Willebrand factor ,biology.protein ,Collagenase ,Medicine ,Surgery ,Desmin ,Cardiology and Cardiovascular Medicine ,business ,Percoll ,medicine.drug - Abstract
The use of microvascular endothelial cells derived from omental tissue has been advocated to seed vascular grafts with autologous endothelial cells in high density. The purpose of our study was to evaluate the precise origin of these cells. Therefore we have compared cellular characteristics of these cells with those of endothelial cells isolated by collagenase treatment of human umbilical veins. The omental cells were isolated from omental tissue from four different patients by incubation in a collagenase-dispase solution. Part of the material was processed by Percoll density gradient centrifugation in an attempt to purify the isolates. Cellular characteristics of both types of cells were determined by studying the morphologic features of the cells and by determining the presence of von Willebrand factor, antigens EN-4 and PAL-E specific for endothelial cells, cytokeratins 8 and 18, vimentin and desmin, and uptake of diI-acetylated low-density lipoprotein. Epitheloid cells from omental tissue, isolated after collagenase treatment and either purified or nonpurified by Percoll density gradient centrifugation, differed from human umbilical vein endothelial cells with respect to the presence of surface microvilli, the expression of von Willebrand factor, EN-4 and PAL-E, and the presence of cytokeratins 8 and 18 and desmin. von Willebrand factor (in a granular staining pattern) and the presence of EN-4 and PAL-E were only detected in human umbilical vein endothelial cells. Vimentin was present in both cell types, whereas cytokeratins 8 and 18 and desmin were only present in cells derived from omentum. From these data we conclude that the so called microvascular endothelial cells from omentum are not endothelial but mesothelial in nature. (J VASC SURG 1991;13:373-81.)
- Published
- 1991
170. Effect of propionyl-L-carnitine on human endothelial cells
- Author
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Victor W.M. van Hinsbergh and M. A. Scheffer
- Subjects
Endothelium ,Cell ,chemistry.chemical_element ,Calcium ,Biology ,complex mixtures ,chemistry.chemical_compound ,Carnitine ,Lactate dehydrogenase ,medicine ,Humans ,Pharmacology (medical) ,Viability assay ,Acetylcarnitine ,Cells, Cultured ,Pharmacology ,Calcium metabolism ,General Medicine ,Molecular biology ,Cell biology ,Lipoproteins, LDL ,medicine.anatomical_structure ,chemistry ,lipids (amino acids, peptides, and proteins) ,Endothelium, Vascular ,Cardiology and Cardiovascular Medicine ,medicine.drug - Abstract
A possible protective effect of propionyl-L-carnitine on human endothelial cells was studied both under basal culture conditions and in the presence of agents capable of influencing oxidative damage, such as glucose/glucose oxidase and oxidized low-density lipoproteins. Propionyl-L-carnitine had no significant effect on the observed decline in various parameters of cell viability, e.g., cell detachment, release of lactate dehydrogenase, and the rate of protein synthesis. Propionyl-L-carnitine progressively decreased the fluorescence intensity in fura-2-loaded endothelial cells obtained during excitation at 340 nm. A similar effect was observed with propionyl-L-carnitine and acetyl-L-carnitine, but not with L-carnitine and D-carnitine. These results suggest that propionyl-L-carnitine and acetyl-L-carnitine decrease the cytoplasmic calcium level in endothelial cells.
- Published
- 1991
171. Extrinsic Activation of Human Coagulation Factors IX and X on the Endothelial Surface
- Author
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Hanneke H Reinalda-Poot, Ramon W Mohanlal, Victor W.M. van Hinsbergh, Victor J. J. Bom, and Rogier M. Bertina
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Factor VII ,Chemistry ,Factor X ,Hematology ,Umbilical vein ,Factor IXa ,chemistry.chemical_compound ,Tissue factor ,Thrombin ,Coagulation ,Biochemistry ,medicine ,Biophysics ,Factor IX ,medicine.drug - Abstract
SummaryIn previous kinetic studies, the catalytic efficiency of the activation of human coagulation factors IX and X by factor VIIa in the presence of purified tissue factor apoprotein was found to be essentially equal. These activation reactions were now studied on the surface of human umbilical vein endothelial cells. The cells were stimulated with endotoxin to express tissue factor. This tissue factor activity was saturable with factor VIIa and could be inhibited by rabbit antibodies against human tissue factor apoprotein. Only stimulated cells supported factor VIIa activity. No difference in the reactivity of factor VII and VIIa was observed in the presence of factor X, due to rapid feedback activation of factor VII by factor Xa. However, the activation of factor IX by factor VII shows a 10 min lag-phase, which reflects that the activation of factor VII by factor IXa is a less efficient process. The kinetic parameters for the factor VIIa dependent activation of factor IX and factor X on the endothelial surface were: Km 0.09 εM, Vmax 0.13 pmol/min, and Km 0.071 εM, Vmax 0.41 pmol/min, respectively. The same ratio between the Vmax for factor X and factor IX activation was observed as in a cell free system. However, the Km of factor IX was 4-fold higher on the endothelial surface than in the cell free system. Together, these kinetic parameters will favour factor X activation 5-fold over factor IX activation at physiological concentrations of these proteins.The activation of factor X by factor VIIa on the endothelial surface was characterized by a short lag-phase, which was absent in factor IX activation. Further, both the activation of factor X and factor IX were down regulated by factor Xa.
- Published
- 1991
172. The angiopoietin-Tie2 system as a therapeutic target in sepsis and acute lung injury
- Author
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Geerten P. van Nieuw Amerongen, Sunita Chedamni, Melanie van der Heijden, A.B. Johan Groeneveld, Victor W.M. van Hinsbergh, Intensive care medicine, Physiology, and ICaR - Ischemia and repair
- Subjects
ARDS ,Clinical Biochemistry ,Acute Lung Injury ,Inflammation ,Lung injury ,TIE1 ,Angiopoietin ,Sepsis ,Drug Discovery ,medicine ,Humans ,Diffuse alveolar damage ,Pharmacology ,integumentary system ,biology ,business.industry ,medicine.disease ,Angiopoietin receptor ,Receptor, TIE-2 ,embryonic structures ,Immunology ,cardiovascular system ,biology.protein ,Molecular Medicine ,medicine.symptom ,business ,Angiopoietins ,circulatory and respiratory physiology - Abstract
Sepsis and acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are life-threatening syndromes characterised by inflammation and increased vascular permeability. Amongst other factors, the angiopoietin-tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (Tie2) system is involved.To explore whether the angiopoietin-Tie2 system provides suitable targets for the treatment of sepsis and ALI/ARDS.Original experimental and patient studies on angiopoietins and sepsis/endotoxemia, inflammation, lung injury, hyperpermeability, apoptosis, organ functions and vital outcomes were reviewed.The angiopoietin-Tie2 system controls the responsiveness of the endothelium to inflammatory, hyperpermeability, apoptosis and vasoreactive stimuli. Angiopoietin-2 provokes inflammation and vascular hyperpermeability, while angiopoietin-1 has a protective effect. Targeted angiopoietin-2 inhibition with RNA aptamers or blocking antibodies is a potential anti-inflammatory and anti-vascular hyperpermeability strategy in the treatment of sepsis and ALI/ARDS.
- Published
- 2008
173. The basement membrane of intramyocardial capillaries is thickened in patients with acute myocardial infarction
- Author
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Hans W.M. Niessen, Paul A.J. Krijnen, Jan Fritz, Victor W.M. van Hinsbergh, Frank R. W. van de Goot, Walter Paulus, Marieke D. Spreeuwenberg, Mark P.V. Begieneman, Pathology, Physiology, Epidemiology and Data Science, and ICaR - Ischemia and repair
- Subjects
Adult ,Male ,medicine.medical_specialty ,Physiology ,Heart Ventricles ,Severity of Illness Index ,Basement Membrane ,Young Adult ,Internal medicine ,medicine ,Animals ,Humans ,In patient ,cardiovascular diseases ,Myocardial infarction ,Anterior Wall Myocardial Infarction ,Aged ,Basement membrane ,Aged, 80 and over ,business.industry ,Coronary Stenosis ,Middle Aged ,medicine.disease ,Coronary Vessels ,Coronary heart disease ,Capillaries ,Rats ,Coronary arteries ,Stenosis ,Disease Models, Animal ,Microscopy, Electron ,medicine.anatomical_structure ,Case-Control Studies ,Circulatory system ,Cardiology ,Female ,Autopsy ,Cardiology and Cardiovascular Medicine ,business ,Blood vessel - Abstract
Background: Atherosclerotic epicardial coronary arteries are a major cause of acute myocardial infarction (AMI). Recently, we found that intramyocardial capillaries may also play a role in AMI induction. We have now evaluated intramyocardial capillaries using ultrastructural analysis in AMI patients. Methods: 43 AMI patients (with AMI in the left ventricle) and 27 controls. No patient included in either group had diabetes mellitus. Basement membrane (BM) thickness of intramyocardial capillaries was determined using electron microscopy. BM thickness was also studied in a rat AMI model. Results: BM thickness in the left ventricle of AMI patients was significantly higher than in controls (102 ± 9 vs. 77 ± 4 nm; p = 0.016). This increase was not found in the right ventricle. In AMI patients, BM thickness was already increased in recent infarcts and did not increase further with infarct age. No correlation was found between BM thickness and the amount of stenosis or atherosclerotic plaque stability of epicardial coronary arteries. In addition, BM thickness did not differ between control rats and AMI rats. Conclusions: These results suggest that BM thickening constitutes significant changes in the intramyocardial capillaries in patients that develop AMI. Also these changes are likely to occur prior to the induction of AMI.
- Published
- 2008
174. Protein kinase C theta activation induces insulin-mediated constriction of muscle resistance arteries
- Author
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Coen D.A. Stehouwer, Wineke Bakker, Yvo M. Smulders, Etto C. Eringa, Victor W.M. van Hinsbergh, Pieter Sipkema, Erik H. Serné, Interne Geneeskunde, RS: NUTRIM - R1 - Metabolic Syndrome, RS: CARIM School for Cardiovascular Diseases, Physiology, Internal medicine, and ICaR - Ischemia and repair
- Subjects
medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Palmitic Acid ,Vasodilation ,Biology ,Nitric Oxide ,Mice ,Insulin resistance ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Humans ,Insulin ,Muscle, Skeletal ,Protein kinase B ,Protein Kinase C ,Protein kinase C ,Mitogen-Activated Protein Kinase 6 ,Mice, Knockout ,Mitogen-Activated Protein Kinase 3 ,Endothelin-1 ,Arteries ,medicine.disease ,Isoenzymes ,Insulin receptor ,Endocrinology ,Protein Kinase C-theta ,Vasoconstriction ,biology.protein ,medicine.symptom ,Proto-Oncogene Proteins c-akt ,Myograph - Abstract
OBJECTIVE—Protein kinase C (PKC) θ activation is associated with insulin resistance and obesity, but the underlying mechanisms have not been fully elucidated. Impairment of insulin-mediated vasoreactivity in muscle contributes to insulin resistance, but it is unknown whether PKCθ is involved. In this study, we investigated whether PKCθ activation impairs insulin-mediated vasoreactivity and insulin signaling in muscle resistance arteries. RESEARCH DESIGN AND METHODS—Vasoreactivity of isolated resistance arteries of mouse gracilis muscles to insulin (0.02–20 nmol/l) was studied in a pressure myograph with or without PKCθ activation by palmitic acid (PA) (100 μmol/l). RESULTS—In the absence of PKCθ activation, insulin did not alter arterial diameter, which was caused by a balance of nitric oxide–dependent vasodilator and endothelin-dependent vasoconstrictor effects. Using three-dimensional microscopy and Western blotting of muscle resistance arteries, we found that PKCθ is abundantly expressed in endothelium of muscle resistance arteries of both mice and humans and is activated by pathophysiological levels of PA, as indicated by phosphorylation at Thr538 in mouse resistance arteries. In the presence of PA, insulin induced vasoconstriction (21 ± 6% at 2 nmol/l insulin), which was abolished by pharmacological or genetic inactivation of PKCθ. Analysis of intracellular signaling in muscle resistance arteries showed that PKCθ activation reduced insulin-mediated Akt phosphorylation (Ser473) and increased extracellular signal–related kinase (ERK) 1/2 phosphorylation. Inhibition of PKCθ restored insulin-mediated vasoreactivity and insulin-mediated activation of Akt and ERK1/2 in the presence of PA. CONCLUSIONS—PKCθ activation induces insulin-mediated vasoconstriction by inhibition of Akt and stimulation of ERK1/2 in muscle resistance arteries. This provides a new mechanism linking PKCθ activation to insulin resistance.
- Published
- 2008
175. Angiopoietin-2, permeability oedema, occurrence and severity of ALI/ARDS in septic and non-septic critically ill patients
- Author
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Victor W.M. van Hinsbergh, G.P. van Nieuw Amerongen, M. van der Heijden, P. Koolwijk, A. B. J. Groeneveld, Intensive care medicine, Physiology, and ICaR - Ischemia and repair
- Subjects
Pulmonary and Respiratory Medicine ,Male ,Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,ARDS ,Endothelium ,medicine.medical_treatment ,Critical Illness ,Pulmonary Edema ,Lung injury ,Gastroenterology ,Sepsis ,Angiopoietin-2 ,chemistry.chemical_compound ,Von Willebrand factor ,Internal medicine ,von Willebrand Factor ,Angiopoietin-1 ,Medicine ,Humans ,Prospective Studies ,Aged ,Mechanical ventilation ,Respiratory Distress Syndrome ,biology ,business.industry ,respiratory system ,Middle Aged ,medicine.disease ,Vascular endothelial growth factor ,medicine.anatomical_structure ,chemistry ,Anesthesia ,Circulatory system ,cardiovascular system ,biology.protein ,Female ,business ,circulatory and respiratory physiology - Abstract
Angiopoietin-2 and vascular endothelial growth factor (VEGF) may impair vascular barrier function while angiopoietin-1 may protect it. It was hypothesised that circulating angiopoietin-2 is associated with pulmonary permeability oedema and severity of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) during septic or non-septic critical illness.Plasma levels of angiopoietin-1 and angiopoietin-2 were measured in mechanically ventilated patients (24 with sepsis, 88 without sepsis), together with the pulmonary leak index (PLI) for 67-gallium-labelled transferrin and extravascular lung water (EVLW) by transpulmonary thermal-dye dilution as measures of pulmonary permeability and oedema, respectively. ALI/ARDS was characterised by consensus criteria and the lung injury score (LIS). Plasma VEGF and von Willebrand factor (VWF) levels were assayed.Angiopoietin-2, VWF, PLI, EVLW and LIS were higher in patients with sepsis than in those without sepsis and higher in patients with ALI/ARDS (n = 10/12 in sepsis, n = 19/8 in non-sepsis) than in those without. VEGF was also higher in patients with sepsis than in those without. Patients with high PLI, regardless of EVLW, had higher angiopoietin-2 levels than patients with normal PLI and EVLW. Angiopoietin-2 correlated with the PLI, LIS and VWF levels (minimum r = 0.34, p0.001) but not with EVLW. Angiopoietin-2 and VWF were predictive for ARDS in receiver operating characteristic curves (minimum area under the curve = 0.69, p = 0.006). Angiopoietin-1 and VEGF did not relate to the permeability oedema of ALI/ARDS.Circulating angiopoietin-2 is associated with pulmonary permeability oedema, occurrence and severity of ALI/ARDS in patients with and without sepsis. The correlation of angiopoietin-2 with VWF suggests activated endothelium as a common source.
- Published
- 2008
176. Thrombin-induced endothelial barrier disruption in intact microvessels: role of RhoA/Rho kinase-myosin phosphatase axis
- Author
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Etto C. Eringa, R.J.P. Musters, Victor W.M. van Hinsbergh, Pieter Sipkema, G. P. van Nieuw Amerongen, Physiology, and ICaR - Ischemia and repair
- Subjects
Umbilical Veins ,Endothelium ,Physiology ,Phosphatase ,macromolecular substances ,Biology ,Myosin-Light-Chain Phosphatase ,Thrombin ,Myosin ,medicine ,Concanavalin A ,Animals ,Humans ,Rats, Wistar ,Cytoskeleton ,Rho-associated protein kinase ,Barrier function ,rho-Associated Kinases ,Microcirculation ,Cell Biology ,Cell biology ,Rats ,medicine.anatomical_structure ,Myosin-light-chain phosphatase ,Endothelium, Vascular ,rhoA GTP-Binding Protein ,medicine.drug - Abstract
Endothelial hyperpermeability is regulated by a myosin light chain-2 (MLC2) phosphorylation-dependent contractile mechanism. Thrombin is a potent inducer of hyperpermeability of cultured monolayers of endothelial cells (ECs) via Rho kinase-mediated MLC2-phosphorylation. The aim of the present study was to investigate the effects of thrombin on in situ endothelial morphology and barrier integrity. Cytoskeletal dynamics, regions of paracellular flux, and MLC2-phosphorylation of ECs were visualized by digital three-dimensional imaging microscopy of pressurized rat kidney arterioles. Myosin phosphatase targeting subunit (MYPT1)-phosphorylation was used as a surrogate marker for Rho kinase activity. Thrombin induced the formation of F-actin filaments in ECs in situ and rounding of the ECs in the absence of obvious formation of gaps between ECs. These changes were accompanied by an increase in MLC2 phosphorylation and a decrease in barrier integrity. In vitro analysis revealed that Rho kinase activity on F-actin filaments was associated with a contractile response that enhanced opening of the barrier. Rho kinase activity was not detectable on F-actin filaments induced by histamine, an inducer of a more transient hyperpermeability response. Inhibition of the myosin phosphatase mimicked the effects of thrombin on barrier function. The thrombin-induced changes in in situ MLC2 phosphorylation and barrier function were Rho kinase dependent. These data demonstrate a direct effect of thrombin on EC morphology and barrier integrity in intact microvessels. Furthermore, they establish an important contribution of enhanced Rho kinase activity to the development of prolonged but not transient types of endothelial barrier dysfunction.
- Published
- 2008
177. Progress of fibrinolysis during tumor necrosis factor infusions in humans. Concomitant increase in tissue-type plasminogen activator, plasminogen activator inhibitor type-1, and fibrin(ogen) degradation products
- Author
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Victor W.M. van Hinsbergh, Kenneth A. Bauer, Matthew L. Sherman, Willem Nieuwenhuizen, Cornelis Kluft, G. Dooijewaard, and Teake Kooistra
- Subjects
medicine.medical_specialty ,biology ,Plasmin ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Tissue plasminogen activator ,Fibrin ,chemistry.chemical_compound ,Endocrinology ,Thrombin ,chemistry ,Plasminogen activator inhibitor-1 ,Internal medicine ,Fibrinolysis ,Plasminogen Inactivators ,medicine ,biology.protein ,business ,Plasminogen activator ,medicine.drug - Abstract
Several investigators have reported that tumor necrosis factor (TNF) can alter the production of plasminogen activator type-1 (PAI-1) and plasminogen activators (PAs) by endothelial cells in vitro. We have examined the in vivo effects of recombinant human TNF administration on fibrinolysis as assessed by parameters in plasma during a 24-hour period of continuous TNF infusion to 17 cancer patients with active disease. The plasma levels of PAI activity increased sevenfold after 3 and 24 hours of TNF infusion. This was the result of an increase of PAI-1 antigen; PAI-2 antigen was not detectable. Plasma concentrations of tissue-type PA (t-PA) antigen increased twofold to fivefold after 3 and 24 hours of TNF infusion, whereas urokinase-type PA antigen levels in plasma remained unaltered. After 3 hours of TNF infusion the plasma levels of α2-antiplasmin were slightly decreased, 5% on average, suggesting that fibrinolysis continued. After 24 hours of TNF infusion a highly significant increase in fibrin- plus fibrinogen-degradation products, and separately of fibrin degradation products and fibrinogen degradation products, was found. This indicates that fibrinolysis persisted, at least partly, in the presence of high levels of PAI activity. Whereas PAI-1 production increased, t-PA production by human endothelial cells in vitro remains unaltered or even decreases on TNF addition. It has been shown previously that TNF infusion in our patients results in thrombin and fibrin generation. Therefore, it is possible that thrombin, not TNF, is the actual stimulus for t-PA production in our patients. We speculate that fibrin is formed during TNF infusions and that plasmin is generated by t-PA action immediately on the initial formation of (soluble) fibrin molecules. Such a process may explain the generation of degradation products of both fibrin and fibrinogen during infusion of TNF in patients. Chemicals/CAS: plasminogen activator inhibitor 1, 140208-23-7; tissue plasminogen activator, 105913-11-9; alpha-Macroglobulins; Fibrin Fibrinogen Degradation Products; Plasmin, EC 3.4.21.7; plasmin-alpha(2)-macroglobulin complex; Plasminogen Inactivators; Recombinant Proteins; Tissue Plasminogen Activator, EC 3.4.21.68; Tumor Necrosis Factor; Urinary Plasminogen Activator, EC 3.4.21.73
- Published
- 1990
178. Tumor necrosis factor induces the production of urokinase-type plasminogen activator by human endothelial cells
- Author
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E.A. van den Berg, Victor W.M. van Hinsbergh, G. Dooijewaard, and Walter Fiers
- Subjects
Urokinase ,medicine.medical_specialty ,Plasmin ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Cell biology ,Endothelial stem cell ,chemistry.chemical_compound ,Endocrinology ,Cytokine ,chemistry ,Internal medicine ,Plasminogen activator inhibitor-1 ,Fibrinolysis ,medicine ,Tumor necrosis factor alpha ,Plasminogen activator ,medicine.drug - Abstract
Endothelial cells play an important role in the regulation of fibrinolysis by the production of several key regulatory proteins. The cytokines tumor necrosis factor (TNF), lymphotoxin, and interleukin-1 (IL-1), but not interleukin-6, increase the production of plasminogen activator inhibitor-1 (PAI-1) by endothelial cells, whereas they have no stimulatory effect on the production of tissue-type plasminogen activator (t-PA). Primary cultures of human endothelial cells release very little urokinase-type plasminogen activator (u-PA). We report here that TNF and lymphotoxin induce, in a concentration-dependent way, the production of both cellular and secreted u-PA antigen in primary and subcultured human endothelial cells. The TNF-induced increase was accompanied by a more than 10-fold increase in u-PA mRNA. Upon stimulation of early passage umbilical vein endothelial cells by TNF, u- PA was predominantly secreted at the basolateral side, whereas PAI activity and t-PA were found in more equal amounts at the apical and basolateral sides of the cell monolayers. TNF-stimulated u-PA secretion by subcultured human aorta endothelial cells showed only a marginal polarity. The u-PA antigen was present in a plasmin-activatable form (single chain u-PA) and in a nonactivatable form (probably u-PA: PAI-1 complex). During the induction of u-PA by TNF, the ratio between plasmin-activatable u-PA and total u-PA decreased markedly. This may indicate that TNF also increases the degree of u-PA activation. The parallel induction of the synthesis and secretion of both u-PA and PAI- 1 by endothelial cells adds a new aspect to the alterations of the fibrinolytic system caused by inflammatory mediators. This aspect may be significant for the regulation of cell-associated and interstitial plasminogen activator activity.
- Published
- 1990
179. Homocysteine affects cardiomyocyte viability:concentration-dependent effects on reversible flip-flop, apoptosis and necrosis
- Author
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Victor W.M. van Hinsbergh, Paul A.J. Krijnen, Cornelis Jakobs, Desirée E.C. Smith, Alice Muller, Hans W.M. Niessen, Christof Meischl, Jan A. Rauwerda, Cindy P. E. Giroth, Jessica A. Sipkens, Coen D.A. Stehouwer, Marieke D. Spreeuwenberg, Yvo M. Smulders, Saskia A. G. M. Cillessen, René J. P. Musters, Dirk Roos, Sociale Geneeskunde, Metamedica, Interne Geneeskunde, RS: NUTRIM School of Nutrition and Translational Research in Metabolism, RS: NUTRIM - R1 - Metabolic Syndrome, RS: CARIM School for Cardiovascular Diseases, Pathology, AGEM - Re-generation and cancer of the digestive system, AGEM - Digestive immunity, CCA - Cancer biology, Internal medicine, Laboratory Medicine, NCA - Brain mechanisms in health and disease, AGEM - Inborn errors of metabolism, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Epidemiology and Data Science, Physiology, Surgery, and Landsteiner Laboratory
- Subjects
Cancer Research ,S-Adenosylmethionine ,Necrosis ,Homocysteine ,Clinical Biochemistry ,Pharmaceutical Science ,Apoptosis ,Mitochondria, Heart ,chemistry.chemical_compound ,Adenosine Triphosphate ,Membrane fluidity ,Myocytes, Cardiac ,Cells, Cultured ,Phospholipids ,Cardiomyocytes ,Membrane Potential, Mitochondrial ,Membrane Glycoproteins ,Caspase 3 ,S-Adenosylhomocysteine ,NADPH Oxidase 2 ,medicine.symptom ,medicine.medical_specialty ,Cell Survival ,Membrane Fluidity ,Heart failure ,Biology ,Models, Biological ,Internal medicine ,medicine ,Animals ,Risk factor ,Biochemistry, medical ,Pharmacology ,Original Paper ,Dose-Response Relationship, Drug ,Biochemistry (medical) ,Cell Membrane ,NADPH Oxidases ,Cell Biology ,medicine.disease ,Hyperhomocysteinaemia ,Rats ,Endocrinology ,chemistry ,Gene Expression Regulation ,Oxidant stress ,Adenosine triphosphate ,Protein Processing, Post-Translational - Abstract
BACKGROUND: Hyperhomocysteinaemia (HHC) is thought to be a risk factor for cardiovascular disease including heart failure. While numerous studies have analyzed the role of homocysteine (Hcy) in the vasculature, only a few studies investigated the role of Hcy in the heart. Therefore we have analyzed the effects of Hcy on isolated cardiomyocytes.METHODS: H9c2 cells (rat cardiomyoblast cells) and adult rat cardiomyocytes were incubated with Hcy and were analyzed for cell viability. Furthermore, we determined the effects of Hcy on intracellular mediators related to cell viability in cardiomyocytes, namely NOX2, reactive oxygen species (ROS), mitochondrial membrane potential (DeltaPsi (m)) and ATP concentrations.RESULTS: We found that incubation of H9c2 cells with 0.1 mM D,L-Hcy (= 60 microM L-Hcy) resulted in an increase of DeltaPsi (m) as well as ATP concentrations. 1.1 mM D,L-Hcy (= 460 microM L-Hcy) induced reversible flip-flop of the plasma membrane phospholipids, but not apoptosis. Incubation with 2.73 mM D,L-Hcy (= 1.18 mM L-Hcy) induced apoptosis and necrosis. This loss of cell viability was accompanied by a thread-to-grain transition of the mitochondrial reticulum, ATP depletion and nuclear NOX2 expression coinciding with ROS production as evident from the presence of nitrotyrosin residues. Notably, only at this concentration we found a significant increase in S-adenosylhomocysteine which is considered the primary culprit in HHC.CONCLUSION: We found concentration-dependent effects of Hcy in cardiomyocytes, varying from induction of reversible flip-flop of the plasma membrane phospholipids, to apoptosis and necrosis.
- Published
- 2007
180. Pulmonary embolism causes endomyocarditis in the human heart
- Author
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Victor W.M. van Hinsbergh, F.R.W. van der Goot, Mark P.V. Begieneman, I.A.C. van der Bilt, A. Vonk Noordegraaf, Marieke D. Spreeuwenberg, H.W.M. Niessen, Walter Paulus, Frans C. Visser, Pathology, Cardiology, Pulmonary medicine, Epidemiology and Data Science, Physiology, and ICaR - Heartfailure and pulmonary arterial hypertension
- Subjects
Adult ,Male ,medicine.medical_specialty ,Pathology ,Myocarditis ,Heart Diseases ,Heart Ventricles ,Hypertension, Pulmonary ,Internal medicine ,medicine ,Humans ,Lymphocytes ,Myocytolysis ,Aged ,Aged, 80 and over ,Endocarditis ,business.industry ,Macrophages ,Thrombosis ,Middle Aged ,medicine.disease ,Pulmonary hypertension ,Pulmonary embolism ,medicine.anatomical_structure ,Ventricle ,Heart failure ,Circulatory system ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business ,Pulmonary Embolism ,Granulocytes - Abstract
BACKGROUND: Pulmonary embolism (PE) is a significant cause of morbidity and mortality. In a recent study in patients with PE, an increased level of macrophages was found in the right ventricle.OBJECTIVE: To evaluate the presence of inflammatory cells, myocytolysis and intracavitary thrombi in the left and right ventricle of patients who died because of PE as a putative new source of heart failure.PATIENTS AND METHODS: 22 patients with PE were studied. For comparison, eight controls and 11 patients who died of chronic pulmonary hypertension (PHT) were used. Slides of the left and right ventricle were stained with antibodies, identifying neutrophilic granulocytes, lymphocytes and macrophages, which were subsequently quantified. Myocytolysis was visualised using complement staining. Thrombi were identified by conventional staining.RESULTS: Compared with controls, in patients with PE a significant increase in extravascular localisation of all three inflammatory cells was found both in the right and left ventricle, coinciding with myocytolysis, indicative for myocarditis. No increase in inflammatory cells was found in patients with PHT. Endocardial cellular infiltration was also found, partly coinciding with the presence of ventricular thrombi.CONCLUSIONS: In patients with PE, endomyocarditis and intracavitary thrombi in the left and right ventricle were found. These abnormalities may be an additional new explanation for the observed cardiac enzyme release and functional abnormalities of the heart in these patients and may contribute to the morbidity and mortality of the disease.
- Published
- 2007
181. Argpyrimidine-modified Heat shock protein 27 in human non-small cell lung cancer: a possible mechanism for evasion of apoptosis
- Author
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Victor W.M. van Hinsbergh, René J. P. Musters, Jeroen W. J. van Heijst, Klaas Hoekman, Hans W.M. Niessen, Casper G. Schalkwijk, Pathology, Physiology, Medical oncology, Laboratory Medicine, and Human genetics
- Subjects
Glycation End Products, Advanced ,Ornithine ,Cancer Research ,Lung Neoplasms ,Cell ,Apoptosis ,Enzyme-Linked Immunosorbent Assay ,Adenocarcinoma ,chemistry.chemical_compound ,Hsp27 ,Carcinoma, Non-Small-Cell Lung ,medicine ,Tumor Cells, Cultured ,Humans ,Lung cancer ,Heat-Shock Proteins ,biology ,Caspase 3 ,Methylglyoxal ,medicine.disease ,Squamous carcinoma ,medicine.anatomical_structure ,Glucose ,Pyrimidines ,Oncology ,chemistry ,Biochemistry ,Caspases ,Cancer cell ,Cancer research ,biology.protein ,Carcinoma, Squamous Cell ,Glycolysis - Abstract
Tumors generally display a high glycolytic rate. One consequence of increased glycolysis is the non-enzymatic glycation of proteins leading to the formation of advanced glycation end-products (AGEs). Therefore, we studied the presence of AGEs in non-small cell lung cancer and consequences thereof. We show the presence of two AGEs, i.e. the major AGE N(epsilon)-(carboxymethyl)lysine (CML) and the methylglyoxal-arginine adduct argpyrimidine, in human non-small cell lung cancer tissues by immunohistochemistry. We found in squamous cell carcinoma and adenocarcinoma tissues a strong CML positivity in both tumour cells and tumour-surrounding stroma. In contrast, argpyrimidine positivity was predominantly found in tumor cells and was strong in squamous cell carcinomas, but only weak in adenocarcinomas (2.6+/-0.5 vs. 1.2+/-0.4, respectively; P
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- 2006
182. N(epsilon)-(carboxymethyl)lysine depositions in intramyocardial blood vessels in human and rat acute myocardial infarction: a predictor or reflection of infarction?
- Author
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C.A. Visser, Alexi Baidoshvili, W. Stooker, Victor W.M. van Hinsbergh, C. Ciurana, P.A.J. Krijnen, H.W.M. Niessen, Chris J.L.M. Meijer, Casper G. Schalkwijk, Remco Nijmeijer, F.C. Visser, Leon Eijsman, W. Bleeker, Koba Kupreishvili, C. E. Hack, Pathology, ACS - Heart failure & arrhythmias, ACS - Atherosclerosis & ischemic syndromes, AII - Inflammatory diseases, Cardiology, Cardio-thoracic surgery, Physiology, Internal medicine, Laboratory Medicine, Human genetics, Other departments, and Landsteiner Laboratory
- Subjects
Male ,medicine.medical_specialty ,Myocarditis ,Time Factors ,Heart disease ,Endothelium ,Myocardial Infarction ,Infarction ,Myocardial Reperfusion ,Risk Factors ,Internal medicine ,Diabetes mellitus ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Myocardial infarction ,cardiovascular diseases ,neoplasms ,Aged ,Peroxidase ,business.industry ,Vascular disease ,Lysine ,Endothelial Cells ,Middle Aged ,medicine.disease ,Prognosis ,Coronary Vessels ,Immunohistochemistry ,Rats ,Coronary arteries ,Oxidative Stress ,medicine.anatomical_structure ,Cardiology ,cardiovascular system ,Female ,Cardiology and Cardiovascular Medicine ,business ,E-Selectin - Abstract
Objective— Advanced glycation end products (AGEs), such as N ε -(carboxymethyl)lysine (CML), are implicated in vascular disease. We previously reported increased CML accumulation in small intramyocardial blood vessels in diabetes patients. Diabetes patients have an increased risk for acute myocardial infarction (AMI). Here, we examined a putative relationship between CML and AMI. Methods and Results— Heart tissue was stained for CML, myeloperoxidase, and E-selectin in AMI patients (n=26), myocarditis patients (n=17), and control patients (n=15). In AMI patients, CML depositions were 3-fold increased compared with controls in the small intramyocardial blood vessels and predominantly colocalized with activated endothelium (E-selectin–positive) both in infarction and noninfarction areas. A trend of increased CML positivity of the intima of epicardial coronary arteries did not reach significance in AMI patients. In the rat heart AMI model, CML depositions were undetectable after 24 hours of reperfusion, but became clearly visible after 5 days of reperfusion. In line with an inflammatory contribution, human myocarditis was also accompanied by accumulation of CML on the endothelium of intramyocardial blood vessels. Conclusions— CML, present predominantly on activated endothelium in small intramyocardial blood vessels in patients with AMI, might reflect an increased risk for AMI rather than being a result of AMI.
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- 2006
183. Hypercholesterolemia reduces collateral artery growth more dominantly than hyperglycemia or insulin resistance in mice
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J. Hajo van Bockel, Paul H.A. Quax, Victor W.M. van Hinsbergh, Peter J. Voshol, Paul H.C. Eilers, Robert E. Verloop, Margreet de Vries, and Vincent van Weel
- Subjects
Blood Glucose ,Male ,medicine.medical_specialty ,Apolipoprotein B ,medicine.medical_treatment ,Hypercholesterolemia ,Apolipoprotein E3 ,Collateral Circulation ,Neovascularization, Physiologic ,Hyperlipidemias ,Mice, Inbred Strains ,Diabetes Mellitus, Experimental ,Mice ,Insulin resistance ,Apolipoproteins E ,Ischemia ,Internal medicine ,Diabetes mellitus ,medicine ,Hyperinsulinemia ,Animals ,Insulin ,Artery occlusion ,NOD mice ,biology ,business.industry ,Arteries ,medicine.disease ,Lipids ,Hindlimb ,Endocrinology ,Cholesterol ,Hyperglycemia ,Acute Disease ,biology.protein ,Arteriogenesis ,Insulin Resistance ,Cardiology and Cardiovascular Medicine ,business - Abstract
Objective— Collateral artery development (arteriogenesis), a vital compensatory mechanism in patients with arterial obstructive disease, may be deregulated by vascular risk factors, eg, diabetes or hypercholesterolemia. Here, we compared the effects of either disturbed glucose metabolism or disturbed lipid metabolism on arteriogenesis. Methods and Results— Femoral artery occlusion was performed in streptozotocin(STZ)-treated mice, nonobese diabetic (NOD) mice, and insulin-resistant Ob/Ob mice on regular diet, and APOE3*Leiden mice on different hypercholesterolemic diets. Angiography and laser Doppler perfusion analysis of hindlimbs were performed postoperatively. Surprisingly, angiographic arteriogenesis was not impaired in diabetic and insulin-resistant mice. Perfusion recovery in STZ-treated and Ob/Ob mice was only decreased by 19% and 16%, respectively ( P P ≤0.01). Correspondingly, perfusion recovery was 41% decreased in APOE3*Leiden mice ( P P =0.02), but not with triglyceride, free fatty acid, glucose, or insulin levels. Conclusions— Hypercholesterolemia reduces arteriogenesis more dominantly than hyperglycemia or hyperinsulinemia in mice. This suggests that a disturbed lipid metabolism as observed in diabetic patients might be crucial for the impairment of collateral formation.
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- 2006
184. Pericellular proteases in angiogenesis and vasculogenesis
- Author
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Marten A. Engelse, Paul H.A. Quax, and Victor W.M. van Hinsbergh
- Subjects
Proteases ,Matrix metalloproteinase inhibitor ,Angiogenesis ,Neovascularization, Physiologic ,Bone Marrow Cells ,Proteases in angiogenesis ,Matrix metalloproteinase ,Protein degradation ,Biology ,Aminopeptidases ,Extracellular matrix ,Mice ,Vasculogenesis ,Cell Movement ,Animals ,Humans ,Extracellular Matrix Proteins ,Neovascularization, Pathologic ,Serine Endopeptidases ,Cell Differentiation ,Tissue Inhibitor of Metalloproteinases ,Cathepsins ,Matrix Metalloproteinases ,Extracellular Matrix ,ADAM Proteins ,Biochemistry ,Cardiology and Cardiovascular Medicine ,Pericytes ,Peptide Hydrolases - Abstract
Pericellular proteases play an important role in angiogenesis and vasculogenesis. They comprise (membrane-type) matrix metalloproteinases [(MT-)MMPs], serine proteases, cysteine cathepsins, and membrane-bound aminopeptidases. Specific inhibitors regulate them. Major roles in initiating angiogenesis have been attributed to MT1-matrix metalloproteinase (MMP), MMP-2, and MMP-9. Whereas MT-MMPs are membrane-bound by nature, MMP-2 and MMP-9 can localize to the membrane by binding to αvβ3-integrin and CD44, respectively. Proteases switch on neovascularization by activation, liberation, and modification of angiogenic growth factors and degradation of the endothelial and interstitial matrix. They also modify the properties of angiogenic growth factors and cytokines. Neovascularization requires cell migration, which depends on the assembly of protease–protein complexes at the migrating cell front. MT1-MMP and urokinase (u-PA) form multiprotein complexes in the lamellipodia and focal adhesions of migrating cells, facilitating proteolysis and sufficient support for endothelial cell migration and survival. Excessive proteolysis causes loss of endothelial cell-matrix interaction and impairs angiogenesis. MMP-9 and cathepsin L stimulate the recruitment and action of blood- or bone-marrow-derived accessory cells that enhance angiogenesis. Proteases also generate fragments of extracellular matrix and hemostasis factors that have anti-angiogenic properties. Understanding the complexity of protease activities in angiogenesis contributes to recognizing new targets for stimulation or inhibition of neovascularization in disease.
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- 2006
185. Shiga toxin-1 affects nitric oxide production by human glomerular endothelial and mesangial cells
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Thea J A M van der Velden, D. Maroeska te Loo, Victor W.M. van Hinsbergh, Leo A. H. Monnens, Mohammed Karmali, and Lambertus P. van den Heuvel
- Subjects
medicine.medical_specialty ,Thrombotic microangiopathy ,Age-related aspects of cancer [ONCOL 2] ,Energy and redox metabolism [NCMLS 4] ,Nitric Oxide Synthase Type III ,Kidney Glomerulus ,Nitric Oxide Synthase Type II ,Biology ,medicine.disease_cause ,Nitric Oxide ,Shiga Toxin 1 ,Nitric oxide ,Pathogenesis ,Genomic disorders and inherited multi-system disorders [IGMD 3] ,chemistry.chemical_compound ,Shiga-like toxin ,Antigen ,Translational research [ONCOL 3] ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Cells, Cultured ,Renal disorder [IGMD 9] ,Toxin ,Endothelial Cells ,Shiga toxin ,medicine.disease ,In vitro ,Renal disorders [UMCN 5.4] ,Endocrinology ,Mitochondrial medicine [IGMD 8] ,chemistry ,Nephrology ,Pediatrics, Perinatology and Child Health ,Mesangial Cells ,biology.protein - Abstract
Acute renal failure hallmarks the pathogenesis of the epidemic form of hemolytic uremic syndrome (D+HUS), which is caused by E. coli strains that produce Shiga-like toxin (Stx). In this study, we investigated the influence of Stx-1 on nitric oxide (NO) production by human glomerular microvascular endothelial cells (GMVEC) and human mesangial cells. NO synthesis by human mesangial cells is in the micromolar range and that of GMVEC in the picomolar range. Stx-1 reduced NO production in non-stimulated GMVEC (5 nmol/l Stx-1 required) without inhibition of protein synthesis. In non-stimulated and TNFalpha-pretreated mesangial cells, NO production was reduced with a maximal reduction at 10 fmol/l shiga toxin. The cellular iNOS antigen content in mesangial cells was reduced in a concentration-dependent way (10 fmol/l-100 pmol/l), while partial inhibition of protein synthesis required 10 nmol/l Stx-1 in these cells. Our in vitro data suggest that Stx may reduce NO synthesis during the course of HUS development, contributing to the aggravation of the thrombotic microangiopathy and renal failure as observed in HUS.
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- 2006
186. Membrane-type matrix metalloproteinases and vascularization in human endometrium during the menstrual cycle
- Author
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Elle K.J. Risse, Victor W.M. van Hinsbergh, Robin M.F. van der Weiden, Clarissa Jungerius, Margreet Plaisier, Pieter Koolwijk, Frans M. Helmerhorst, Roeland Hanemaaijer, and Robert A. Verwey
- Subjects
Embryology ,medicine.medical_specialty ,Endothelium ,Matrix Metalloproteinases, Membrane-Associated ,Angiogenesis ,Neovascularization, Physiologic ,Biology ,Matrix metalloproteinase ,Endometrium ,Neovascularization ,Andrology ,In vivo ,Internal medicine ,Genetics ,medicine ,Humans ,Molecular Biology ,Cells, Cultured ,Menstrual Cycle ,Tube formation ,Cell Membrane ,Obstetrics and Gynecology ,Endothelial Cells ,Cell Biology ,medicine.anatomical_structure ,Endocrinology ,Reproductive Medicine ,Immunohistochemistry ,Female ,medicine.symptom ,Developmental Biology - Abstract
Endometrial angiogenesis is essential for a vascularized receptive endometrium. Previously, we described that membrane type-3 metalloproteinase (MT3-MMP) is associated with endometrial angiogenesis in vitro. The association of MT-MMPs with endometrial angiogenesis in vivo is unknown. Therefore, this study analysed the presence of MT-MMPs in human endometrium and their correlation with neovascularization. RNA/protein expressions of the six MT-MMPs were determined in cultured endometrial cells. Vascularization parameters and MT-MMP expressions in vivo were evaluated by immunohistochemistry in serial endometrium sections. MT1-, MT2-, MT3- and MT4-MMP antigens were expressed in cultured endometrial endothelial cells. MT2-, MT3- and MT4-MMP were expressed by endothelium during the proliferative and secretory phase. Strikingly, these phases showed elevated vascularization, elevated total vascular surface in proliferative phases, elevated number of vessels in proliferative/late secretory phases and increased luminal surface in the proliferative phases. All MT-MMP antigens were expressed in various endometrial cell types in vivo, with decreased levels during the early secretory phase. In conclusion, all MT-MMPs are expressed in endometrium in a cycle-dependent pattern. The vascular expression of MT2-, MT3- and MT4-MMP correlated with angiogenic episodes of the cycle. Since MT2- and MT3-MMP are known to regulate tube formation, these findings support earlier in vitro data on the role of MT3-MMP in endometrial angiogenesis. Additionally, MT2-MMP appears to be associated with endometrial neovascularization also.
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- 2006
187. Direct grafting of RGD-motif containing peptide on the surface of polycaprolactone films
- Author
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Andrej Zentner, Victor W.M. van Hinsbergh, Arie V Van Nieuw Amerongen, Geerten P van Nieuw Amerongen, Matthias Gabriel, Orthodontie (OUD, ACTA), and Orale Biochemie (OUD, ACTA)
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Male ,Materials science ,Surface Properties ,Polyesters ,Biomedical Engineering ,Biophysics ,Bioengineering ,Peptide ,Biocompatible Materials ,Biomaterials ,chemistry.chemical_compound ,Polymer chemistry ,Materials Testing ,Cell Adhesion ,Animals ,Humans ,Microscopy, Phase-Contrast ,Amination ,Cells, Cultured ,RGD motif ,chemistry.chemical_classification ,Polymer ,Peptide Fragments ,Endothelial stem cell ,chemistry ,Models, Chemical ,Covalent bond ,Polycaprolactone ,Surface modification ,Cattle ,Endothelium, Vascular ,Oligopeptides - Abstract
Direct surface modification of biodegradable polycaprolactone (PCL) was performed without the necessity of synthesis of functionisable co-polymers. An easy-to-perform three-step procedure consisting of amination, reaction with hetero-bifunctional cross-linkers and conjugation of an RGD-motif-containing peptide was used to modify polymer films and improve the attachment of endothelial cells. The biological activity of modified surfaces was assessed by estimating microvascular endothelial cell attachment. Covalent coating with RGD resulted in an approximately 11-fold increase of endothelial cell attachment on modified PCL surfaces compared with untreated polymer. The specificity of the attachment enhancement was confirmed by using a control peptide. It is concluded that chemical surface modification is an appropriate method of rendering degradable polymers, such as PCL, cell-adhesive.
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- 2006
188. Pathophysiological role of Amadori-glycated proteins in diabetic microangiopathy
- Author
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Victor W.M. van Hinsbergh, Casper G. Schalkwijk, Coen D.A. Stehouwer, and Mariska Lieuw-a-Fa
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Glycation End Products, Advanced ,medicine.medical_specialty ,Glycosylation ,Nephropathy ,Diabetic nephropathy ,Glycation ,Internal medicine ,Diabetes mellitus ,Glycated Serum Proteins ,medicine ,Humans ,Diabetic Nephropathies ,Glycated Serum Albumin ,Serum Albumin ,Glycoproteins ,Diabetic Retinopathy ,biology ,business.industry ,Albumin ,Transforming growth factor beta ,Blood Proteins ,medicine.disease ,Blood proteins ,Endocrinology ,biology.protein ,Cardiology and Cardiovascular Medicine ,business ,Diabetic Angiopathies ,Retinopathy - Abstract
Early and advanced nonenzymatic glycation of proteins are increased in diabetes. Although Amadori-glycated proteins are the major glycated modifications, most studies so far have focused on the role of advanced glycation end-products (AGEs) in diabetes-related vascular complications. It was only recently that the role of Amadori-glycated proteins has come under consideration. Here we review data that point to an important role of Amadori-modified glycated serum proteins in diabetic microangiopathy. Amadori-glycated albumin induces the activation of glomerular mesangial and endothelial cells to a phenotype that may be linked to the pathogenesis of diabetic microangiopathy, that is, by the stimulation of protein kinase C, activation of transforming growth factor beta, and the expression of extracellular matrix proteins. In type 1 diabetic patients, levels of Amadori-glycated proteins are independently associated with nephropathy and retinopathy. Reduction of Amadori-glycated albumin levels in diabetic animal models ameliorates the progression of nephropathy and retinopathy, indicating a causal role of Amadori-glycated proteins in the pathogenesis of diabetic nephropathy and retinopathy. Based on these data, inhibition of Amadori-glycated albumin may be a target for reduction of diabetic vascular complications.
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- 2005
189. Human embryo-conditioned medium stimulates in vitro endometrial angiogenesis
- Author
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Kitty Kapiteijn, Victor W.M. van Hinsbergh, Margreet Plaisier, Robin M.F. van der Weiden, Pieter Koolwijk, Geerten P. van Nieuw Amerongen, and Frans M. Helmerhorst
- Subjects
Placental growth factor ,medicine.medical_specialty ,Recombinant Epidermal Growth Factor ,Angiogenesis ,Cell Survival ,medicine.medical_treatment ,Cell Culture Techniques ,Neovascularization, Physiologic ,Biology ,Andrology ,Neovascularization ,chemistry.chemical_compound ,Internal medicine ,medicine ,Humans ,Angiogenic Proteins ,Cells, Cultured ,Cell Proliferation ,Tube formation ,Tissue Engineering ,Growth factor ,Obstetrics and Gynecology ,Endothelial Cells ,Embryo, Mammalian ,Vascular endothelial growth factor ,Endocrinology ,Reproductive Medicine ,chemistry ,Culture Media, Conditioned ,medicine.symptom ,Transforming growth factor - Abstract
Objective: Successful implantation and placentation depend on the interaction between the endometrium and the embryo. Angiogenesis is crucial at this time. In this article we investigate the direct influence of the human embryo on in vitro endometrial angiogenesis. Design: In vitro study. Setting: Human endometrial microvascular endothelial cells (hEMVEC) grown on an in vitro angiogenesis model. Intervention(s): Conditioned media (CM) of human embryos were used to stimulate in vitro angiogenesis. Main Outcome Measure(s): In vitro angiogenesis of hEMVEC. Result(s): Conditioned media of human embryos, containing significant amounts of vascular endothelial growth factor (VEGF)-A, as determined by enzyme-linked immunosorbent assay (ELISA), caused an increase in hEMVEC tube formation. This effect was prevented by soluble VEGF receptor 1, which quenches VEGF-A activity. Recombinant EGF alone and leukemia inhibitory factor in combination with VEGF-A stimulated hEMVEC tube formation. None of the other tested recombinant mediators, which have been described as produced by the early embryo/trophoblast (interleukin (IL) 10, transforming growth factor (TGF) β, placental growth factor, hCG, colony-stimulating factor 1, interferon-γ, insulin-like growth factor I and II, IL-6, platelet-derived growth factor, and TGFα), had an effect on tube formation by hEMVEC. Conclusion(s): For the first time, it is shown that the human embryo is able to stimulate in vitro endometrial angiogenesis at the time of implantation, a process that is mediated by VEGF-A. © 2006 American Society for Reproductive Medicine.
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- 2005
190. Modification of Low-Density Lipoprotein by Methylglyoxal Alters its Physico-Chemical and Biological Properties
- Author
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Victor W.M. van Hinsbergh, Nicole Verzijl, Mario A. Vermeer, Hans M.G. Princen, Casper G. Schalkwijk, Coen D.A. Stehouwer, and Johan te Koppele
- Subjects
chemistry.chemical_compound ,chemistry ,Biochemistry ,Superoxide ,Glycation ,Low-density lipoprotein ,Methylglyoxal ,LDL receptor ,Cholesteryl ester ,lipids (amino acids, peptides, and proteins) ,Scavenger receptor ,Lipoprotein - Abstract
Nonenzymatic glycosylation of low-density lipoprotein (LDL) has been suggested to be involved in the development of atherosclerosis in patients with diabetes. Since α-dicarbonyl compounds were identified as intermediates in nonenzymatic glycosylation, we investigated the effect of the physiological α-dicarbonyl compound methylglyoxal (MG) on the physico-chemical and biological properties of LDL. MG modifies LDL in a timeand concentration-dependent manner as indicated by the production of fluorescent products and the increase in net-negative charge. Despite the production of superoxide anion radicals, LDL modification by MG is not accompanied by peroxidation of the polyunsaturated fatty acids. MG-LDL showed impaired recognition by the LDL receptor, but increased binding to scavenger receptors. However, MG-LDL did not enhance cholesteryl ester synthesis in murine macrophages.
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- 2005
191. The hemostatic system in angiogenesis
- Author
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Klaas Hoekman, Pieter Koolwijk, and Victor W.M. van Hinsbergh
- Subjects
Angiogenesis ,Chemistry ,Thrombin receptor ,Cancer research ,Fibrin matrix ,Thymidine phosphorylase - Published
- 2005
192. Chapter 14 Chronic lung vascular hyperpermeability
- Author
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Victor W.M. van Hinsbergh, Geerten P. van Nieuw Amerongen, and Bradford C. Berk
- Subjects
Clinical Practice ,Thrombin ,Lung ,medicine.anatomical_structure ,Immunology ,medicine ,Gene induction ,Inflammation ,Biology ,Hypoxia (medical) ,medicine.symptom ,Barrier function ,medicine.drug - Abstract
Publisher Summary This chapter discusses the chronic signaling responses involved in the regulation of barrier function and dysfunction, including altered protein synthesis and gene induction, and describes how they relate to responses induced by mediators such as thrombin, cytokines, and conditions such as mechanical stress or hypoxia. The chapter also describes the stages of endothelial hyperpermeability. Understanding of the processes that impair the vascular barrier function has considerably improved by the recognition that various forms of vascular leakages occur. This is most evident in inflammatory diseases such as asthma but is also encountered in many other pulmonary diseases. Depending on the severity and duration of an inflammatory reaction, three main steps contribute to vascular leakages: initial acute permeability, prolongation of inflammation, and remodeling. Distinction of different types of vascular leakages is of importance for clinical practice as they require different pharmacological approaches. Mechanisms and mediators of endothelial hyperpermeability are also described in the chapter.
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- 2005
193. Fructose-mediated non-enzymatic glycation: sweet coupling or bad modification
- Author
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Coen D.A. Stehouwer, Victor W.M. van Hinsbergh, and Casper G. Schalkwijk
- Subjects
Glycation End Products, Advanced ,medicine.medical_specialty ,Glycosylation ,Endocrinology, Diabetes and Metabolism ,Fructose 1,6-bisphosphatase ,Fructose ,chemistry.chemical_compound ,symbols.namesake ,Endocrinology ,Polyol pathway ,Glycation ,Dietary Sucrose ,Internal medicine ,Internal Medicine ,medicine ,Diabetes Mellitus ,Animals ,Humans ,Aldose reductase ,biology ,business.industry ,Maillard Reaction ,Maillard reaction ,Biochemistry ,chemistry ,Fructolysis ,biology.protein ,symbols ,business - Abstract
The Maillard reaction is a process in which reducing sugars react spontaneously with amino groups in proteins to advanced glycation end products (AGEs). Although an elevated level of glucose had been thought to play a primary role in the Maillard reaction, on a molecular basis, glucose is among the least reactive sugars within biological systems. The formation of AGEs is now also known to result from the action of various metabolites other than glucose, which are primarily located intracellularly and participate in the non-enzymatic glycation reaction at a much faster rate, such as fructose, trioses and dicarbonyl compounds. In this review, we considered the glycation reaction with particular attention to the potential role of fructose and fructose metabolites. The two sources for fructose are an exogenous supply from the diet and the endogenous formation from glucose through the aldose reductase pathway. Despite its approximately eightfold higher reactivity, the contribution of extracellular glycation by fructose is considerably less than that by glucose, because of the low plasma concentration of fructose (5 mmol/L glucose vs 35 micro mol/L fructose). Intracellularly, fructose is elevated in a number of tissues of diabetic patients in which the polyol pathway is active. In the cells of these tissues, the concentrations of fructose and glucose are of the same magnitude. Although direct evidence is not yet available, it is likely that the high reactivity of fructose and its metabolites may substantially contribute to the formation of intracellular AGEs and may contribute to alterations of cellular proteins, dysfunction of cells and, subsequently, to vascular complications.
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- 2004
194. N(omega)-(carboxymethyl)lysine depositions in human aortic heart valves: similarities with atherosclerotic blood vessels
- Author
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C. Erik Hack, W. Stooker, Casper G. Schalkwijk, Rien A.J.M. Huybregts, Leon Eijsman, Victor W.M. van Hinsbergh, Alexi Baidoshvili, Jan A. Rauwerda, Hans W.M. Niessen, Chris J.L.M. Meijer, Pathology, Internal medicine, Laboratory Medicine, Surgery, Physiology, and Human genetics
- Subjects
Aortic valve ,Adult ,Glycation End Products, Advanced ,Male ,medicine.medical_specialty ,Endothelium ,Arteriosclerosis ,chemistry.chemical_compound ,Reference Values ,Internal medicine ,Mitral valve ,Culture Techniques ,hemic and lymphatic diseases ,Cadaver ,Medicine ,Humans ,Heart valve ,Aged ,Probability ,Aged, 80 and over ,business.industry ,Vascular disease ,Lysine ,Fibroblasts ,Middle Aged ,medicine.disease ,Immunohistochemistry ,medicine.anatomical_structure ,chemistry ,Aortic valve stenosis ,Aortic Valve ,Cardiology ,cardiovascular system ,Advanced glycation end-product ,Blood Vessels ,Mitral Valve ,Female ,Endothelium, Vascular ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers - Abstract
Recent studies indicate a role of atherosclerosis-like changes involved in the pathogenesis of aortic valve stenosis. Interestingly, one of the major advanced glycation end products (AGEs), N(omega)-(carboxymethyl)lysine (CML) has been related to the process of atherosclerosis in blood vessels. In the present study, we have analyzed the presence of CML in degenerative altered aortic valves with atherosclerosis-like changes, and in degenerated mitral valves without atherosclerosis-like changes, derived from patients suffering from acute rheumatism during childhood. Degenerated and non-degenerated valves were derived from autopsy or obtained during cardiac surgery. The presence of CML was examined by immunohistochemistry. CML was found on the endothelium and fibroblasts in control aortic and mitral valves. Minor differences in CML staining were observed between control and degeneratively affected mitral valves. In contrast, in degenerated aortic valves, CML accumulation was found in macrophages and on calcification sites, comparable to that in atherosclerotic arteries, while the presence of CML staining on the endothelium and fibroblasts was significantly less as compared with control aortic valves. Our data support the hypothesis that the process of degeneration of aortic valves resembles that of atherosclerosis in blood vessels. They suggest that CML also plays a role in the process of atherosclerosis in aortic valves.
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- 2004
195. Increased accumulation of the glycoxidation product Nepsilon-(carboxymethyl)lysine in hearts of diabetic patients: generation and characterisation of a monoclonal anti-CML antibody
- Author
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Coen D.A. Stehouwer, Alexi Baidoshvili, Victor W.M. van Hinsbergh, Casper G. Schalkwijk, and Hans W.M. Niessen
- Subjects
Adult ,Male ,medicine.medical_specialty ,Inflammation ,Enzyme-Linked Immunosorbent Assay ,chemistry.chemical_compound ,Glycation ,hemic and lymphatic diseases ,Internal medicine ,Diabetes mellitus ,Diabetes Mellitus ,Medicine ,Humans ,neoplasms ,Molecular Biology ,Aged ,Aged, 80 and over ,Lung ,business.industry ,Lysine ,Myocardium ,Infant, Newborn ,Antibodies, Monoclonal ,Cell Biology ,medicine.disease ,Immunohistochemistry ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Heart failure ,Monoclonal ,Advanced glycation end-product ,Female ,medicine.symptom ,business ,Oxidation-Reduction - Abstract
Heart failure is a condition closely linked to diabetes. Hyperglycaemia amplifies the generation of a major advanced glycation end product Nepsilon-(carboxymethyl)lysine (CML), which has been associated with the development of vascular and inflammatory complications. An increased accumulation of CML in hearts of diabetic patients may be one of the mechanisms related to the high risk of heart failure. Therefore, we investigated the localization of CML in diabetic hearts. To investigate the presence and accumulation of CML in tissues, a monoclonal anti-CML antibody was generated and characterised. With this novel monoclonal antibody against CML, the localization of CML was investigated by immunohistochemistry, in heart tissue of controls (n = 9) and heart tissue of diabetic patients (n = 8) without signs of inflammation or infarction. In addition, in the same subjects we studied the presence of CML in renal and lung tissues. CML staining was approximately sixfold higher in hearts from diabetic patients as compared to control hearts (2.0 +/- 0.3 and 0.3 +/- 0.2 A.U., respectively, P < 0.01). CML deposition was localized in the small intramyocardial arteries in endothelial cells and smooth muscle cells, but not in cardiomyocytes. These arteries did not show morphological abnormalities. The intensity of staining between arteries at the epicardial, midcardial and endocardial side did not vary significantly within patients. In renal tissues, CML staining was most prominent in tubules and in atherosclerotic vessels, without differences in intensity between controls and diabetic patients. In non-infected lungs, no CML was detected. In conclusion, CML adducts are abundantly present in small intramyocardial arteries in the heart tissue of diabetic patients. The accumulation of CML in diabetic hearts may contribute to the increased risk of heart failure in hyperglycaemia.
- Published
- 2004
196. Vascular endothelial growth factor overexpression in ischemic skeletal muscle enhances myoglobin expression in vivo
- Author
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Reinier O. Schlingemann, Paul H.A. Quax, Victor W.M. van Hinsbergh, J. Hajo van Bockel, J.H.P. Lardenoye, Jos M. Grimbergen, Vincent van Weel, Martine Deckers, Kees van Leuven, Geerten P. van Nieuw Amerongen, ACS - Amsterdam Cardiovascular Sciences, ANS - Amsterdam Neuroscience, and Ophthalmology
- Subjects
Male ,Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,Physiology ,Angiogenesis ,Genetic Vectors ,Muscle Fibers, Skeletal ,Gene Expression ,Neovascularization, Physiologic ,Biology ,Amputation, Surgical ,Adenoviridae ,chemistry.chemical_compound ,Gastrocnemius muscle ,Mice ,Ischemia ,Internal medicine ,medicine ,Animals ,Humans ,RNA, Messenger ,Muscle, Skeletal ,Semaxanib ,Aged ,Myogenesis ,Myoglobin ,Skeletal muscle ,Genetic Therapy ,Middle Aged ,Surgery ,Capillaries ,Vascular endothelial growth factor ,Radiography ,Vascular endothelial growth factor A ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Female ,Cardiology and Cardiovascular Medicine ,medicine.drug - Abstract
Therapeutic angiogenesis using vascular endothelial growth factor (VEGF) is considered a promising new therapy for patients with arterial obstructive disease. Clinical improvements observed consist of improved muscle function and regression of rest pain or angina. However, direct evidence for improved vascularization, as evaluated by angiography, is weak. In this study, we report an angiogenesis-independent effect of VEGF on ischemic skeletal muscle, ie, upregulation of myoglobin after VEGF treatment. Mice received intramuscular injection with adenoviral VEGF-A or either adenoviral LacZ or PBS as control, followed by surgical induction of acute hindlimb ischemia at day 3. At day 6, capillary density was increased in calf muscle of Ad.VEGF-treated versus control mice ( P P ≤0.01). In addition, the number of myoglobin-stained myofibers was 2.6-fold increased in Ad.VEGF-treated mice ( P =0.001). Furthermore, in ischemic muscle of 15 limb amputation patients, VEGF and myoglobin were coexpressed. Finally, in cultured C2C12 myotubes treated with rhVEGF, myoglobin mRNA was 2.8-fold raised as compared with PBS-treated cells ( P =0.02). This effect could be blocked with the VEGF receptor tyrosine kinase inhibitor SU5416. In conclusion, we show that VEGF upregulates myoglobin in ischemic muscle both in vitro and in vivo. Increased myoglobin expression in VEGF-treated muscle implies an improved muscle oxygenation, which may, at least partly, explain observed clinical improvements in VEGF-treated patients, in the absence of improved vascularization.
- Published
- 2004
197. Increased levels of N(epsilon)-(carboxymethyl)lysine and N(epsilon)-(carboxyethyl)lysine in type 1 diabetic patients with impaired renal function: correlation with markers of endothelial dysfunction
- Author
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Victor W.M. van Hinsbergh, Tom Teerlink, Rob Barto, Jos W. R. Twisk, Casper G. Schalkwijk, Coen D.A. Stehouwer, and Mariska L. M. Lieuw-A-Fa
- Subjects
Adult ,Male ,medicine.medical_specialty ,Endothelium ,Thrombomodulin ,Renal function ,Vascular Cell Adhesion Molecule-1 ,Kidney ,Endothelial activation ,chemistry.chemical_compound ,Von Willebrand factor ,Internal medicine ,medicine ,Humans ,Endothelial dysfunction ,Aged ,Transplantation ,biology ,business.industry ,Lysine ,C-reactive protein ,Middle Aged ,medicine.disease ,Blood Coagulation Factors ,medicine.anatomical_structure ,Endocrinology ,C-Reactive Protein ,Diabetes Mellitus, Type 1 ,chemistry ,Nephrology ,Plasminogen activator inhibitor-1 ,Case-Control Studies ,biology.protein ,Female ,Endothelium, Vascular ,business ,E-Selectin ,Plasminogen activator ,Glomerular Filtration Rate - Abstract
BACKGROUND Diabetic and non-diabetic patients with renal failure have an increased risk for cardiovascular disease, which may be the result of uraemic toxins, including advanced glycation end-products (AGEs). The aim of the study was to investigate the levels of well-characterized AGEs, N(epsilon)-(carboxymethyl)lysine (CML) and N(epsilon)-(carboxyethyl)lysine (CEL) in relation to kidney function and to study the relationship of these AGEs to endothelial function and inflammation in type 1 diabetic patients. METHODS Plasma levels of CML and CEL were measured in 60 type 1 diabetic patients categorized as having normal glomerular filtration rate (GFR) (>80 ml/min, n = 31) or decreased GFR (
- Published
- 2004
198. Involvement of Membrane-Type Matrix Metalloproteinases (MT-MMPs) in capillary tube formation by human endometrial microvascular endothelial Cells: Role of MT3-MMP
- Author
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Kitty Kapiteijn, Victor W.M. van Hinsbergh, Pieter Koolwijk, Margreet Plaisier, Catherine Fijten, Roeland Hanemaaijer, Jos M. Grimbergen, Adri Mulder-Stapel, Frans M. Helmerhorst, Paul H.A. Quax, and Gaubius Instituut TNO
- Subjects
Biomedical Research ,Unclassified drug ,Plasmin ,Matrix metalloproteinase inhibitor ,Angiogenesis ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Matrix metalloproteinase ,Biochemistry ,Neovascularization ,Prepuce ,Capillary ,Endometrium ,Endocrinology ,Endometrium cell ,Adenovirus ,Fibrinolysin ,Urokinase ,Enzyme regulation ,Cells, Cultured ,Tube formation ,Gelatinase A ,Messenger RNA ,Metalloendopeptidases ,Immunohistochemistry ,Endothelial stem cell ,Enzyme inhibition ,Urinary Plasminogen Activator ,Female ,medicine.symptom ,medicine.drug ,medicine.medical_specialty ,Matrix Metalloproteinases, Membrane-Associated ,Neovascularization, Physiologic ,Biology ,Genetic transduction ,Collagen Type I ,Membrane type 4 metalloproteinase ,Adenoviridae ,Membrane type 3 metalloproteinase ,Interstitial collagenase ,Internal medicine ,Vascular endothelium ,medicine ,Humans ,Tissue Inhibitor of Metalloproteinase-3 ,Fibrin ,Tissue Inhibitor of Metalloproteinase-1 ,Biochemistry (medical) ,Endothelial Cells ,Matrix Metalloproteinase 16 ,Tissue inhibitor of metalloproteinase ,Urokinase-Type Plasminogen Activator ,Human cell ,Immunoglobulin G ,Protein expression ,Cell culture ,Controlled study ,Endothelium cell - Abstract
In the endometrium, angiogenesis is a physiological process, whereas in most adult tissues neovascularization is initiated only during tissue repair or pathological conditions. Pericellular proteolysis plays an important role in angiogenesis being required for endothelial cell migration, invasion, and tube formation. We studied the expression of proteases by human endometrial microvascular endothelial cells (hEMVECs) and their involvement in the formation of capillary tubes and compared these requirements with those of foreskin MVECs (hFMVECs). Inhibition of urokinase and matrix metalloproteinase (MMP) both reduced tube formation in a fibrin or fibrin/collagen matrix. hEMVECs expressed various MMP mRNAs and proteins; in particular MMP-1, MMP-2, and membrane-type (MT)1-, MT3-, and MT4-MMPs. MT3- and MT4-MMP mRNA expressions were significantly higher in hEMVECs than in hFMVECs. Other MT-MMP mRNAs and MMP-9 were hardly detectable. Immunohistochemistry confirmed the presence of MT3-MMP in endothelial cells of endometrial tissue. Overexpression of tissue inhibitor of MMP (TIMP)-1 or TIMP-3 by adenoviral transduction of hEMVECs reduced tube formation to the same extent, whereas only TIMP-3 was able to inhibit tube formation by hFMVECs. Tube formation by hEMVECs was partly inhibited by the presence of anti-MT3-MMP IgG. Thus, in contrast to tube formation by hFMVECs, which largely depends on MT1-MMP, capillary-like tube formation by hEMVECs is, at least in part, regulated by MT3-MMP. Chemicals / CAS: collagen, 9007-34-5; fibrin, 9001-31-4; gelatinase A, 146480-35-5; immunoglobulin G, 97794-27-9; interstitial collagenase, 9001-12-1; tissue inhibitor of metalloproteinase 1, 140208-24-8; tissue inhibitor of metalloproteinase 3, 145809-21-8, 164781-40-2; urokinase, 139639-24-0; Collagen Type I; Matrix Metalloproteinase 16, EC 3.4.24.-; Matrix Metalloproteinases, Membrane-Associated, EC 3.4.24.-; Metalloendopeptidases, EC 3.4.24.-; MMP16 protein, human; Plasmin, EC 3.4.21.7; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-3; Urinary Plasminogen Activator, EC 3.4.21.73
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- 2004
199. Elevated levels of vascular endothelial growth factor in serum of patients with D+ HUS
- Author
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Lambertus P. van den Heuvel, Victor W.M. van Hinsbergh, Paul N. Span, Nienke Bosma, Ruud Clarijs, C.G.J. Sweep, Robert M.W. de Waal, D. Maroeska te Loo, Leo A. H. Monnens, and Gaubius Instituut TNO
- Subjects
Nephrology ,Male ,Vascular Endothelial Growth Factor A ,Enterobacter infection ,Angiogenesis ,glomerulus ,Recovery phase ,urologic and male genital diseases ,Kidney ,Pathogenesis ,chemistry.chemical_compound ,Child ,medicine.diagnostic_test ,disease course ,Vascular endothelial growth factor ,Vascular endothelial growth factor A ,medicine.anatomical_structure ,D+ hemolytic uremic syndrome ,Child, Preschool ,Flt-1 and KDR ,immunohistochemistry ,Immunohistochemistry ,disease severity ,Female ,Renal biopsy ,medicine.medical_specialty ,Endothelial damage ,kidney biopsy ,disease classification ,Physiological Sciences ,Internal medicine ,medicine ,Humans ,controlled study ,tissue repair ,Biology ,Endocrinology and reproduction [UMCN 5.2] ,business.industry ,vasculotropin ,vasculotropin receptor ,Infant ,major clinical study ,human tissue ,enzyme linked immunosorbent assay ,Tumor microenvironment [UMCN 1.3] ,Renal disorders [UMCN 5.4] ,Endocrinology ,Receptors, Vascular Endothelial Growth Factor ,Genetic defects of metabolism [UMCN 5.1] ,chemistry ,protein blood level ,Pediatrics, Perinatology and Child Health ,Hemolytic-Uremic Syndrome ,hemolytic uremic syndrome ,business - Abstract
The pathogenesis of hemolytic uremic syndrome (D+ HUS) is characterized by endothelial damage of glomeruli and tubules within the kidney. In several other diseases in which glomerular endothelial damage occurs, elevated serum levels of vascular endothelial growth factor (VEGF) have been reported. VEGF is involved in angiogenesis, permeabilization of blood vessel endothelium, and wound repair. In this study we evaluated VEGF levels in the serum of 40 D+ HUS patients in the acute phase and during the course of the disease. VEGF levels were measured using a double-sandwich ELISA. Indirect immunohistochemistry was performed for the detection of VEGF in renal biopsy material of 3 HUS patients. Significantly elevated VEGF levels were found in HUS patients compared with controls in both serum (P
- Published
- 2004
200. Role of methylglyoxal adducts in the development of vascular complications in diabetes mellitus
- Author
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C.D.A. Stehouwer, Casper G. Schalkwijk, Victor W.M. van Hinsbergh, and M. Bourajjaj
- Subjects
medicine.medical_specialty ,Methylglyoxal ,Imidazoles ,medicine.disease ,Pyruvaldehyde ,Biochemistry ,Pathogenesis ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Glycation ,Diabetes mellitus ,Internal medicine ,medicine ,Humans ,Glycolysis ,Diabetic Vascular Complications ,Vascular tissue ,Intracellular ,Diabetic Angiopathies - Abstract
Various theories have been proposed to explain the hyperglycaemia-induced pathogenesis of vascular complications of diabetes, including detrimental effects of AGEs (advanced glycation end products) on vascular tissues. Increased formation of the very reactive dicarbonyl compound MGO (methylglyoxal), one of the side-products of glycolysis, and MGO-derived AGEs seem to be implicated in the development of diabetic vascular complications. Although the exact role of MGO and MGO adducts in the development of vascular complications is unknown, receptor-mediated activation of vascular cells by the MGO–arginine adduct hydroimidazolone, as well as intracellular modifications of protein by MGO, seem to be involved. The aim of this mini-review is to assess to what extent MGO is related to vascular complications in diabetes.
- Published
- 2003
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