118 results on '"Helen M. Arthur"'
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2. VEGFR2 Expression Correlates with Postnatal Development of Brain Arteriovenous Malformations in a Mouse Model of Type I Hereditary Hemorrhagic Telangiectasia
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Chul Han, Candice L. Nguyen, Lea Scherschinski, Tyler D. Schriber, Helen M. Arthur, Michael T. Lawton, and Suk Paul Oh
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endoglin ,brain arteriovenous malformation ,hereditary hemorrhagic telangiectasia ,angiogenesis ,vascular disorder ,magnetic resonance angiography ,Biology (General) ,QH301-705.5 - Abstract
Brain arteriovenous malformations (BAVMs) are a critical concern in hereditary hemorrhagic telangiectasia (HHT) patients, carrying the risk of life-threatening intracranial hemorrhage. While traditionally seen as congenital, the debate continues due to documented de novo cases. Our primary goal was to identify the precise postnatal window in which deletion of the HHT gene Endoglin (Eng) triggers BAVM development. We employed SclCreER(+);Eng2f/2f mice, enabling timed Eng gene deletion in endothelial cells via tamoxifen. Tamoxifen was given during four postnatal periods: P1–3, P8–10, P15–17, and P22–24. BAVM development was assessed at 2–3 months using latex dye perfusion. We examined the angiogenic activity by assessing vascular endothelial growth factor receptor 2 (VEGFR2) expression via Western blotting and Flk1-LacZ reporter mice. Longitudinal magnetic resonance angiography (MRA) was conducted up to 9 months. BAVMs emerged in 88% (P1–3), 86% (P8–10), and 55% (P15–17) of cases, with varying localization. Notably, the P22–24 group did not develop BAVMs but exhibited skin AVMs. VEGFR2 expression peaked in the initial 2 postnatal weeks, coinciding with BAVM onset. These findings support the “second hit” theory, highlighting the role of early postnatal angiogenesis in initiating BAVM development in HHT type I mice.
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- 2023
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3. An update on preclinical models of hereditary haemorrhagic telangiectasia: Insights into disease mechanisms
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Helen M. Arthur and Beth L. Roman
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HHT ,arteriovenous malformation (AVM) ,endoglin (CD105) ,activin receptor-like kinase 1 (ACVRL1) ,BMP-SMAD signalling pathway ,cell polarity and migration ,Medicine (General) ,R5-920 - Abstract
Endoglin (ENG) is expressed on the surface of endothelial cells (ECs) where it efficiently binds circulating BMP9 and BMP10 ligands to initiate activin A receptor like type 1 (ALK1) protein signalling to protect the vascular architecture. Patients heterozygous for ENG or ALK1 mutations develop the vascular disorder known as hereditary haemorrhagic telangiectasia (HHT). Many patients with this disorder suffer from anaemia, and are also at increased risk of stroke and high output heart failure. Recent work using animal models of HHT has revealed new insights into cellular and molecular mechanisms causing this disease. Loss of the ENG (HHT1) or ALK1 (HHT2) gene in ECs leads to aberrant arteriovenous connections or malformations (AVMs) in developing blood vessels. Similar phenotypes develop following combined EC specific loss of SMAD1 and 5, or EC loss of SMAD4. Taken together these data point to the essential role of the BMP9/10-ENG-ALK1-SMAD1/5-SMAD4 pathway in protecting the vasculature from AVMs. Altered directional migration of ECs in response to shear stress and increased EC proliferation are now recognised as critical factors driving AVM formation. Disruption of the ENG/ALK1 signalling pathway also affects EC responses to vascular endothelial growth factor (VEGF) and crosstalk between ECs and vascular smooth muscle cells. It is striking that the vascular lesions in HHT are both localised and tissue specific. Increasing evidence points to the importance of a second genetic hit to generate biallelic mutations, and the sporadic nature of such somatic mutations would explain the localised formation of vascular lesions. In addition, different pro-angiogenic drivers of AVM formation are likely to be at play during the patient’s life course. For example, inflammation is a key driver of vessel remodelling in postnatal life, and may turn out to be an important driver of HHT disease. The current wealth of preclinical models of HHT has led to increased understanding of AVM development and revealed new therapeutic approaches to treat AVMs, and form the topic of this review.
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- 2022
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4. Disruption of embryonic ROCK signaling reproduces the sarcomeric phenotype of hypertrophic cardiomyopathy
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Kate E. Bailey, Guy A. MacGowan, Simon Tual-Chalot, Lauren Phillips, Timothy J. Mohun, Deborah J. Henderson, Helen M. Arthur, Simon D. Bamforth, and Helen M. Phillips
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Medicine - Published
- 2020
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5. MiR-126-3p Is Dynamically Regulated in Endothelial-to-Mesenchymal Transition during Fibrosis
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Nina P. Jordan, Samuel J. Tingle, Victoria G. Shuttleworth, Katie Cooke, Rachael E. Redgrave, Esha Singh, Emily K. Glover, Hafiza B. Ahmad Tajuddin, John A. Kirby, Helen M. Arthur, Chris Ward, Neil S. Sheerin, and Simi Ali
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endothelial-to-mesenchymal transition ,fibrosis ,microRNA ,miR-126 ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
In fibrotic diseases, myofibroblasts derive from a range of cell types including endothelial-to-mesenchymal transition (EndMT). Increasing evidence suggests that miRNAs are key regulators in biological processes but their profile is relatively understudied in EndMT. In human umbilical vein endothelial cells (HUVEC), EndMT was induced by treatment with TGFβ2 and IL1β. A significant decrease in endothelial markers such as VE-cadherin, CD31 and an increase in mesenchymal markers such as fibronectin were observed. In parallel, miRNA profiling showed that miR-126-3p was down-regulated in HUVECs undergoing EndMT and over-expression of miR-126-3p prevented EndMT, maintaining CD31 and repressing fibronectin expression. EndMT was investigated using lineage tracing with transgenic Cdh5-Cre-ERT2; Rosa26R-stop-YFP mice in two established models of fibrosis: cardiac ischaemic injury and kidney ureteric occlusion. In both cardiac and kidney fibrosis, lineage tracing showed a significant subpopulation of endothelial-derived cells expressed mesenchymal markers, indicating they had undergone EndMT. In addition, miR-126-3p was restricted to endothelial cells and down-regulated in murine fibrotic kidney and heart tissue. These findings were confirmed in patient kidney biopsies. MiR-126-3p expression is restricted to endothelial cells and is down-regulated during EndMT. Over-expression of miR-126-3p reduces EndMT, therefore, it could be considered for miRNA-based therapeutics in fibrotic organs.
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- 2021
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6. Cardiosphere-Derived Cells Require Endoglin for Paracrine-Mediated Angiogenesis
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Rachael E. Redgrave, Simon Tual-Chalot, Benjamin J. Davison, Esha Singh, Darroch Hall, Muhammad M. Amirrasouli, Derek Gilchrist, Alexander Medvinsky, and Helen M. Arthur
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Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Clinical trials of stem cell therapy to treat ischemic heart disease primarily use heterogeneous stem cell populations. Small benefits occur via paracrine mechanisms that include stimulating angiogenesis, and increased understanding of these mechanisms would help to improve patient outcomes. Cardiosphere-derived-cells (CDCs) are an example of these heterogeneous stem cell populations, cultured from cardiac tissue. CDCs express endoglin, a co-receptor that binds specific transforming growth factor β (TGFβ) family ligands, including bone morphogenetic protein 9 (BMP9). In endothelial cells endoglin regulates angiogenic responses, and we therefore hypothesized that endoglin is required to promote the paracrine pro-angiogenic properties of CDCs. Cre/LoxP technology was used to genetically manipulate endoglin expression in CDCs, and we found that the pro-angiogenic properties of the CDC secretome are endoglin dependent both in vitro and in vivo. Importantly, BMP9 pre-treatment of endoglin-depleted CDCs restores their pro-angiogenic paracrine properties. As BMP9 signaling is normally required to maintain endoglin expression, we propose that media containing BMP9 could be critical for therapeutic CDC preparation.
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- 2017
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7. Hereditary Haemorrhagic Telangiectasia, an Inherited Vascular Disorder in Need of Improved Evidence-Based Pharmaceutical Interventions
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Ryan O. Snodgrass, Timothy J. A. Chico, and Helen M. Arthur
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BMP9/10 ,ENG ,ACVRL1 ,VEGF ,angiogenesis ,arteriovenous malformation ,Genetics ,QH426-470 - Abstract
Hereditary haemorrhagic telangiectasia (HHT) is characterised by arteriovenous malformations (AVMs). These vascular abnormalities form when arteries and veins directly connect, bypassing the local capillary system. Large AVMs may occur in the lungs, liver and brain, increasing the risk of morbidity and mortality. Smaller AVMs, known as telangiectases, are prevalent on the skin and mucosal lining of the nose, mouth and gastrointestinal tract and are prone to haemorrhage. HHT is primarily associated with a reduction in endoglin (ENG) or ACVRL1 activity due to loss-of-function mutations. ENG and ACVRL1 transmembrane receptors are expressed on endothelial cells (ECs) and bind to circulating ligands BMP9 and BMP10 with high affinity. Ligand binding to the receptor complex leads to activation of the SMAD1/5/8 signalling pathway to regulate downstream gene expression. Various genetic animal models demonstrate that disruption of this pathway in ECs results in AVMs. The vascular abnormalities underlying AVM formation result from abnormal EC responses to angiogenic and haemodynamic cues, and include increased proliferation, reduced migration against the direction of blood flow and an increased EC footprint. There is growing evidence that targeting VEGF signalling has beneficial outcomes in HHT patients and in animal models of this disease. The anti-VEGF inhibitor bevacizumab reduces epistaxis and has a normalising effect on high cardiac output in HHT patients with hepatic AVMs. Blocking VEGF signalling also reduces vascular malformations in mouse models of HHT1 and HHT2. However, VEGF signalling is complex and drives numerous downstream pathways, and it is not yet clear which pathway (or combination of pathways) is critical to target. This review will consider the recent evidence gained from HHT clinical and preclinical studies that are increasing our understanding of HHT pathobiology and informing therapeutic strategies.
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- 2021
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8. Using MRI to predict future adverse cardiac remodelling in a male mouse model of myocardial infarction
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Rachael E. Redgrave, Simon Tual-Chalot, Benjamin J. Davison, Elizabeth Greally, Mauro Santibanez-Koref, Jurgen E. Schneider, Andrew M. Blamire, and Helen M. Arthur
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Myocardial infarction ,Animal models of human disease ,Remodelling ,MRI ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background: Mice are frequently used in research to examine outcomes of myocardial infarction (MI) and to investigate therapeutic interventions at an early pre-clinical stage. The MI model is generated by surgically occluding a major coronary artery, but natural variation in murine coronary anatomy can generate variable outcomes that will inevitably affect the accuracy of such investigations. The aim of this study was to use MRI to derive the most sensitive early variable that could be used to predict subsequent adverse cardiac remodelling in a male mouse model of MI. Methods: Using a longitudinal study design, heart structure and function were evaluated using cardiac MRI at one week following surgical MI to generate the early measurements and again at four weeks, when the scar had matured. The primary variables measured at week one were left ventricular volumes at end systole (LV-ESV) and at end diastole (LV-EDV), infarct size, LV-cardiac mass, and ejection fraction (EF). Results: Univariate and multiple regression analyses showed that LV-ESV at one week following MI could be used to accurately predict various parameters of adverse LV remodelling at four weeks post-MI. However, the highest correlation was between LV-ESV at one week following MI and LV-EDV at four weeks (r = 0.99; p
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- 2016
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9. Soluble endoglin regulates expression of angiogenesis-related proteins and induction of arteriovenous malformations in a mouse model of hereditary hemorrhagic telangiectasia
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Eunate Gallardo-Vara, Simon Tual-Chalot, Luisa M. Botella, Helen M. Arthur, and Carmelo Bernabeu
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Angiogenesis ,Endoglin ,HHT ,AVM ,TGF-β ,Endothelial cells ,Medicine ,Pathology ,RB1-214 - Abstract
Endoglin is a transmembrane glycoprotein expressed in vascular endothelium that plays a key role in angiogenesis. Mutations in the endoglin gene (ENG) cause hereditary hemorrhagic telangiectasia type 1 (HHT1), characterized by arteriovenous malformations (AVMs) in different organs. These vascular lesions derive from abnormal processes of angiogenesis, whereby aberrant vascular remodeling leads to focal loss of capillaries. Current treatments for HHT1 include antiangiogenic therapies. Interestingly, a circulating form of endoglin (also known as soluble endoglin, sEng), proteolytically released from the membrane-bound protein and displaying antiangiogenic activity, has been described in several endothelial-related pathological conditions. Using human and mouse endothelial cells, we find that sEng downregulates several pro-angiogenic and pro-migratory proteins involved in angiogenesis. However, this effect is much reduced in endothelial cells that lack endogenous transmembrane endoglin, suggesting that the antiangiogenic activity of sEng is dependent on the presence of endogenous transmembrane endoglin protein. In fact, sEng partially restores the phenotype of endoglin-silenced endothelial cells to that of normal endothelial cells. Moreover, using an established neonatal retinal model of HHT1 with depleted endoglin in the vascular endothelium, sEng treatment decreases the number of AVMs and has a normalizing effect on the vascular phenotype with respect to vessel branching, vascular density and migration of the vascular plexus towards the retinal periphery. Taken together, these data show that circulating sEng can influence vascular development and AVMs by modulating angiogenesis, and that its effect on endothelial cells depends on the expression of endogenous endoglin. This article has an associated First Person interview with the first author of the paper.
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- 2018
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10. Correction: Endothelial Expression of TGFβ Type II Receptor Is Required to Maintain Vascular Integrity during Postnatal Development of the Central Nervous System.
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Kathleen R. Allinson, Hye Shin Lee, Marcus Fruttiger, Joseph McCarty, and Helen M. Arthur
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Medicine ,Science - Published
- 2012
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11. Exogenous TGFβ1 and its mimic HpTGM attenuate the heart’s inflammatory response to ischaemic injury and improve long term cardiac outcomes
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Rachael E. Redgrave, Esha Singh, Simon Tual-Chalot, Catherine Park, Darroch Hall, Karim Bennaceur, Danielle J. Smyth, Rick M. Maizels, Ioakim Spyridopoulos, and Helen M. Arthur
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RationaleSuccessful and timely coronary reperfusion following acute ST-elevation myocardial infarction (STEMI) is standard therapy to salvage transiently ischaemic heart muscle. However, the subsequent inflammatory response within the infarct can lead to further loss of viable myocardium. Robust interventions are required in the acute MI setting to minimise cardiac injury and reduce risk of further detrimental progression.ObjectiveTGFβ1 is an anti-inflammatory cytokine released endogenously in response to infection or tissue injury. The goal of this study was to investigate its protective effects when given exogenously following myocardial infarction.Methods and ResultsTGFβ1 is found at increased levels in the blood of STEMI patients immediately following myocardial infarction. We observe a significant correlation (p=0.003) between higher circulating TGFβ1 levels at 24h post MI and a reduction in infarct size over the following 3 months, suggesting that an early increase in circulating TGFβ1 is protective in these patients. Using a mouse model of cardiac ischaemia-reperfusion we demonstrate that additional exogenous TGFβ1 delivered in the acute setting has multiple beneficial outcomes. At 24 hours post-reperfusion It leads to a significantly smaller infarct size (30% reduction, p=0.025), reduced inflammatory infiltrate (28% reduction, p=0.015), lower intra-cardiac expression of inflammatory cytokines IL1β and CCL2 (>50 % reduction, p=0.038 and 0.0004, respectively) and reduced scar size at 4 weeks (21% reduction, p=0.015). Furthermore exogenous delivery of an equivalent dose of HpTGM, a recently described low-fibrogenic mimic of TGFβ1, secreted by a helminth parasite to evade immune rejection, has an almost identical protective effect on injured mouse hearts. Furthermore using a genetic approach we show the benefit is mediated by the vascular endothelium.ConclusionsThis work reveals the potential of exogenous TGFβ1 and HpTGM delivered in the acute MI setting to provide protective anti-inflammatory effects and reduce infarct size, leading to a smaller scar and reduced detrimental progression.
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- 2023
12. Therapeutic Potential of Senolytics in Cardiovascular Disease
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Emily Dookun, Gavin D. Richardson, João F. Passos, and Helen M. Arthur
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0301 basic medicine ,Senescence ,Aging ,Invited Review Article ,Apoptosis ,Disease ,Cardiovascular ,Bioinformatics ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Senotherapeutics ,Genetic model ,medicine ,Animals ,Humans ,Senolytic ,Pharmacology (medical) ,Myocardial infarction ,Cellular Senescence ,Aged ,Cause of death ,Inflammation ,Pharmacology ,business.industry ,Remodelling ,General Medicine ,Atherosclerosis ,Prognosis ,medicine.disease ,030104 developmental biology ,Cardiovascular Diseases ,Ageing ,Disease Progression ,Senescence-Associated Secretory Phenotype ,Cardiology and Cardiovascular Medicine ,business ,030217 neurology & neurosurgery - Abstract
Ageing is the biggest risk factor for impaired cardiovascular health, with cardiovascular disease being the leading cause of death in 40% of individuals over 65 years old. Ageing is associated with both an increased prevalence of cardiovascular disease including heart failure, coronary artery disease, and myocardial infarction. Furthermore, ageing is associated with a poorer prognosis to these diseases. Genetic models allowing the elimination of senescent cells revealed that an accumulation of senescence contributes to the pathophysiology of cardiovascular ageing and promotes the progression of cardiovascular disease through the expression of a proinflammatory and profibrotic senescence-associated secretory phenotype. These studies have resulted in an effort to identify pharmacological therapeutics that enable the specific elimination of senescent cells through apoptosis induction. These senescent cell apoptosis-inducing compounds are termed senolytics and their potential to ameliorate age-associated cardiovascular disease is the focus of this review.
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- 2020
13. Arterial endoglin does not protect against arteriovenous malformations
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Esha Singh, Helen M. Arthur, Rachael Redgrave, and Helen M. Phillips
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0301 basic medicine ,Cancer Research ,Receptor complex ,Pathology ,medicine.medical_specialty ,Notch ,Physiology ,Angiogenesis ,Clinical Biochemistry ,Brief Communication ,Retina ,Vascular remodelling in the embryo ,Veins ,Arteriovenous malformation ,Arteriovenous Malformations ,03 medical and health sciences ,chemistry.chemical_compound ,medicine ,Animals ,Endothelium ,Hereditary haemorrhagic telangiectasia ,Acvrl1 ,Mice, Knockout ,Gene knockdown ,Retinal angiogenesis ,030102 biochemistry & molecular biology ,business.industry ,Endoglin ,ACVRL1 ,Retinal ,Arteries ,medicine.disease ,Capillaries ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Vascular Disorder ,business - Abstract
Introduction Endoglin (ENG) forms a receptor complex with ALK1 in endothelial cells (ECs) to promote BMP9/10 signalling. Loss of function mutations in either ENG or ALK1 genes lead to the inherited vascular disorder hereditary haemorrhagic telangiectasia (HHT), characterised by arteriovenous malformations (AVMs). However, the vessel-specific role of ENG and ALK1 proteins in protecting against AVMs is unclear. For example, AVMs have been described to initiate in arterioles, whereas ENG is predominantly expressed in venous ECs. To investigate whether ENG has any arterial involvement in protecting against AVM formation, we specifically depleted the Eng gene in venous and capillary endothelium whilst maintaining arterial expression, and investigated how this affected the incidence and location of AVMs in comparison with pan-endothelial Eng knockdown. Methods Using the mouse neonatal retinal model of angiogenesis, we first established the earliest time point at which Apj-Cre-ERT2 activity was present in venous and capillary ECs but absent from arterial ECs. We then compared the incidence of AVMs following pan-endothelial or venous/capillary-specific ENG knockout. Results Activation of Apj-Cre-ERT2 with tamoxifen from postnatal day (P) 5 ensured preservation of arterial ENG protein expression. Specific loss of ENG expression in ECs of veins and capillaries led to retinal AVMs at a similar frequency to pan-endothelial loss of ENG. AVMs occurred in the proximal as well as the distal part of the retina consistent with a defect in vascular remodelling during maturation of the vasculature. Conclusion Expression of ENG is not required in arterial ECs to protect against AVM formation.
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- 2020
14. MiR-126-3p Is Dynamically Regulated in Endothelial-to-Mesenchymal Transition during Fibrosis
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John A. Kirby, Rachael Redgrave, Samuel J Tingle, Hafiza B. Ahmad Tajuddin, Katie Cooke, Emily K. Glover, Simi Ali, Chris Ward, Helen M. Arthur, Neil S. Sheerin, Esha Singh, Nina P. Jordan, and Victoria G. Shuttleworth
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CD31 ,Cell type ,QH301-705.5 ,Biology ,Kidney ,Catalysis ,Umbilical vein ,Article ,Inorganic Chemistry ,Mice ,Fibrosis ,microRNA ,medicine ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,Biology (General) ,Physical and Theoretical Chemistry ,Myofibroblasts ,QD1-999 ,Molecular Biology ,Spectroscopy ,Cells, Cultured ,Myocardium ,Organic Chemistry ,Mesenchymal stem cell ,fibrosis ,Endothelial Cells ,Mesenchymal Stem Cells ,General Medicine ,miR-126 ,medicine.disease ,Computer Science Applications ,endothelial-to-mesenchymal transition ,Fibronectin ,Mice, Inbred C57BL ,Chemistry ,MicroRNAs ,Cell Transdifferentiation ,Cancer research ,biology.protein ,cardiovascular system ,Myofibroblast - Abstract
In fibrotic diseases, myofibroblasts derive from a range of cell types including endothelial-to-mesenchymal transition (EndMT). Increasing evidence suggests that miRNAs are key regulators in biological processes but their profile is relatively understudied in EndMT. In human umbilical vein endothelial cells (HUVEC), EndMT was induced by treatment with TGFβ2 and IL1β. A significant decrease in endothelial markers such as VE-cadherin, CD31 and an increase in mesenchymal markers such as fibronectin were observed. In parallel, miRNA profiling showed that miR-126-3p was down-regulated in HUVECs undergoing EndMT and over-expression of miR-126-3p prevented EndMT, maintaining CD31 and repressing fibronectin expression. EndMT was investigated using lineage tracing with transgenic Cdh5-Cre-ERT2, Rosa26R-stop-YFP mice in two established models of fibrosis: cardiac ischaemic injury and kidney ureteric occlusion. In both cardiac and kidney fibrosis, lineage tracing showed a significant subpopulation of endothelial-derived cells expressed mesenchymal markers, indicating they had undergone EndMT. In addition, miR-126-3p was restricted to endothelial cells and down-regulated in murine fibrotic kidney and heart tissue. These findings were confirmed in patient kidney biopsies. MiR-126-3p expression is restricted to endothelial cells and is down-regulated during EndMT. Over-expression of miR-126-3p reduces EndMT, therefore, it could be considered for miRNA-based therapeutics in fibrotic organs.
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- 2021
15. Synergistic TOR and ERK inhibition mitigates the hereditary haemorrhagic telangiectasia-like phenotype and excess kugel formation in endoglin mutant zebrafish
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Ryan Snodgrass, Timothy James Chico, and Helen M. Arthur
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MAPK/ERK pathway ,Tivozanib ,biology ,medicine.drug_class ,Telangiectases ,Endoglin ,biology.organism_classification ,Phenotype ,Tyrosine-kinase inhibitor ,Dorsal aorta ,medicine ,Cancer research ,Zebrafish ,medicine.drug - Abstract
RationaleHereditary haemorrhagic telangiectasia (HHT) is an inherited bleeding disorder characterised by arteriovenous malformations (AVMs). Such AVMs affect lungs, liver and brain, whilst telangiectases in mucocutaneous tissues are prone to haemorrhage. HHT type I is caused by loss-of-function endoglin (ENG) mutations. Evidence suggests AVMs result from abnormal responses to VEGF signalling.ObjectiveWe therefore characterised the vascular abnormalities in eng mutant zebrafish and investigated whether these are prevented by inhibiting different pathways downstream of VEGF signalling.Methods and ResultsWe used light sheet fluorescence microscopy to visualise the vasculature in engmu130 mutant zebrafish. In addition to previously described significantly enlarged dorsal aorta and posterior cardinal vein at 3d post fertilisation, engmu130 embryos had an enlarged basilar artery (BA), and increased formation of endothelial “kugeln” on cerebral vessels. Adult engmu130 fish developed skin AVMs, retinal vascular abnormalities, and an enlarged heart. Tivozanib (AV951), a VEGF receptor tyrosine kinase inhibitor, prevented development of the abnormally enlarged major vessels and normalised the number of kugeln in engmu130 embryos. Inhibiting discrete signalling pathways downstream of VEGFR2 in engmu130 embryos gave further insights. Inhibiting TOR or MEK prevented the abnormal trunk and cerebral vasculature phenotype, whilst targeting NOS and MAPK had no effect. Combining subtherapeutic TOR and MEK inhibition prevented the vascular phenotype, suggesting synergy between TOR and MEK/ERK signalling pathways.ConclusionsThese results indicate the HHT-like phenotype in zebrafish endoglin mutants can be mitigated through modulation of VEGF signalling, and implicate combination low dose ERK and TOR pathway inhibitors as a therapeutic strategy in HHT.Graphical Abstract
- Published
- 2021
16. BS11 Inhibition of VEGF signalling mitigates the hereditary haemorrhagic telangiectasia-like phenotype in endoglin mutant zebrafish
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Ryan Snodgrass, Timothy J. A. Chico, and Helen M. Arthur
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Mutation ,biology ,business.industry ,Mutant ,Embryo ,Telangiectases ,Endoglin ,medicine.disease_cause ,biology.organism_classification ,Phenotype ,Dorsal aorta ,otorhinolaryngologic diseases ,medicine ,Cancer research ,business ,Zebrafish - Abstract
Introduction Hereditary haemorrhagic telangiectasia (HHT) is characterised by arteriovenous malformations (AVMs). Large AVMs may affect lungs, liver and brain, whilst telangiectases in mucocutaneous tissues are prone to haemorrhage. HHT type I is caused by loss-of-function ENG mutations. There is growing evidence targeting VEGF signalling is beneficial in HHT. However, VEGF signalling is complex and drives numerous downstream pathways, and it is not clear which are critical to target. We therefore pharmacologically inhibited either global VEGF signalling or components of downstream pathways in zebrafish eng mutants to determine which pathways drive the HHT phenotype. Methods We studied zebrafish in a Tg(kdrl:Hsa.HRAS-mCherry)s916 background which fluorescently labels endothelial cells. The effect of engmu130 mutation and/or 24hr treatment with VEGF pathway inhibitors on vascular development was quantified by lightsheet fluorescence microscopy in 3d post fertilisation embryos (10-15/group). Results engmu130 embryos had a significantly enlarged dorsal aorta (DA) diameter (wt 22.3μm ± 0.9μm, mut 26.1μm ± 0.3μm, p Conclusion The HHT-like phenotype of zebrafish eng mutants can be mitigated by inhibition of the TOR and MEK pathways of VEGF signalling. These represent potential therapeutic targets in HHT. Conflict of Interest The authors declare that there is no conflict of interest
- Published
- 2021
17. Decreased Expression of Vascular Endothelial Growth Factor Receptor 1 Contributes to the Pathogenesis of Hereditary Hemorrhagic Telangiectasia Type 2
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Franck Lebrin, Simon Tual-Chalot, Helen M. Arthur, Steven Kroon, Frans Disch, Noël Lamandé, Christine L. Mummery, Damien Dos-Santos-Luis, Jérémy H. Thalgott, Johannes J. Mager, Ton J. Rabelink, Repke J. Snijder, Georgios Galaris, Karine Raymond, Anna E Hosman, Yihai Cao, Samly Srun, Sabrina Martin, Hetty C. de Boer, Diane Bracquart, Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
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Adult ,Male ,0301 basic medicine ,Heterozygote ,Activin Receptors, Type II ,[SDV]Life Sciences [q-bio] ,arteriovenous malformation ,Neovascularization, Physiologic ,Antibodies ,Mycoplasma pulmonis ,Arteriovenous Malformations ,Pathogenesis ,Mice ,angiogenesis ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,Animals ,Humans ,hereditary hemorrhagic telangiectasia ,Medicine ,vascular endothelial growth factors ,Telangiectasia ,Skin ,Vascular Endothelial Growth Factor Receptor-1 ,business.industry ,Genetic disorder ,Retinal Vessels ,Mouse Embryonic Stem Cells ,ACVRL1 ,Arteriovenous malformation ,Middle Aged ,medicine.disease ,Mice, Inbred C57BL ,Platelet Endothelial Cell Adhesion Molecule-1 ,Disease Models, Animal ,030104 developmental biology ,030220 oncology & carcinogenesis ,cardiovascular system ,Cancer research ,Female ,Telangiectasia, Hereditary Hemorrhagic ,pathological ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Haploinsufficiency ,Activin Receptors, Type I ,Signal Transduction - Abstract
Background: Hereditary Hemorrhagic Telangiectasia type 2 (HHT2) is an inherited genetic disorder characterized by vascular malformations and hemorrhage. HHT2 results from ACVRL1 haploinsufficiency, the remaining wild-type allele being unable to contribute sufficient protein to sustain endothelial cell function. Blood vessels function normally but are prone to respond to angiogenic stimuli, leading to the development of telangiectasic lesions that can bleed. How ACVRL1 haploinsufficiency leads to pathological angiogenesis is unknown. Methods: We took advantage of Acvrl1 +/− mutant mice that exhibit HHT2 vascular lesions and focused on the neonatal retina and the airway system after Mycoplasma pulmonis infection, as physiological and pathological models of angiogenesis, respectively. We elucidated underlying disease mechanisms in vitro by generating Acvrl1 +/− mouse embryonic stem cell lines that underwent sprouting angiogenesis and performed genetic complementation experiments. Finally, HHT2 plasma samples and skin biopsies were analyzed to determine whether the mechanisms evident in mice are conserved in humans. Results: Acvrl1 +/− retinas at postnatal day 7 showed excessive angiogenesis and numerous endothelial “tip cells” at the vascular front that displayed migratory defects. Vascular endothelial growth factor receptor 1 (VEGFR1; Flt-1) levels were reduced in Acvrl1 +/− mice and HHT2 patients, suggesting similar mechanisms in humans. In sprouting angiogenesis, VEGFR1 is expressed in stalk cells to inhibit VEGFR2 (Flk-1, KDR) signaling and thus limit tip cell formation. Soluble VEGFR1 (sVEGFR1) is also secreted, creating a VEGF gradient that promotes orientated sprout migration. Acvrl1 +/− embryonic stem cell lines recapitulated the vascular anomalies in Acvrl1 +/− (HHT2) mice. Genetic insertion of either the membrane or soluble form of VEGFR1 into the ROSA26 locus of Acvrl1 +/− embryonic stem cell lines prevented the vascular anomalies, suggesting that high VEGFR2 activity in Acvrl1 +/− endothelial cells induces HHT2 vascular anomalies. To confirm our hypothesis, Acvrl1 +/− mice were infected by Mycoplasma pulmonis to induce sustained airway inflammation. Infected Acvrl1 +/− tracheas showed excessive angiogenesis with the formation of multiple telangiectases, vascular defects that were prevented by VEGFR2 blocking antibodies. Conclusions: Our findings demonstrate a key role of VEGFR1 in HHT2 pathogenesis and provide mechanisms explaining why HHT2 blood vessels respond abnormally to angiogenic signals. This supports the case for using anti-VEGF therapy in HHT2.
- Published
- 2018
18. Rapid fall in circulating non-classical monocytes in ST elevation myocardial infarction patients correlates with cardiac injury
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Catherine Park, Sarah Marsh, Simi Ali, Luke Spray, Rachael Redgrave, Helen M. Arthur, Stephen E. Boag, Ioakim Spyridopoulos, Esha Singh, and Lilia Draganova
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0301 basic medicine ,Male ,medicine.medical_specialty ,Endothelium ,medicine.medical_treatment ,Culprit ,Biochemistry ,Monocytes ,03 medical and health sciences ,Coronary circulation ,Mice ,0302 clinical medicine ,St elevation myocardial infarction ,Internal medicine ,Genetics ,medicine ,Animals ,Humans ,Myocardial infarction ,Prospective Studies ,Molecular Biology ,Retrospective Studies ,Innate immune system ,business.industry ,Monocyte ,Percutaneous coronary intervention ,Middle Aged ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Heart Injuries ,Coronary vessel ,Cardiology ,ST Elevation Myocardial Infarction ,Female ,business ,Reperfusion injury ,030217 neurology & neurosurgery ,Biotechnology ,Artery - Abstract
ObjectiveMyocardial infarction leads to a rapid innate immune response that is ultimately required for repair of damaged heart tissue. We therefore examined circulating monocyte dynamics immediately after reperfusion of the culprit coronary vessel in STEMI patients to determine whether this correlated with level of cardiac injury. A mouse model of cardiac ischaemia/reperfusion injury was subsequently used to establish the degree of monocyte margination to the coronary vasculature that could potentially contribute to the drop in circulating monocytes.Approach and ResultsWe retrospectively analysed blood samples from 51 STEMI patients to assess the number of non-classical (NC), classical and intermediate monocytes immediately following primary percutaneous coronary intervention. Classical and intermediate monocytes showed minimal change. On the other hand circulating numbers of NC monocytes fell by approximately 50% at 90 minutes post-reperfusion. This rapid decrease in NC monocytes was greatest in patients with the largest infarct size (pConclusionsRapid depletion of NC monocytes from the circulation in STEMI patients following coronary artery reperfusion correlates with the level of acute cardiac injury and involves rapid margination to the coronary vasculature.Graphical AbstractHighlights3-5 bullet points that summarize the major findings of the study.Circulating non classical monocytes show a rapid fall in STEMI patients within 90 minutes of re-opening the culprit coronary artery.The extent of the drop in non classical monocytes correlates with loss of cardiac function and increased infarct size.A mouse model of cardiac ischaemia and reperfusion shows rapid margination of monocytes to the coronary vasculature
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- 2021
19. Role of CMV-serostatus and CX3CR1 on lymphocyte kinetics and left ventricular remodelling in patients with acute myocardial infarction
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Stephen Boag, Suzanne Cormack, Gavin D. Richardson, Luke Spray, A Mohammad, Ioakim Spyridopoulos, Catherine Park, Konstantinos Stellos, Pedram Panahi, Karim Bennaceur, and Helen M. Arthur
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medicine.medical_specialty ,business.industry ,Lymphocyte ,medicine.disease ,medicine.anatomical_structure ,Internal medicine ,CX3CR1 ,Cardiology ,medicine ,In patient ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,business ,Serostatus - Abstract
Background Patients with latent cytomegalovirus (CMV) infection have higher rates of adverse cardiovascular outcomes, but the reasons for this remain elusive. CMV-induced changes to T-lymphocyte populations, with a proliferation of CMV-specific, CX3CR1+ effector memory cells, may contribute. Effector T-cells are associated with cardiovascular mortality in CMV positive patients, and ischaemia-reperfusion injury after ST-elevation myocardial infarction (STEMI) and primary percutaneous coronary intervention (pPCI). Purpose To investigate the effect of CMV status on lymphocyte kinetics and cardiac MRI (cMRI) parameters in 52 STEMI patients receiving pPCI, and examine the prognostic relevance of pre-reperfusion lymphocyte count in a large cohort. Methods We retrospectively analysed the association between pre-reperfusion lymphocyte count, troponin, and long-term survival in 4874 consecutive STEMI patients. Using flow cytometry, we analysed lymphocyte kinetics in 52 STEMI patients, of known CMV status, during and after pPCI. We assessed the impact of CMV status on infarct size, left-ventricular (LV) function and microvascular obstruction with cMRI in the first week after reperfusion in 101 patients. Repeat cMRI at 12 weeks, to assess LV remodelling, was obtained in 48 patients. Results Pre-reperfusion lymphopenia is an independent predictor of mortality over 7.5 years (hazard ratio for lowest vs highest quartile: 2.0; 95% CI 1.7–2.4; p Conclusions Lymphopenia occurs prior to reperfusion in STEMI, and predicts long-term mortality. Effector T-cells drop substantially after reperfusion only in CMV positive patients, likely mediated by CX3CR1-fractalkine interaction, and this is associated with adverse cMRI findings. Remodeling is worse in CMV positive patients at 12 weeks post-STEMI. Lymphocytes, troponin and survival Funding Acknowledgement Type of funding source: Public Institution(s)
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- 2020
20. Dynamic changes in endoglin expression in the developing mouse heart
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Helen M. Arthur, Helen M. Phillips, and Esha Singh
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CD31 ,Cell type ,Pathology ,medicine.medical_specialty ,Mesenchyme ,Population ,Biology ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Genetics ,medicine ,Animals ,Myocytes, Cardiac ,education ,Molecular Biology ,Endocardium ,030304 developmental biology ,0303 health sciences ,education.field_of_study ,Heart development ,Mesenchymal stem cell ,Endoglin ,Gene Expression Regulation, Developmental ,Heart ,Mesenchymal Stem Cells ,Coronary Vessels ,Mice, Inbred C57BL ,medicine.anatomical_structure ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Endoglin (ENG) is essential for cardiovascular development and is expressed in the heart from its earliest developmental stages. ENG expression has been reported in the cardiac crescent, endocardium, valve mesenchyme and coronary vascular endothelial cells. However, its expression in these cell types is non-uniform and the dynamic changes in ENG expression during heart development have not been systematically studied. Using immunofluorescent staining we tracked ENG protein expression in mouse embryonic hearts aged from 11.5 to 17.5 days, and in postnatal and adult hearts. ENG is expressed in the endocardium and in venous endothelial cells throughout these developmental stages. ENG protein is down-regulated by approximately two-fold as a subset of early coronary veins reprogram to form arteries within the developing myocardium from E13.5. This two-fold higher ratio of ENG protein in veins versus arteries is maintained throughout cardiac development and in the adult heart. ENG is also down-regulated two-fold following mesenchymal transition of endocardial cells to form cardiac valve mesenchyme, whilst expression of the pan-endothelial marker CD31 is completely lost. A subset of epicardial cells (which do not express ENG protein) delaminate and undergo a similar mesenchymal transition to form epicardially derived cells (EPDCs). This transient intra-myocardial mesenchymal cell population expresses low levels of ENG protein, similar to valve mesenchyme. In conclusion, ENG shows dynamic changes of expression in vascular endothelial cells, endocardial cells and mesenchymal cells in the developing heart that vary according to cardiovascular cell type.
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- 2020
21. Oncogenes in Brain Arteriovenous Malformations
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Lars Jakobsson and Helen M. Arthur
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Mitogen-Activated Protein Kinase Kinases ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Physiology ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,brain ,models, animal ,vascular disease ,Oncogenes ,Virology ,Arteriovenous Malformations ,Proto-Oncogene Proteins p21(ras) ,cell size ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Medicine ,Humans ,Endothelium ,Cardiology and Cardiovascular Medicine ,business ,endothelium, vascular ,Original Research - Abstract
Supplemental Digital Content is available in the text., Rationale: We previously identified somatic activating mutations in the KRAS (Kirsten rat sarcoma viral oncogene homologue) gene in the endothelium of the majority of human sporadic brain arteriovenous malformations; a disorder characterized by direct connections between arteries and veins. However, whether this genetic abnormality alone is sufficient for lesion formation, as well as how active KRAS signaling contributes to arteriovenous malformations, remains unknown. Objective: To establish the first in vivo models of somatic KRAS gain of function in the endothelium in both mice and zebrafish to directly observe the phenotypic consequences of constitutive KRAS activity at a cellular level in vivo, and to test potential therapeutic interventions for arteriovenous malformations. Methods and Results: Using both postnatal and adult mice, as well as embryonic zebrafish, we demonstrate that endothelial-specific gain of function mutations in Kras (G12D or G12V) are sufficient to induce brain arteriovenous malformations. Active KRAS signaling leads to altered endothelial cell morphogenesis and increased cell size, ectopic sprouting, expanded vessel lumen diameter, and direct connections between arteries and veins. Furthermore, we show that these lesions are not associated with altered endothelial growth dynamics or a lack of proper arteriovenous identity but instead seem to feature exuberant angiogenic signaling. Finally, we demonstrate that KRAS-dependent arteriovenous malformations in zebrafish are refractory to inhibition of the downstream effector PI3K but instead require active MEK (mitogen-activated protein kinase kinase 1) signaling. Conclusions: We demonstrate that active KRAS expression in the endothelium is sufficient for brain arteriovenous malformations, even in the setting of uninjured adult vasculature. Furthermore, the finding that KRAS-dependent lesions are reversible in zebrafish suggests that MEK inhibition may represent a promising therapeutic treatment for arteriovenous malformation patients.
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- 2020
22. Overexpression of Activin Receptor-Like Kinase 1 in Endothelial Cells Suppresses Development of Arteriovenous Malformations in Mouse Models of Hereditary Hemorrhagic Telangiectasia
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Helen M. Arthur, Young Jae Lee, Phuong Nhung Vu, Se-woon Choe, S. Paul Oh, Calvin P.H. Vary, Chang Jin Jeon, and Yong Hwan Kim
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RNA, Untranslated ,Physiology ,Activin Receptors, Type II ,Green Fluorescent Proteins ,Biology ,Article ,Arteriovenous Malformations ,Mitochondrial Proteins ,Mice ,Transforming Growth Factor beta ,medicine ,Growth Differentiation Factor 2 ,Animals ,Telangiectasia ,Gene ,Alleles ,Receptor like kinase ,Skin ,Smad4 Protein ,Receptors, Notch ,Endoglin ,Endothelial Cells ,Retinal Vessels ,Arteriovenous malformation ,medicine.disease ,Endothelial stem cell ,Disease Models, Animal ,Cancer research ,Telangiectasia, Hereditary Hemorrhagic ,medicine.symptom ,Signal transduction ,Cardiology and Cardiovascular Medicine ,Apoptosis Regulatory Proteins ,Signal Transduction - Abstract
Rationale: Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease caused by mutations in ENG , ALK1 , or SMAD4 . Since proteins from all 3 HHT genes are components of signal transduction of TGF-β (transforming growth factor β) family members, it has been hypothesized that HHT is a disease caused by defects in the ENG-ALK1-SMAD4 linear signaling. However, in vivo evidence supporting this hypothesis is scarce. Objective: We tested this hypothesis and investigated the therapeutic effects and potential risks of induced-ALK1 or -ENG overexpression (OE) for HHT. Methods and Results: We generated a novel mouse allele (ROSA26 Alk1 ) in which HA (human influenza hemagglutinin)-tagged ALK1 and bicistronic eGFP expression are induced by Cre activity. We examined whether ALK1-OE using the ROSA26 Alk1 allele could suppress the development of arteriovenous malformations (AVMs) in wounded adult skin and developing retinas of Alk1 - and Eng -inducible knockout (iKO) mice. We also used a similar approach to investigate whether ENG-OE could rescue AVMs. Biochemical and immunofluorescence analyses confirmed the Cre-dependent OE of the ALK1-HA transgene. We could not detect any pathological signs in ALK1-OE mice up to 3 months after induction. ALK1-OE prevented the development of retinal AVMs and wound-induced skin AVMs in Eng -iKO as well as Alk1 -iKO mice. ALK1-OE normalized expression of SMAD and NOTCH target genes in ENG-deficient endothelial cells (ECs) and restored the effect of BMP9 (bone morphogenetic protein 9) on suppression of phosphor-AKT levels in these endothelial cells. On the other hand, ENG-OE could not inhibit the AVM development in Alk1 -iKO models. Conclusions: These data support the notion that ENG and ALK1 form a linear signaling pathway for the formation of a proper arteriovenous network during angiogenesis. We suggest that ALK1 OE or activation can be an effective therapeutic strategy for HHT. Further research is required to study whether this therapy could be translated into treatment for humans.
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- 2020
23. Clearance of senescent cells following cardiac ischemia-reperfusion injury improves recovery
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David J. Grieve, James Chapman, Gavin D. Richardson, Emily Dookun, Anna Walaszczyk, Eleanor K Gill, Helen M. Arthur, Rachael Redgrave, Eduard Jirkovsky, Oliver E Yausep, Averina Suwana, Pawel Palmowski, Yohan Santin, Michael J. Taggart, Leticia Donastorg Sosa, Simon Tual-Chalot, João F. Passos, Jeanne Mialet-Perez, Ioakim Spyridopoulos, and W. Andrew Owens
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Senescence ,0303 health sciences ,Navitoclax ,business.industry ,Inflammation ,030204 cardiovascular system & hematology ,Pharmacology ,medicine.disease ,medicine.disease_cause ,3. Good health ,Proinflammatory cytokine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,Fibrosis ,medicine ,cardiovascular diseases ,medicine.symptom ,Senolytic ,business ,Reperfusion injury ,Oxidative stress ,030304 developmental biology - Abstract
A key component of cardiac ischemia-reperfusion injury (IRI) is the increased generation of reactive oxygen species, leading to enhanced inflammation and tissue dysfunction in patients following intervention for myocardial infarction. In this study we hypothesized that oxidative stress, due to ischemia-reperfusion, induces senescence which contributes to the pathophysiology of cardiac IRI. We demonstrate that IRI induces cellular senescence in both cardiomyocytes and interstitial cell populations and treatment with the senolytic drug navitoclax after ischemia-reperfusion improves left ventricular function, increases myocardial vascularization, and decreases scar size. SWATH-MS based proteomics reveal that biological processes associated with fibrosis and inflammation, that were increased following ischemia-reperfusion, were attenuated upon senescent cell clearance. Furthermore, navitoclax treatment reduced the expression of proinflammatory, profibrotic and anti-angiogenic cytokines, including interferon gamma-induced protein-10, TGF-β3, interleukin-11, interleukin-16 and fractalkine. Our study provides proof-of-concept evidence that cellular senescence contributes to impaired heart function and adverse remodeling following cardiac ischemia-reperfusion. We also establish that post-IRI senescent cells play a considerable role in the inflammatory response. Subsequently, senolytic treatment, at a clinically feasible time point, attenuates multiple components of this response and improves clinically important parameters. Thus, cellular senescence represents a potential novel therapeutic avenue to improve patient outcomes following cardiac ischemia-reperfusion.
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- 2020
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24. CMV-independent increase in CD27−CD28+ CD8+ EMRA T cells is inversely related to mortality in octogenarians
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Rachael Redgrave, Gavin D. Richardson, Carmen Martin-Ruiz, Bernard Keavney, Evgeniya V. Shmeleva, Thomas von Zglinicki, Ioakim Spyridopoulos, Jedrzej Hoffmann, Lilia Draganova, Joanna Collerton, Helen M. Arthur, Shmeleva, Evgeniya [0000-0002-7654-2960], Richardson, Gavin [0000-0002-2310-9987], Draganova, Lilia [0000-0003-1371-104X], Keavney, Bernard [0000-0001-9573-0812], Spyridopoulos, Ioakim [0000-0002-2750-2444], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Senescence ,Aging ,T cell ,030204 cardiovascular system & hematology ,Brief Communication ,03 medical and health sciences ,0302 clinical medicine ,692/53 ,Medicine ,ddc:610 ,business.industry ,brief-communication ,Hazard ratio ,RC952-954.6 ,CD28 ,Immunosenescence ,medicine.disease ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,631/80/509 ,Geriatrics ,Heart failure ,Immunology ,Geriatrics and Gerontology ,business ,Serostatus ,Biomarkers ,CD8 - Abstract
Cytomegalovirus (CMV) seropositivity in adults has been linked to increased cardiovascular disease burden. Phenotypically, CMV infection leads to an inflated CD8 T-lymphocyte compartment. We employed a 8-colour flow cytometric protocol to analyse circulating T cells in 597 octogenarians from the same birth cohort together with NT-proBNP measurements and followed all participants over 7 years. We found that, independent of CMV serostatus, a high number of CD27−CD28+ CD8 EMRA T-lymphocytes (TEMRA) protected from all-cause death after adjusting for known risk factors, such as heart failure, frailty or cancer (Hazard ratio 0.66 for highest vs lowest tertile; confidence interval 0.51–0.86). In addition, CD27−CD28+ CD8 EMRA T-lymphocytes protected from both, non-cardiovascular (hazard ratio 0.59) and cardiovascular death (hazard ratio 0.65). In aged mice treated with the senolytic navitoclax, in which we have previously shown a rejuvenated cardiac phenotype, CD8 effector memory cells are decreased, further indicating that alterations in T cell subpopulations are associated with cardiovascular ageing. Future studies are required to show whether targeting immunosenescence will lead to enhanced life- or healthspan.
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- 2020
25. Loss of Endothelial Endoglin Promotes High-Output Heart Failure Through Peripheral Arteriovenous Shunting Driven by VEGF Signaling
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Yixin Wang, Simon Tual-Chalot, Allan Lawrie, Esha Singh, Maria Garcia-Collado, Catherine Park, Hua Lin, Rachael Redgrave, Benjamin J. Davison, Saimir Luli, Lars Jakobsson, Yi Jin, and Helen M. Arthur
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Male ,Vascular Endothelial Growth Factor A ,Physiology ,Blood Pressure ,Bone morphogenetic protein ,Arteriovenous Malformations ,Mice ,Medicine ,VEGF signaling ,Animals ,Arteriovenous shunting ,Cardiac and Cardiovascular Systems ,arteriovenous malformations ,High-output heart failure ,Cell Proliferation ,Original Research ,Heart Failure ,endoglin ,Kardiologi ,business.industry ,hypoxia ,Endothelial Cells ,Endoglin ,Hypoxia (medical) ,Vascular Endothelial Growth Factor Receptor-2 ,endothelial cells ,Peripheral ,Mice, Inbred C57BL ,Vascular Disorder ,Cancer research ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Female ,vascular diseases ,Endothelium, Vascular ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Signal Transduction - Abstract
Supplemental Digital Content is available in the text., Rationale: ENG (endoglin) is a coreceptor for BMP (bone morphogenetic protein) 9/10 and is strongly expressed in endothelial cells. Mutations in ENG lead to the inherited vascular disorder hereditary hemorrhagic telangiectasia characterized by local telangiectases and larger arteriovenous malformations (AVMs); but how ENG functions to regulate the adult vasculature is not understood. Objective: The goal of the work was to determine how ENG maintains vessel caliber in adult life to prevent AVM formation and thereby protect heart function. Methods and Results: Genetic depletion of endothelial Eng in adult mice led to a significant reduction in mean aortic blood pressure. There was no evidence of hemorrhage, anemia, or AVMs in major organs to explain the reduced aortic pressure. However, large AVMs developed in the peripheral vasculature intimately associated with the pelvic cartilaginous symphysis—a noncapsulated cartilage with a naturally high endogenous expression of VEGF (vascular endothelial growth factor). The increased blood flow through these peripheral AVMs explained the drop in aortic blood pressure and led to increased cardiac preload, and high stroke volumes, ultimately resulting in high-output heart failure. Development of pelvic AVMs in this region of high VEGF expression occurred because loss of ENG in endothelial cells leads to increased sensitivity to VEGF and a hyperproliferative response. Development of AVMs and associated progression to high-output heart failure in the absence of endothelial ENG was attenuated by targeting VEGF signaling with an anti-VEGFR2 (VEGF receptor 2) antibody. Conclusions: ENG promotes the normal balance of VEGF signaling in quiescent endothelial cells to maintain vessel caliber—an essential function in conditions of increased VEGF expression such as local hypoxia or inflammation. In the absence of endothelial ENG, increased sensitivity to VEGF drives abnormal endothelial proliferation in local regions of high VEGF expression, leading to AVM formation and a rapid injurious impact on heart function.
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- 2020
26. 5234KAND567, the first selective small molecule CX3CR1 antagonist in clinical development, mediates anti-inflammatory cardioprotective effects in rodent models of atherosclerosis and myocardial infarction
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T Olin, John Pernow, R Fritsche Danielson, Ioakim Spyridopoulos, S Abdelmoaty, M Wagberg, Anders Gabrielsen, and Helen M. Arthur
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Chemokine ,biology ,medicine.drug_class ,business.industry ,Ischemia ,Antagonist ,Infarction ,Inflammation ,Pharmacology ,medicine.disease ,Anti-inflammatory ,Atheroma ,Reperfusion therapy ,medicine ,biology.protein ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background Fractalkine is a chemokine that mediates recruitment and extravasation of CX3CR1-expressing subsets of leukocytes and monocytes and has been implicated in the inflammation-driven pathology of cardiovascular disease. More specifically, fractalkine signaling has been proposed to contribute to increased infarct size and enhanced atherosclerotic plaque vulnerability in patients and experimental models. Blocking fractalkine/CX3CR1 signaling is suggested as a promising anti-inflammatory strategy for the treatment of both acute and chronic cardiovascular disease. KAND567 is a small molecule, selective, non-competitive, allosteric antagonist of the fractalkine receptor CX3CR1, that is under preparation for a clinical phase IIa study in AMI patients. Purpose To explore the therapeutic effects of the short and long term administration of KAND567 in experimental rodent models of acute myocardial infarction and atherosclerosis, respectively. Methods Myocardial infarction was induced in Wistar rats (N=6–8 per group) by ligation of the left anterior descending (LAD) coronary artery for 30 minutes followed by 2 h of reperfusion. The drug or vehicle infusion started either 5 min before or 30 min after start of reperfusion and continued during the remainder of the experiment. Hearts were collected and subjected to triphenyl tetrazolium chlorine (TTC) staining and the infarction area/area at risk of the left ventricle was determined by planimetry and compared against vehicle group. Atherosclerosis-prone LDL-receptor deficient mice on a high-cholesterol diet, (N=15–25 per group) were treated with KAND567 for 15–23 weeks. Atherosclerotic plaque development in the thoracic arch was determined by ultrasound imaging and histology. Immunohistochemistry was used to follow changes in the cellular composition in the atherosclerotic lesions. Results In the acute myocardial infarction study, the infusion of KAND567 before the start of reperfusion significantly reduced infarcted/risk area (by up to 50%) as compared to the vehicle group. However, the infusion had no effect on the infarct size when administration was initiated 30 min after start of reperfusion. In the atherogenesis study, oral treatment with KAND567 significantly reduced vascular macrophage infiltration by 50% and reduced intima media thickness. Furthermore, reduced plaque volume and a more stable plaque phenotype was noted following treatment with KAND567. KAND567 experimental results Conclusion Specific inhibition of fractalkine-driven inflammation by KAND567 provides cardioprotective, anti-atherosclerotic and plaque stabilizing effects via mechanisms related to immune cell infiltration, in rodent models. Further studies should be initiated to test if KAND567 is a potential candidate drug, targeting the excessive inflammatory injury associated with ischemia/reperfusion in myocardial infarction and providing plaque stabilization by reducing inflammatory risk for recurrent coronary events.
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- 2019
27. 6089Increased vascular endothelial growth factor signalling following loss of endothelial endoglin leads to peripheral arteriovenous shunting and high output heart failure
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M Garcia-Collado, Simon Tual-Chalot, Esha Singh, Benjamin J. Davison, Helen M. Arthur, Lars Jakobsson, Yi Jin, Rachael Redgrave, Yixin Wang, Saimir Luli, and Allan Lawrie
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medicine.medical_specialty ,business.industry ,Endoglin ,Peripheral ,Vascular endothelial growth factor ,chemistry.chemical_compound ,Signalling ,chemistry ,Internal medicine ,Cardiology ,Medicine ,Arteriovenous shunting ,Cardiology and Cardiovascular Medicine ,business ,High-output heart failure - Abstract
Background Endoglin is a co-receptor for TGFbeta/BMP9/10 signalling and ENG mutations lead to the vascular disorder hereditary haemorrhagic telangiectasia type I (HHT). Endoglin is also required for normal vascular development and angiogenesis, but little is known about endoglin's role in quiescent adult vascular endothelium. Purpose The goal of this present study is to determine how endoglin maintains vessel calibre in adult life to prevent AVM formation and thereby protect heart function. Methods To investigate this role, tamoxifen was administered to adult Cdh5(PAC)-CreERT2; Engfl/fl mice to generate endothelial-specific depletion of endoglin (Eng-iKOe). Cardiac magnetic resonance imaging, myography, vascular casting, microsphere injection, immunohistology, qPCR and aortic telemetry were used to evaluate cardiovascular changes after endoglin knockdown. Results Endothelial-specific loss of endoglin leads to an enlarged heart and cardiomyocyte hypertrophy within 5 weeks, progressing to high output heart failure (HOHF). In vivo aortic telemetry revealed significant loss of aortic pressure within a few days of endoglin depletion. Increased cardiac size and reduced cardiac afterload were confirmed by ventricular pressure loop analysis. As HOHF could result from arteriovenous malformations (AVMs), and these are found primarily in mucocutaneous and pulmonary tissues in HHT, we systematically screened for AVMs using microspheres and vascular casting. Although AVMs were absent in the majority of tissues, they were observed in the pelvic region and may account for the rapid increase in cardiac output. The pelvic cartilaginous symphysis is a noncapsulated cartilage with a naturally high endogenous expression of vascular endothelial growth factor (VEGF). Development of pelvic AVMs in this region of high VEGF expression occurred because loss of endoglin in endothelial cells leads to increased sensitivity to VEGF and a hyper-proliferative response. Finally, we found that inhibition of VEGFR2 was protective against AVMs development, enlargement of the heart and dilatation of the ventricles. Conclusion Our results showed the essential role of endoglin in the maintenance of adult cardio-vasculature through crosstalk with the VEGF signalling pathway. Acknowledgement/Funding British Heart Foundation, Cure HHT, The Swedish Research Council, The Cardiovascular Programme at Karolinska Institutet, The Swedish Cancer Society
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- 2019
28. The secret life of nonclassical monocytes
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Sarah A. Marsh, Ioakim Spyridopoulos, and Helen M. Arthur
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0301 basic medicine ,Histology ,business.industry ,CX3C Chemokine Receptor 1 ,Cell Biology ,030204 cardiovascular system & hematology ,medicine.disease ,Monocytes ,Pathology and Forensic Medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immunology ,Humans ,Medicine ,Receptors, Chemokine ,Myocardial infarction ,Acute Coronary Syndrome ,business - Published
- 2017
29. BS31 The role of fractalkine and CX3CR1-expressing lymphocytes during myocardial ischaemia/reperfusion injury
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Ioakim Spyridopoulos, Helen M. Arthur, Lilia Draganova, Rachael Redgrave, Simon Tual-Chalot, and Sarah Marsh
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Cardiac function curve ,Pathology ,medicine.medical_specialty ,business.industry ,T cell ,030204 cardiovascular system & hematology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,CX3CR1 ,Knockout mouse ,medicine ,030212 general & internal medicine ,Myocardial infarction ,business ,CX3CL1 ,Reperfusion injury ,Infiltration (medical) - Abstract
Introduction Primary percutaneous coronary intervention (PPCI) is the standard care for treatment of acute myocardial infarction, reducing both mortality and morbidity. However, ischaemia/reperfusion (I/R) injury remains an important complication, contributing up to 50% of the final infarct size. Evidence from our clinical studies suggests that lymphocytes expressing the fractalkine receptor (CX3CR1) are associated with microvascular obstruction and hence poorer long-term patient outcomes. This project aims to investigate the role of fractalkine in lymphocyte-mediated myocardial I/R injury and evaluate whether this damage can be reduced by inhibiting fractalkine/receptor (CX3CL1/CX3CR1) interaction. Methods We are using a mouse model of myocardial I/R injury to study lymphocyte infiltration following MI. Multicolour flow cytometry, immunofluorescence staining, qPCR, imaging mass cytometry and magnetic resonance imaging (MRI) are used to evaluate T cell recruitment and cardiac function in a CX3CR1 knockout mouse line. Results CX3CR1 knockout leads to over 30% reduction in immune cell infiltration at the site of cardiac ischaemic injury 2 hours after reperfusion, both in heterozygous (p ≤ 0.01) and knockout (p ≤ 0.001) mice. By 24 hours I/R, infiltration of CD45+ cells in heterozygous and knockout animals returns to, and surpasses, wild type (WT) levels (p ≤ 0.05). Despite the 20% increase in leukocyte infiltration at 24 hours, we see a 2-fold decrease in T cells at the site of I/R injury in the knockout animals, compared to both WT (p ≤ 0.001) and heterozygous mice (p ≤ 0.0001). T cell infiltration in the knockout is also reduced (although not significantly) when heart infiltrates at 24h reperfusion are investigated by an alternative method: flow cytometry analysis of digested cardiac tissue. Furthermore, our studies show a reduction of 30% in the number of CX3CR1-expressing T cells (p ≤ 0.0001) and 50% in total CX3CR1+ cells (p ≤ 0.01) that infiltrate the left ventricle wall in knockout mice, compared to heterozygous animals. Functional studies using cardiac MRI show no difference between heterozygous and KO mice 6 weeks following I/R injury. Conclusion These findings suggest that knockout of CX3CR1 leads to delayed recruitment of leukocytes following cardiac I/R. This results in an altered immune cell infiltrate including reduced number of T cells in the injured tissue. In addition, the role for CX3CR1-expressing T cells in myocardial I/R is supported by our data showing that the number of CX3CR1+ CD3+ cells is significantly reduced from heterozygous to knockout animals following injury. Conflict of interest None
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- 2019
30. 147 Role of CX3CR1HI non-classical monocytes in myocardial ischemia-reperfusion
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Ioakim Spyridopoulos, Helen M. Arthur, and Sarah Marsh
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Cardiac function curve ,medicine.medical_specialty ,biology ,business.industry ,Monocyte ,CD16 ,medicine.disease ,medicine.anatomical_structure ,Integrin alpha M ,Internal medicine ,Heart failure ,CX3CR1 ,biology.protein ,Cardiology ,medicine ,Receptor ,business ,CX3CL1 - Abstract
Introduction Aside from their patrolling behaviour, the early functions of CX3CR1hi non-classical (NC) monocytes following acute myocardial ischemia-reperfusion (I/R) are largely unknown. NC monocyte behaviour is orchestrated in part by their high expression of the fractalkine receptor, CX3CR1, however the signalling pathways activated by fractalkine stimulation remain largely undefined. Increasing evidence has now implicated the CX3CR1/CX3CL1 system in myocardial I/R injury, which conclusively suggest that fractalkine has a detrimental effect on myocardial ischemia and accelerates the progress of heart failure. Neutralization of the receptor is successful in improving cardiac function in a mouse model of MI, and STEMI patient CX3CL1 concentration is a prognostic marker following MI. The first aim of this project was therefore to characterise circulating CX3CR1hi NC monocyte dynamics in ST elevation MI (STEMI) patients immediately following reperfusion, and evaluate their prognostic value. Using a mouse model of cardiac I/R, we evaluated the effect of genetic CX3CR1 knockout on non-classical monocyte recruitment into the injured myocardium at 2h and 24h post-I/R. Since contemporary efforts to promote myocardial repair have failed to translate into clinical therapies thus far, we hypothesize that CX3CR1 may be a prime candidate to target myocardial repair following I/R. Method Flow Cytometry (FC) quantified monocyte subpopulations in the blood of 59 STEMI patients pre and post PPCI. Infarct size and microvascular obstruction (MVO) were assessed using cardiac MRI. Monocytes were quantified in a second study of 14 STEMI patients. A mouse model of cardiac I/R injury was used to study monocyte infiltration following MI. The recruitment of classical monocytes [CD11b+ GFPmid CCR2hi] and NC monocytes [CD11b+ GFPhi CCR2lo] into the injured myocardium at 2h and 24h post-IR was studied by immunofluorescence in CX3CR1+/GFP CX3CR1GFP/GFP mice. FC quantified absolute monocyte subset counts in mouse blood at 2h and 24h post-IR. Results STEMI patients showed a 46%(±4) drop in circulating CX3CR1hi CD16++ NC monocytes (p Conclusion & Future Work: NC monocytes appear to specifically respond to cardiac I/R, and may be predictive of cardiac function following STEMI. The 2-fold reduction in CX3CR1hi LY6Clo NC monocyte infiltration in CX3CR1GFP/GFP mice suggests that CX3CR1 has an important function in the NC monocyte response to cardiac I/R. Conflict of Interest non
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- 2019
31. 127 Developmental rock downregulation disrupts sarcomeric structure resulting in the development of hypertrophic cardiomyopathy
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Deborah J. Henderson, Helen M. Phillips, L. Phillips, Helen M. Arthur, Simon D. Bamforth, Timothy J. Mohun, Simon Tual-Chalot, Kate E Bailey, and Guy A. MacGowan
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Troponin complex ,Heart disease ,Downregulation and upregulation ,business.industry ,medicine ,Cardiomyopathy ,Hypertrophic cardiomyopathy ,Concentric hypertrophy ,medicine.disease ,business ,Sarcomere ,Cell biology ,Muscle hypertrophy - Abstract
Introduction Congenital heart defects are common, affecting ∼1% of live births, while adult heart disease is the main cause of death in the UK. Defects acquired during foetal development can have a lasting detrimental effect on adult heart function. Therefore, understanding the underlying mechanisms involved in cardiac development and disease progression are of particular importance. Cardiomyopathy is a disease of the heart muscle. Hypertrophic cardiomyopathy (HCM) is one of the most common forms of cardiomyopathy; mutations have been identified in the troponin complex, a key component of the sarcomere, signifying that disruption to sarcomeric integrity plays an important role in disease progression. Rho Kinase (ROCK) is expressed in the heart during development and is known to be a regulator of actin-myosin contraction through the phosphorylation of the troponin complex. Our aim was to determine the effect of developmental ROCK downregulation on sarcomeric integrity and impact this had on the function of the adult heart. Methods Cre-LoxP technology was utilised to create a conditional mouse model in which ROCK was specifically downregulated in the cardiomyocytes from E9.25, during cardiac development. Histological techniques were used to assess the embryonic and adult heart phenotype. Analysis of the cytoarchitecture was performed by TEM while cine cardiac MRI was used to assess overall adult heart function. Results and Conclusions: Developmental downregulation of ROCK in the cardiomyocytes resulted in loss of sarcomere integrity at E10.5, associated with a reduction in the levels of phosphorylation of cardiac Troponin I and T, and reduced cardiomyocyte proliferation at E11.5. This caused abnormal myocardial wall development, where the compact myocardium failed to thicken. The impact of these embryonic abnormalities, triggered compensatory foetal cardiomyocyte hypertrophy, which persisted throughout postnatal development and into adult life. Over time this continued hypertrophy became detrimental, triggering cardiac remodelling. Mutants exhibit key features of HCM including concentric hypertrophy with systolic dysfunction, fibrosis and re-expression of foetal genes. This data suggests a novel developmental origin of the sarcomeric phenotype of HCM and indicates disruption in ROCK signalling may contribute to the pathogenesis of HCM. (Bailey et al., Disruption of embryonic ROCK signalling reproduces the sarcomeric phenotype of Hypertrophic Cardiomyopathy. JCI Insight, in press) Conflict of Interest None
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- 2019
32. Length‐independent telomere damage drives post‐mitotic cardiomyocyte senescence
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Rhys Anderson, Anthony Lagnado, Damien Maggiorani, Anna Walaszczyk, Emily Dookun, James Chapman, Jodie Birch, Hanna Salmonowicz, Mikolaj Ogrodnik, Diana Jurk, Carole Proctor, Clara Correia‐Melo, Stella Victorelli, Edward Fielder, Rolando Berlinguer‐Palmini, Andrew Owens, Laura C Greaves, Kathy L Kolsky, Angelo Parini, Victorine Douin‐Echinard, Nathan K LeBrasseur, Helen M Arthur, Simon Tual
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- 2019
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33. Pharmacological clearance of senescent cells improves survival and recovery in aged mice following acute myocardial infarction
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Anna Walaszczyk, Emily Dookun, Rachael Redgrave, Simon Tual‐Chalot, Stella Victorelli, Ioakim Spyridopoulos, Andrew Owens, Helen M. Arthur, João F. Passos, Gavin D. Richardson
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- 2019
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34. Hereditary Haemorrhagic Telangiectasia, an Inherited Vascular Disorder in Need of Improved Evidence-Based Pharmaceutical Interventions
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Helen M. Arthur, Ryan Snodgrass, and Timothy J. A. Chico
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0301 basic medicine ,Receptor complex ,lcsh:QH426-470 ,Angiogenesis ,arteriovenous malformation ,Review ,Telangiectases ,030204 cardiovascular system & hematology ,angiogenesis ,03 medical and health sciences ,0302 clinical medicine ,ACVRL1 ,Growth Differentiation Factor 2 ,Genetics ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Alleles ,Genetics (clinical) ,Evidence-Based Medicine ,business.industry ,BMP9/10 ,Disease Management ,Endothelial Cells ,Arteriovenous malformation ,Endoglin ,medicine.disease ,VEGF ,Hedgehog signaling pathway ,lcsh:Genetics ,ENG ,Phenotype ,030104 developmental biology ,Bone Morphogenetic Proteins ,Mutation ,Vascular Disorder ,Cancer research ,Telangiectasia, Hereditary Hemorrhagic ,business - Abstract
Hereditary haemorrhagic telangiectasia (HHT) is characterised by arteriovenous malformations (AVMs). These vascular abnormalities form when arteries and veins directly connect, bypassing the local capillary system. Large AVMs may occur in the lungs, liver and brain, increasing the risk of morbidity and mortality. Smaller AVMs, known as telangiectases, are prevalent on the skin and mucosal lining of the nose, mouth and gastrointestinal tract and are prone to haemorrhage. HHT is primarily associated with a reduction in endoglin (ENG) or ACVRL1 activity due to loss-of-function mutations. ENG and ACVRL1 transmembrane receptors are expressed on endothelial cells (ECs) and bind to circulating ligands BMP9 and BMP10 with high affinity. Ligand binding to the receptor complex leads to activation of the SMAD1/5/8 signalling pathway to regulate downstream gene expression. Various genetic animal models demonstrate that disruption of this pathway in ECs results in AVMs. The vascular abnormalities underlying AVM formation result from abnormal EC responses to angiogenic and haemodynamic cues, and include increased proliferation, reduced migration against the direction of blood flow and an increased EC footprint. There is growing evidence that targeting VEGF signalling has beneficial outcomes in HHT patients and in animal models of this disease. The anti-VEGF inhibitor bevacizumab reduces epistaxis and has a normalising effect on high cardiac output in HHT patients with hepatic AVMs. Blocking VEGF signalling also reduces vascular malformations in mouse models of HHT1 and HHT2. However, VEGF signalling is complex and drives numerous downstream pathways, and it is not yet clear which pathway (or combination of pathways) is critical to target. This review will consider the recent evidence gained from HHT clinical and preclinical studies that are increasing our understanding of HHT pathobiology and informing therapeutic strategies.
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- 2021
35. Persistent infiltration and pro-inflammatory differentiation of monocytes cause unresolved inflammation in brain arteriovenous malformation
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Helen M. Arthur, Rui Zhang, Wan Zhu, Michael Wong, S. Paul Oh, Hua Su, Shuai Kang, Zhenying Han, Marie E. Faughnan, Eun-Jung Choi, Zhengda Sun, Lei Zhan, Fanxia Shen, and Vincent Degos
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0301 basic medicine ,Cancer Research ,Pathology ,Physiology ,Angiogenesis ,Activin Receptors ,Activin Receptors, Type II ,Clinical Biochemistry ,Type I ,Gene mutation ,Cardiovascular ,Transgenic ,Monocytes ,Mice ,0302 clinical medicine ,Arteriovenous malformations ,Smooth Muscle ,2.1 Biological and endogenous factors ,Aetiology ,Cerebrovascular disease ,Pediatric ,Mice, Knockout ,Neovascularization, Pathologic ,Microglia ,CD68 ,Endoglin ,Cell Differentiation ,Pharmacology and Pharmaceutical Sciences ,Animal models ,Endothelial stem cell ,medicine.anatomical_structure ,Monocyte differentiation ,medicine.symptom ,Intracranial Arteriovenous Malformations ,medicine.medical_specialty ,Knockout ,Clinical Sciences ,Myocytes, Smooth Muscle ,Mice, Transgenic ,Inflammation ,Type II ,Article ,03 medical and health sciences ,Rare Diseases ,Genetics ,medicine ,Animals ,Humans ,Oncology & Carcinogenesis ,Neovascularization ,Pathologic ,Myocytes ,Animal ,business.industry ,Macrophages ,Neurosciences ,Endothelial Cells ,Coculture Techniques ,Disease Models, Animal ,030104 developmental biology ,Disease Models ,Congenital Structural Anomalies ,business ,Activin Receptors, Type I ,030217 neurology & neurosurgery - Abstract
An abnormally high number of macrophages are present in human brain arteriovenous malformations (bAVM) with or without evidence of prior hemorrhage, causing unresolved inflammation that may enhance abnormal vascular remodeling and exacerbate the bAVM phenotype. The reasons for macrophage accumulation at the bAVM sites are not known. We tested the hypothesis that persistent infiltration and pro-inflammatory differentiation of monocytes in angiogenic tissues increase the macrophage burden in bAVM using two mouse models and human monocytes. Mouse bAVM was induced through deletion of AVM causative genes, Endoglin (Eng) globally or Alk1 focally, plus brain focal angiogenic stimulation. An endothelial cell and vascular smooth muscle cell co-culture system was used to analyze monocyte differentiation in the angiogenic niche. After angiogenic stimulation, the Eng-deleted mice had fewer CD68(+) cells at 2weeks (P=0.02), similar numbers at 4weeks (P=0.97), and more at 8weeks (P=0.01) in the brain angiogenic region compared with wild-type (WT) mice. Alk1-deficient mice also had a trend toward more macrophages/microglia 8weeks (P=0.064) after angiogenic stimulation and more RFP(+) bone marrow-derived macrophages than WT mice (P=0.01). More CD34(+) cells isolated from peripheral blood of patients with ENG or ALK1 gene mutation differentiated into macrophages than those from healthy controls (P 
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- 2016
36. Endoglin is required in Pax3-derived cells for embryonic blood vessel formation
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Helen M. Arthur, Thomas Gridley, Kira Young, Lucy Liaw, Calvin P.H. Vary, Eric Tweedie, Maria Cecilia Mancini, Luke T. Krebs, and Barbara A. Conley
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0301 basic medicine ,Vascular smooth muscle ,Angiogenesis ,Dorsal aorta ,Myocytes, Smooth Muscle ,Neovascularization, Physiologic ,Vascular malformation ,Biology ,Muscle, Smooth, Vascular ,Article ,HHT ,03 medical and health sciences ,Mice ,hemic and lymphatic diseases ,otorhinolaryngologic diseases ,Myocyte ,Animals ,Paired Box Transcription Factors ,Progenitor cell ,PAX3 Transcription Factor ,Molecular Biology ,Alleles ,Aorta ,Recombination, Genetic ,Pax3 ,Integrases ,Staining and Labeling ,Endoglin ,Intracellular Signaling Peptides and Proteins ,Neural crest ,Endothelial Cells ,Cell Biology ,Embryo, Mammalian ,Actins ,Cell biology ,030104 developmental biology ,Phenotype ,Somites ,Vascular smooth muscle cell differentiation ,embryonic structures ,Immunology ,Intersomitic ,Embryo Loss ,Blood Vessels ,Stem cell ,Gene Deletion ,Developmental Biology - Abstract
Mutations in endoglin, a TGFβ/BMP coreceptor, are causal for hereditary hemorrhagic telangiectasia (HHT). Endoglin-null (Eng-/-) mouse embryos die at embryonic day (E)10.5-11.5 due to defects in angiogenesis. In part, this is due to an absence of vascular smooth muscle cell differentiation and vessel investment. Prior studies from our lab and others have shown the importance of endoglin expression in embryonic development in both endothelial cells and neural crest stem cells. These studies support the hypothesis that endoglin may play cell-autonomous roles in endothelial and vascular smooth muscle cell precursors. However, the requirement for endoglin in vascular cell precursors remains poorly defined. Our objective was to specifically delete endoglin in neural crest- and somite-derived Pax3-positive vascular precursors to understand the impact on somite progenitor cell contribution to embryonic vascular development. Pax3Cre mice were crossed with Eng+/- mice to obtain compound mutant Pax3(Cre/+);Eng+/- mice. These mice were then crossed with homozygous endoglin LoxP-mutated (Eng(LoxP/LoxP)) mice to conditionally delete the endoglin gene in specific lineages that contribute to endothelial and smooth muscle constituents of developing embryonic vessels. Pax3(Cre/+);Eng(LoxP/)(-) mice showed a variety of vascular defects at E10.5, and none of these mice survived past E12.5. Embryos analyzed at E10.5 showed malformations suggestive of misdirection of the intersomitic vessels. The dorsal aorta showed significant dilation with associated vascular smooth muscle cells exhibiting disorganization and enhanced expression of smooth muscle differentiation proteins, including smooth muscle actin. These results demonstrate a requirement for endoglin in descendants of Pax3-expressing vascular cell precursors, and thus provides new insight into the cellular basis underlying adult vascular diseases such as HHT.
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- 2016
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37. Length-independent telomere damage drives cardiomyocyte senescence
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Douin-Echinard, Marissa J. Schafer, João F. Passos, Diana Jurk, Stella Victorelli, Rolando Berlinguer-Palmini, Helen M. Arthur, Neil Robertson, Damien Maggiorani, Emily Dookun, Laura C. Greaves, Simon Tual-Chalot, Carolyn M Roos, Clara Correia-Melo, Jordan D. Miller, Mikolaj Ogrodnik, Rhys Anderson, Anna Walaszczyk, Anthony B. Lagnado, Carole J. Proctor, James L. Kirkland, Edward Fielder, Jelena Mann, James Chapman, Gavin D. Richardson, Tamara Tchkonia, Nathan K. LeBrasseur, A Owens, Hanna Salmonowicz, Angelo Parini, Peter D. Adams, Kathy L Kolsky, Jodie Birch, and Jeanne Mialet-Perez
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Senescence ,Fibrosis ,DNA damage ,Ageing ,Regeneration (biology) ,medicine ,Biology ,medicine.disease ,Phenotype ,Mitosis ,Telomere ,Cell biology - Abstract
Ageing is the biggest risk factor for cardiovascular health and is associated with increased incidence of cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age-related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post-mitotic cardiomyocytes and investigate if clearance of senescent cells attenuates age related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent-like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction, and crucially can occur independently of cell-division and telomere length. Length-independent telomere damage in cardiomyocytes activates the classical senescence-inducing pathways, p21CIPand p16INK4aand results in a non-canonical senescence-associated secretory phenotype. Pharmacological or genetic clearance of senescent cells in mice alleviates myocardial hypertrophy and fibrosis, detrimental features of cardiac ageing, and promotes cardiomyocyte regeneration. Our data describes a mechanism by which senescence can occur and contribute to ageing in post-mitotic tissues.
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- 2018
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38. 152 Circulating non-classical monocytes are preferentially depleted from the circulation immediately after reperfusion in stemi patients and are associated with patient outcomes
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Helen M. Arthur, Lilia Draganova, Rajiv Das, Ioakim Spyridopoulos, Evgeniya V. Shmeleva, Karim Bennaceur, Alan Bagnall, Bernard Keavney, Simi Ali, Azfar Zaman, Mohaned Egred, Stephen Boag, Nicholas Howard, and Sarah Marsh
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medicine.medical_specialty ,CCR2 ,Ejection fraction ,business.industry ,ST elevation ,Monocyte ,CCL2 ,CD16 ,medicine.disease ,medicine.anatomical_structure ,Internal medicine ,CX3CR1 ,medicine ,Cardiology ,Myocardial infarction ,business - Abstract
Background In patients with acute myocardial infarction (MI), monocytes are rapidly recruited to the injured tissue, where they contribute to the inflammatory milieu. Different monocyte subsets exhibit distinct roles. Classical monocytes (CD16-CCR2 +CX3CR1-) migrate to sites of injury in response to CCL2 and differentiate into inflammatory macrophage, whilst non-classical monocytes (CD16 +CCR2- CX3CR1+) patrol the endothelium where they potentially interact with Fractalkine. The aim of this project was to characterise these circulating monocyte subpopulations dynamics in ST elevation MI patients immediately following reperfusion, and evaluate their prognostic value. Methods Flow Cytometry was used to quantify monocyte subpopulations in the blood of 59 STEMI patients the time of primary percutaneous coronary intervention for acute MI and at different times thereafter. Infarct size and microvascular obstruction (MVO) were assessed using cardiac MRI. Results STEMI patients showed a significant drop in circulating CD16 ++monocyte counts at 90 min post-reperfusion, whereas the CD16- monocyte counts remained unchanged at this early stage. This rapid decrease in CD16 ++monocytes was greater in individuals with a larger infarct size and lower left ventricular ejection fraction (LVEF). Conclusion This data suggests that CD16 ++monocytes during the acute phase post-MI may hold predictive value for myocardial injury and long-term patient outcome. Further work using a CX3CR1-GFP mouse model of ischemia-reperfusion (IR) is being used to investigate monocyte recruitment to the injured myocardium at 2 and 24 hours post IR and the role of Fractalkine signalling.
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- 2018
39. 106 Senescence as a therapeutic target for myocardial ageing
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Helen M. Arthur, Anna Walaszczyk, Simon Tual-Chalot, Rhys Anderson, Gavin D. Richardson, Ioakim Spyridopoulos, Rachael Redgrave, A Owens, Emily Dookun, and João F. Passos
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Senescence ,Cardiac function curve ,medicine.medical_specialty ,Navitoclax ,business.industry ,medicine.disease ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Ageing ,Fibrosis ,Internal medicine ,Heart failure ,medicine ,Myocardial infarction ,Senolytic ,business - Abstract
Ageing is the biggest risk factor for impaired cardiovascular health, cardiovascular disease being the leading cause of death in 40% of individuals over 65 years old. Ageing is associated not only with an increased prevalence of cardiovascular disease but also with a poorer prognosis, including increased mortality or incidence of heart failure after myocardial infarction (MI). We have demonstrated that aged (23 month old) mice have an accumulation of cardiomyocyte senescence, reduced regenerative potential and display increased mortality as well as impaired recovery following MI. Cellular senescence is defined not only by the irreversible loss of division potential but also by the production of a senescence-associated secretory phenotype (SASP). This cocktail of pro-inflammatory cytokines, chemokines, matrix proteases and growth factors can impact on tissue function, inducing fibrosis, extracellular matrix degeneration and driving inflammation. We have therefore begun to test if clearance of senescent cardiomyocytes, using the senolytic compound Navitoclax, has the potential to improve cardiac health and post MI outcomes in aged animals. Following treatment with Navitoclax, but prior to MI, aged mice demonstrated a reduction in senescent cardiomyocytes which was associated increased cardiomyocyte generation, a decline in myocardial hypertrophy and a decrease in fibrosis. Following MI, Navitoclax treated mice displayed a tendency towards improved survival and had a significant improvement in cardiac function when compared to vehicle controls. We conclude that clearance of senescent cells is a potential therapeutic strategy for the treatment of age related cardiac dysfunction.
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- 2018
40. 126 Endothelial endoglin is required to protect against high output heart failure
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Esha Singh, Benjamin J. Davison, Allan Lawrie, Helen M. Arthur, Simon Tual-Chalot, and Rachael Redgrave
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medicine.medical_specialty ,Cardiac output ,business.industry ,Angiogenesis ,Endoglin ,medicine.disease ,Afterload ,hemic and lymphatic diseases ,Internal medicine ,otorhinolaryngologic diseases ,Ventricular pressure ,Aortic pressure ,Cardiology ,Medicine ,Enlarged heart ,business ,High-output heart failure - Abstract
Objectives Endoglin is a co-receptor for TGFbeta/BMP9/10 signalling and ENG mutations lead to the vascular disorder hereditary haemorrhagic telangiectasia type I (HHT). Endoglin is also required for normal vascular development and angiogenesis, but little is known about endoglin’s role in quiescent adult vascular endothelium. Methods To investigate this role, tamoxifen was administered to adult Cdh5(PAC)-CreERT2;Engfl/fl mice to generate endothelial-specific depletion of endoglin (Eng-iKOe). Cardiac magnetic resonance imaging, myography, vascular casting, microsphere injection, immunohistology, qPCR and aortic telemetry were used to evaluate cardiovascular changes after endoglin knockdown. Results Endothelial-specific loss of endoglin leads to an enlarged heart and cardiomyocyte hypertrophy within 5 weeks, progressing to high output heart failure (HOHF). In vivo aortic telemetry revealed significant loss of aortic pressure within a few days of endoglin depletion. Increased cardiac size and reduced cardiac afterload were confirmed by ventricular pressure loop analysis. As HOHF could result from arteriovenous malformations (AVMs), and these are found primarily in mucocutaneous and pulmonary tissues in HHT, we systematically screened for AVMs using microspheres and vascular casting. Although AVMs were absent in the majority of tissues, they were observed in the pelvic region and may account for the rapid increase in cardiac output. Having also observed an increase of VEGF-A protein in tissues from Eng-iKOe mice, we found that inhibition of VEGFR2 was protective against enlargement of the heart and dilatation of the ventricles. Conclusion Our results showed the essential role of endoglin in the maintenance of adult cardiovasculature through crosstalk with the VEGF signalling pathway.
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- 2018
41. 142 Accumulation of cardiomyocyte senescence following ischaemia-reperfusion injury (IRI); a potential therapeutic target?
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Gavin D. Richardson, Rachael Redgrave, Emily Dookun, A Owens, Simon Tual-Chalot, Ioakim Spyridopoulos, Anna Walaszczyk, Oliver E Yausep, Helen M. Arthur, and João F. Passos
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Genetically modified mouse ,Senescence ,business.industry ,Regeneration (biology) ,medicine.disease ,medicine.disease_cause ,Telomere ,Heart failure ,Cancer research ,Medicine ,Myocardial infarction ,Ligation ,business ,Oxidative stress - Abstract
Introduction Myocardial infarction (MI) is a prominent cause of morbidity and mortality globally. While reperfusion via primary percutaneous coronary intervention is the gold-standard therapy, it can lead to the phenomenon ischemia-reperfusion injury (IRI), characterised by progressive remodelling and heart failure. Little is understood regarding to the mechanisms driving IRI, however, increased oxidative stress is known to play a role. Our previous studies demonstrate that during ageing increased oxidative stress drives telomere associated DNA damage foci (TAF) induced cardiomyocyte senescence, which is directly associated with a hypertrophic phenotype. Furthermore senescent cardiomyocytes express a pro-fibrotic profile; in particular an up-regulation of TGF-β expression. We now hypothesise that cardiomyocyte senescence contributes to remodelling subsequent to MI and IRI via similar mechanisms, and as such represents a potential therapeutic target. Methods Young three month old mice underwent 60 min surgical ligation of the left anterior descending coronary artery to mimic MI followed by reperfusion. Histological analysis at numerous time points post-MI for several senescence markers was performed. Results and conclusions In support of our hypothesis, we have observed that within the surviving myocardium, proximal to the infarct region, cardiomyocytes acquire a senescent-like phenotype. This is demonstrated by an increase in senescence markers including SA-β-Gal, p21 and p16, in addition to an accumulation of TAF. As well as this we verified that mice displayed classical pathophysiological aspects related to MI. Using in vitro studies and transgenic mouse models we aim to better understand the biology underlying cardiomyocyte senescence, and to establish the mechanisms underlying senescence contribution to remodelling. Furthermore we aim to ascertain if modulation or clearance of cardiomyocyte senescence promotes regeneration and improves outcome following IRI.
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- 2018
42. Executive summary of the 12th HHT international scientific conference
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Johannes J. Mager, Helen M. Arthur, Christine L. Mummery, Luisa María Botella, Christopher C.W. Hughes, Marco C. Post, Elisabetta Buscarini, Anna E Hosman, Franck Lebrin, Jillian W. Andrejecsk, Sophie Dupuis-Girod, and Claire L. Shovlin
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0301 basic medicine ,EXPRESSION ,Cancer Research ,History ,Physiology ,BEVACIZUMAB ,education ,Clinical Biochemistry ,MEDLINE ,PHENOTYPE ,Clinical biochemistry ,HHT ,Arteriovenous malformation ,03 medical and health sciences ,PULMONARY ARTERIOVENOUS-MALFORMATIONS ,Oncology & Carcinogenesis ,Medical education ,Executive summary ,Science & Technology ,Endoglin ,Autosomal dominant trait ,1103 Clinical Sciences ,Activin receptor-like kinase 1 (ALK1) ,RANDOMIZED CLINICAL-TRIAL ,030104 developmental biology ,SEVERITY ,Epistaxis ,Peripheral Vascular Disease ,Hereditary hemorrhagic telangiectasia ,Cardiovascular System & Cardiology ,1115 Pharmacology And Pharmaceutical Sciences ,Life Sciences & Biomedicine ,VASCULAR MALFORMATIONS ,Theme (narrative) - Abstract
Hereditary hemorrhagic telangiectasia is an autosomal dominant trait affecting approximately 1 in 5000 people. A pathogenic DNA sequence variant in the ENG, ACVRL1 or SMAD4 genes, can be found in the majority of patients. The 12th International Scientific HHT Conference was held on June 8–11, 2017 in Dubrovnik, Croatia to present and discuss the latest scientific achievements, and was attended by over 200 scientific and clinical researchers. In total 174 abstracts were accepted of which 58 were selected for oral presentations. This article covers the basic science and clinical talks, and discussions from three theme-based workshops. We focus on significant emergent themes and unanswered questions. Understanding these topics and answering these questions will help to define the future of HHT research and therapeutics, and ultimately bring us closer to a cure.
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- 2018
43. Soluble endoglin regulates expression of angiogenesis-related proteins and induction of arteriovenous malformations in a mouse model of hereditary hemorrhagic telangiectasia
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Carmelo Bernabeu, Luisa María Botella, Simon Tual-Chalot, Helen M. Arthur, Eunate Gallardo-Vara, Ministerio de Economía, Industria y Competitividad (España), Centro de Investigación Biomédica en Red Enfermedades Raras (España), British Heart Foundation, Instituto de Salud Carlos III, Gallardo-Vara, Eunate [0000-0003-4733-0878], Botella, Luisa María [0000-0002-6310-2245], Arthur, Helen M. [0000-0001-6522-1363], Bernabéu, Carmelo [0000-0002-1563-6162], Gallardo-Vara, Eunate, Botella, Luisa María, Arthur, Helen M., and Bernabéu, Carmelo
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TGF-β ,0301 basic medicine ,Angiogenesis ,Endothelial cells ,Neuroscience (miscellaneous) ,lcsh:Medicine ,Medicine (miscellaneous) ,Endogeny ,Biology ,Models, Biological ,Retina ,General Biochemistry, Genetics and Molecular Biology ,HHT ,Arteriovenous Malformations ,03 medical and health sciences ,chemistry.chemical_compound ,Immunology and Microbiology (miscellaneous) ,Cell Movement ,TGF beta signaling pathway ,lcsh:Pathology ,Human Umbilical Vein Endothelial Cells ,otorhinolaryngologic diseases ,Animals ,Humans ,TGF-beta ,Lung ,Pathological ,Mice, Knockout ,Wound Healing ,Neovascularization, Pathologic ,lcsh:R ,Endoglin ,Retinal ,AVM ,Phenotype ,Transmembrane protein ,Disease Models, Animal ,030104 developmental biology ,Gene Expression Regulation ,Solubility ,chemistry ,Cancer research ,Telangiectasia, Hereditary Hemorrhagic ,Biomarkers ,lcsh:RB1-214 ,Research Article - Abstract
22 p.-6 fig.-1 tab.-3 fig. supl.-2 tab.supl., Endoglin is a transmembrane glycoprotein expressed in vascular endothelium that plays a key role in angiogenesis. Mutations in the endoglin gene (ENG) cause Hereditary Hemorrhagic Telangiectasia type 1 (HHT1), characterized by arteriovenous malformations (AVMs) in different organs. These vascular lesions derive from abnormal processes of angiogenesis where aberrant vascular remodeling leads to focal loss of capillaries. Current treatments for HHT1 include anti-angiogenic therapies. Interestingly, a circulating form of endoglin (also known as soluble endoglin, sEng), proteolytically released from the membrane-bound protein and displaying anti-angiogenic activity, has been described in several endothelial-related pathological conditions. Using human and mouse endothelial cells, we find that sEng downregulates several pro-angiogenic and pro-migratory proteins involved in angiogenesis. However, this effect is much reduced in endothelial cells that lack endogenous transmembrane endoglin, suggesting that the anti-angiogenic activity of sEng is dependent on the presence of endogenous transmembrane endoglin protein. In fact, sEng partially restores the phenotype of endoglin-silenced endothelial cells back to that of normal endothelial cells. Moreover, using an established neonatal retinal model of HHT1 with depleted endoglin in the vascular endothelium, sEng treatment decreases the number of AVMs and has a normalizing effect on the vascular phenotype with respect to vessel branching, vascular density and migration of the vascular plexus towards the retinal periphery. Taken together these data show that circulating sEng can influence vascular development and AVMs by modulating angiogenesis and that its effect on endothelial cells depends on expression of endogenous endoglin., This work was supported by grants from Ministerio de Economia, Industria y Competitividad of Spain (SAF2010-19222 and SAF2013-43421-R to CB), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER; ISCIII-CB06/07/0038) and the British Heart Foundation (PG/14/86/31177 to HMA). EG-V was supported by the international mobility program of Ministerio deEconomía, Industria y Competitividad (EEBB-I-14-09020 and EEBB-I-15-10398). CIBERER is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain supported by FEDER funds.
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- 2018
44. Executive summary of the 11th HHT international scientific conference
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Urban W. Geisthoff, Helen M. Arthur, Pascal Lacombe, Whitney Wooderchak-Donahue, Beth L. Roman, Scott O. Trerotola, Sebastiaan Velthuis, Christopher C.W. Hughes, Mary E. Meek, James R. Gossage, and Paul Oh
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Cancer Research ,Medical education ,Pathology ,medicine.medical_specialty ,Executive summary ,Physiology ,business.industry ,Activin Receptors, Type II ,Clinical Biochemistry ,Medizin ,Endoglin ,Receptors, Cell Surface ,Congresses as Topic ,ANTIGENS CD ,Activin Receptors Type II ,Antigens, CD ,medicine ,Humans ,Telangiectasia, Hereditary Hemorrhagic ,business ,AKA ,Smad4 Protein ,Theme (narrative) - Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a hereditary condition that results in vascular malfor- mations throughout the body, which have a proclivity to rupture and bleed. HHT has a worldwide incidence of about 1:5000 and approximately 80 % of cases are due to mutations in ENG, ALK1 (aka activin receptor-like kinase 1 or ACVRL1) and SMAD4. Over 200 international clinicians and scientists met at Captiva Island, Florida from June 11-June 14, 2015 to present and discuss the latest research on HHT. 156 abstracts were accepted to the meeting and 60 were selected for oral presentations. The first two sections of this article present summaries of the basic science and clinical talks. Here we have summarized talks covering key themes, focusing on areas of agreement, disagreement, and unanswered questions. The final four sections summarize discussions in the Workshops, which were theme-based topical discussions led by two moderators. We hope this overview will educate as well as inspire those within the field and from outside, who have an interest in the science and treatment of HHT.
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- 2015
45. 11th International HHT Scientific Conference
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Y Yin, Simon Tual-Chalot, Rachael Redgrave, Benjamin J. Davison, Lars Jakobsson, and Helen M. Arthur
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Cardiac function curve ,Cancer Research ,Adult life ,medicine.medical_specialty ,Physiology ,business.industry ,Internal medicine ,Clinical Biochemistry ,Cardiology ,medicine ,Endoglin ,business - Published
- 2015
46. Inhibiting DPP4 in a mouse model of HHT1 results in a shift towards regenerative macrophages and reduces fibrosis after myocardial infarction
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Janita A. Maring, Anke M. Smits, Karien C. Wiesmeijer, Marie-José Goumans, Wineke Bakker, Helen M. Arthur, Calinda K. E. Dingenouts, Asja T. Moerkamp, and Kirsten Lodder
- Subjects
0301 basic medicine ,Male ,Physiology ,Myocardial Infarction ,Haploinsufficiency ,030204 cardiovascular system & hematology ,Cardiovascular Physiology ,Pathology and Laboratory Medicine ,Monocytes ,Mice ,White Blood Cells ,0302 clinical medicine ,Fibrosis ,Transforming Growth Factor beta ,Animal Cells ,Medicine and Health Sciences ,Myocardial infarction ,Immune Response ,Multidisciplinary ,Chemistry ,Endoglin ,Heart ,Animal Models ,Experimental Organism Systems ,Medicine ,Telangiectasia, Hereditary Hemorrhagic ,medicine.symptom ,Cellular Types ,Anatomy ,Research Article ,medicine.medical_specialty ,Heterozygote ,Stromal cell ,Cardiac Ventricles ,Dipeptidyl Peptidase 4 ,Heart Ventricles ,Immune Cells ,Science ,Immunology ,Cardiology ,Inflammation ,Mice, Transgenic ,Mouse Models ,Research and Analysis Methods ,Peripheral blood mononuclear cell ,03 medical and health sciences ,Model Organisms ,Signs and Symptoms ,Diagnostic Medicine ,Internal medicine ,medicine ,Animals ,Humans ,Regeneration ,Dipeptidyl-Peptidase IV Inhibitors ,Blood Cells ,Macrophages ,Myocardium ,Wild type ,Biology and Life Sciences ,Cell Biology ,medicine.disease ,Chemokine CXCL12 ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Cardiovascular Anatomy ,Myocardial infarction complications - Abstract
AimsHereditary Hemorrhagic Telangiectasia type-1 (HHT1) is a genetic vascular disorder caused by haploinsufficiency of the TGFβ co-receptor endoglin. Dysfunctional homing of HHT1 mononuclear cells (MNCs) towards the infarcted myocardium hampers cardiac recovery. HHT1-MNCs have elevated expression of dipeptidyl peptidase-4 (DPP4/CD26), which inhibits recruitment of CXCR4-expressing MNCs by inactivation of stromal cell-derived factor 1 (SDF1). We hypothesize that inhibiting DPP4 will restore homing of HHT1-MNCs to the infarcted heart and improve cardiac recovery.Methods and resultsAfter inducing myocardial infarction (MI), wild type (WT) and endoglin heterozygous (Eng+/-) mice were treated for 5 days with the DPP4 inhibitor Diprotin A (DipA). DipA increased the number of CXCR4+ MNCs residing in the infarcted Eng+/- hearts (Eng+/- 73.17±12.67 vs. Eng+/- treated 157.00±11.61, P = 0.0003) and significantly reduced infarct size (Eng+/- 46.60±9.33% vs. Eng+/- treated 27.02±3.04%, P = 0.03). Echocardiography demonstrated that DipA treatment slightly deteriorated heart function in Eng+/- mice. An increased number of capillaries (Eng+/- 61.63±1.43 vs. Eng+/- treated 74.30±1.74, P = 0.001) were detected in the infarct border zone whereas the number of arteries was reduced (Eng+/- 11.88±0.63 vs. Eng+/- treated 6.38±0.97, P = 0.003). Interestingly, while less M2 regenerative macrophages were present in Eng+/- hearts prior to DipA treatment, (WT 29.88±1.52% vs. Eng+/- 12.34±1.64%, PConclusionsIn this study, we demonstrate that systemic DPP4 inhibition restores the impaired MNC homing in Eng+/- animals post-MI, and enhances cardiac repair, which might be explained by restoring the balance between the inflammatory and regenerative macrophages present in the heart.
- Published
- 2017
47. Developmental Vascular Biology and Genetics Workshop VI and Vascular Inflammation Workshop organized by NAVBO
- Author
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P Oh, Helen M. Arthur, Rachael Redgrave, and Simon Tual-Chalot
- Subjects
Cancer Research ,Expression (architecture) ,Physiology ,Angiogenesis ,Clinical Biochemistry ,Vascular patterning ,ACVRL1 ,Biology ,Endoglin ,Neuroscience ,Cell biology - Published
- 2014
48. LRG1 promotes angiogenesis by modulating endothelial TGF-β signalling
- Author
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Vineeta Tripathi, Matthew Swire, Zhenhua Zhai, John Greenwood, Helen M. Arthur, Stephen E. Moss, Ulrich F O Luhmann, Sabu Abraham, Jenny A. G. McKenzie, Clemens Lange, Natasha Jeffs, Xiaomeng Wang, and James W B Bainbridge
- Subjects
Angiogenic Switch ,Angiogenesis ,In Vitro Techniques ,Retinal Neovascularization ,Biology ,Article ,Transforming Growth Factor beta1 ,Neovascularization ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Cells, Cultured ,Glycoproteins ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Multidisciplinary ,Retinal Vessels ,Endoglin ,Hedgehog signaling pathway ,3. Good health ,Mice, Inbred C57BL ,Choroidal neovascularization ,LRG1 ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Endothelium, Vascular ,medicine.symptom ,Receptors, Transforming Growth Factor beta ,Signal Transduction ,Transforming growth factor - Abstract
Aberrant neovascularization contributes to diseases such as cancer, blindness and atherosclerosis, and is the consequence of inappropriate angiogenic signalling. Although many regulators of pathogenic angiogenesis have been identified, our understanding of this process is incomplete. Here we explore the transcriptome of retinal microvessels isolated from mouse models of retinal disease that exhibit vascular pathology, and uncover an upregulated gene, leucine-rich alpha-2-glycoprotein 1 (Lrg1), of previously unknown function. We show that in the presence of transforming growth factor-β1 (TGF-β1), LRG1 is mitogenic to endothelial cells and promotes angiogenesis. Mice lacking Lrg1 develop a mild retinal vascular phenotype but exhibit a significant reduction in pathological ocular angiogenesis. LRG1 binds directly to the TGF-β accessory receptor endoglin, which, in the presence of TGF-β1, results in promotion of the pro-angiogenic Smad1/5/8 signalling pathway. LRG1 antibody blockade inhibits this switch and attenuates angiogenesis. These studies reveal a new regulator of angiogenesis that mediates its effect by modulating TGF-β signalling. LRG1 is identified as a new regulator of TGF-β signalling that promotes angiogenesis via a TβRII–ALK1–ENG–Smad1/5/8 signalling pathway; antibody-mediated inhibition of LRG1 reduces pathogenic neovascularization in a mouse model of retinal injury. Defective angiogenesis is a common feature in many diseases including age-related macular degeneration, atherosclerosis, rheumatoid arthritis and cancer. Here John Greenwood and colleagues identify a novel angiogenic glycoprotein of previously unknown function — leucine-rich-alpha-2-glycoprotein 1 (LRG1) — that exerts its effect through modifying TGF-β signalling. LRG1, upregulated in vitreous samples from humans with proliferative diabetic retinopathy, activates an angiogenic switch by binding to the receptor endoglin and promoting pro-angiogenic TGF-β signalling. Antibody-mediated inhibition of LRG1 reduces pathogenic neovascularization in a mouse model of retinal injury, which suggests that LRG1 is a possible therapeutic target for controlling pathological angiogenesis in ocular disease.
- Published
- 2013
49. Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination
- Author
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Peter ten Dijke, Sara I. Cunha, Zhenhua Zhai, Eliane Cortez, Marie-José Goumans, Charlotte Anderberg, Jonas Fuxe, Evangelia Pardali, Marta Paez-Ribes, Bengt Johansson, Oriol Casanovas, Helen M. Arthur, Kristian Pietras, Ross A. Cordiner, Jill R. Johnson, and Marcela Franco
- Subjects
Vascular Endothelial Growth Factor A ,Pathology ,medicine.medical_specialty ,Epithelial-Mesenchymal Transition ,Endothelium ,Angiogenesis ,Immunology ,Neovascularization, Physiologic ,Biology ,Article ,Neovascularization ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Liver Neoplasms, Experimental ,0302 clinical medicine ,hemic and lymphatic diseases ,otorhinolaryngologic diseases ,medicine ,Animals ,Immunology and Allergy ,Epithelial–mesenchymal transition ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,GTPase-Activating Proteins ,Twist-Related Protein 1 ,Endoglin ,Intracellular Signaling Peptides and Proteins ,Cancer ,Cell Biology ,medicine.disease ,Extravasation ,3. Good health ,Pancreatic Neoplasms ,Vascular endothelial growth factor ,Neuroendocrine Tumors ,medicine.anatomical_structure ,chemistry ,Cancer and Oncology ,030220 oncology & carcinogenesis ,Female ,Endothelium, Vascular ,medicine.symptom ,030215 immunology - Abstract
Genetic deficiency for endoglin leads to increased metastatic capability by weakening the endothelial cell barrier., Therapy-induced resistance remains a significant hurdle to achieve long-lasting responses and cures in cancer patients. We investigated the long-term consequences of genetically impaired angiogenesis by engineering multiple tumor models deprived of endoglin, a co-receptor for TGF-β in endothelial cells actively engaged in angiogenesis. Tumors from endoglin-deficient mice adapted to the weakened angiogenic response, and refractoriness to diminished endoglin signaling was accompanied by increased metastatic capability. Mechanistic studies in multiple mouse models of cancer revealed that deficiency for endoglin resulted in a tumor vasculature that displayed hallmarks of endothelial-to-mesenchymal transition, a process of previously unknown significance in cancer biology, but shown by us to be associated with a reduced capacity of the vasculature to avert tumor cell intra- and extravasation. Nevertheless, tumors deprived of endoglin exhibited a delayed onset of resistance to anti-VEGF (vascular endothelial growth factor) agents, illustrating the therapeutic utility of combinatorial targeting of multiple angiogenic pathways for the treatment of cancer.
- Published
- 2013
50. Modulation of endoglin expression in islets of langerhans by VEGF reveals a novel regulator of islet endothelial cell function
- Author
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Claire E. Clarkin, Helen M. Arthur, Aileen King, Bo Liu, Caroline P.D. Wheeler-Jones, Emmanuel O. Sobamowo, Marwa Mahmoud, and Peter M. Jones
- Subjects
Male ,Vascular Endothelial Growth Factor A ,0301 basic medicine ,CD31 ,endocrine system diseases ,Antigens, CD34 ,Tissue Culture Techniques ,Mice ,0302 clinical medicine ,hemic and lymphatic diseases ,Medicine(all) ,Regulation of gene expression ,Mice, Inbred ICR ,geography.geographical_feature_category ,Endoglin ,General Medicine ,Islet ,VEGF ,Recombinant Proteins ,Cell biology ,Platelet Endothelial Cell Adhesion Molecule-1 ,Endothelial stem cell ,Vascular endothelial growth factor A ,030220 oncology & carcinogenesis ,Islets ,Signal Transduction ,Research Article ,endocrine system ,medicine.medical_specialty ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Islets of Langerhans ,03 medical and health sciences ,Internal medicine ,otorhinolaryngologic diseases ,medicine ,Animals ,RNA, Messenger ,Hypoxia inducible factor-1 alpha ,geography ,Biochemistry, Genetics and Molecular Biology(all) ,Endothelial Cells ,Kinase insert domain receptor ,Vascular Endothelial Growth Factor Receptor-2 ,030104 developmental biology ,Endocrinology ,Gene Expression Regulation ,Transforming growth factor - Abstract
Background: Endoglin/CD105 is an auxiliary receptor for transforming growth factor-β with established roles in vascular remodelling. It has recently been shown that heterozygous endoglin deficiency in mice decreases insulin secretion in an animal model of obesity, highlighting a potential role for endoglin in the regulation of islet function. We have previously identified two different populations of endoglin expressing cells in human and mouse islets which are: (i) endothelial cells (ECs) and (ii) islet mesenchymal stromal cells. The contribution of islet EC endoglin expression to islet development and sensitivity to VEGF is unknown and is the focus of this study. Results: In vitro culture of mouse islets with VEGF164 for 48 h increased endoglin mRNA levels above untreated controls but VEGF did not modulate VEGFR2, CD31 or CD34 mRNA expression or islet viability. Removal of EC-endoglin expression in vivo reduced islet EC area but had no apparent effect on islet size or architecture. Conclusion: EC-specific endoglin expression in islets is sensitive to VEGF and plays partial roles in driving islet vascular development, however such regulation appears to be distinct to mechanisms required to modulate islet viability and size.
- Published
- 2016
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