31 results on '"Helen M. Arthur"'
Search Results
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. 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
12. 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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13. 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
14. 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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15. 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
16. 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
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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.
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- 2017
17. Interaction Between ALK1 Signaling and Connexin40 in the Development of Arteriovenous Malformations
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Konstantinos Gkatzis, Jérémy Thalgott, Damien Dos-Santos-Luis, Sabrina Martin, Noël Lamandé, Marie France Carette, Frans Disch, Repke J. Snijder, Cornelius J. Westermann, Johannes J. Mager, S. Paul Oh, Lucile Miquerol, Helen M. Arthur, Christine L. Mummery, Franck Lebrin, Institut de Biologie du Développement de Marseille (IBDM), and Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Activin Receptors, Type II ,Mutant ,Mice, Transgenic ,Vasodilation ,Haploinsufficiency ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Vascular Remodeling ,Biology ,Transfection ,Connexins ,alpha-smooth muscle actin ,03 medical and health sciences ,connexin 40 ,medicine ,Animals ,Humans ,hereditary hemorrhagic telangiectasia ,Genetic Predisposition to Disease ,arteriovenous malformations ,Cells, Cultured ,mouse ,chemistry.chemical_classification ,Reactive oxygen species ,Neovascularization, Pathologic ,Kinase ,Endothelial Cells ,Retinal Vessels ,ACVRL1 ,Molecular biology ,Mice, Mutant Strains ,Disease Models, Animal ,Phenotype ,030104 developmental biology ,chemistry ,RNA Interference ,Telangiectasia, Hereditary Hemorrhagic ,erythrocyte ,Signal transduction ,Reactive Oxygen Species ,Cardiology and Cardiovascular Medicine ,Activin Receptors, Type I ,Signal Transduction - Abstract
Objective— To determine the role of Gja5 that encodes for the gap junction protein connexin40 in the generation of arteriovenous malformations in the hereditary hemorrhagic telangiectasia type 2 (HHT2) mouse model. Approach and Results— We identified GJA5 as a target gene of the bone morphogenetic protein-9/activin receptor-like kinase 1 signaling pathway in human aortic endothelial cells and importantly found that connexin40 levels were particularly low in a small group of patients with HHT2. We next took advantage of the Acvrl1 +/− mutant mice that develop lesions similar to those in patients with HHT2 and generated Acvrl1 +/− ; Gja5 EGFP/+ mice. Gja5 haploinsufficiency led to vasodilation of the arteries and rarefaction of the capillary bed in Acvrl1 +/− mice. At the molecular level, we found that reduced Gja5 in Acvrl1 +/− mice stimulated the production of reactive oxygen species, an important mediator of vessel remodeling. To normalize the altered hemodynamic forces in Acvrl1 +/− ; Gja5 EGFP/+ mice, capillaries formed transient arteriovenous shunts that could develop into large malformations when exposed to environmental insults. Conclusions— We identified GJA5 as a potential modifier gene for HHT2. Our findings demonstrate that Acvrl1 haploinsufficiency combined with the effects of modifier genes that regulate vessel caliber is responsible for the heterogeneity and severity of the disease. The mouse models of HHT have led to the proposal that 3 events—heterozygosity, loss of heterozygosity, and angiogenic stimulation—are necessary for arteriovenous malformation formation. Here, we present a novel 3-step model in which pathological vessel caliber and consequent altered blood flow are necessary events for arteriovenous malformation development.
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- 2016
18. ENDOGLIN Is Dispensable for Vasculogenesis, but Required for Vascular Endothelial Growth Factor-Induced Angiogenesis
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Helen M. Arthur, Michelle Letarte, Evangelia Pardali, Janita A. Maring, Franck Lebrin, Laurens A. van Meeteren, Sabrina Martin, Jeroen Korving, Christine L. Mummery, Midory Thorikay, Charles P. Theuer, Sander van den Driesche, Lukas J. A. C. Hawinkels, Zhen Liu, Maarten van Dinther, Marie-José Goumans, Peter ten Dijke, Kazuki Kobayashi, and Stieneke van der Brink
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Vascular Endothelial Growth Factor A ,Angiogenesis ,Fluorescent Antibody Technique ,Neovascularization, Physiologic ,lcsh:Medicine ,Embryoid body ,Biology ,Cardiovascular ,Mice ,chemistry.chemical_compound ,Vasculogenesis ,Vascular Biology ,Molecular Cell Biology ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,lcsh:Science ,Embryonic Stem Cells ,Peripheral Vascular Diseases ,Multidisciplinary ,Stem Cells ,Mechanisms of Signal Transduction ,lcsh:R ,Endoglin ,Intracellular Signaling Peptides and Proteins ,Endothelial Cells ,Cell Differentiation ,Flow Cytometry ,Cell biology ,Vascular endothelial growth factor ,Vascular endothelial growth factor B ,Vascular endothelial growth factor A ,chemistry ,Vascular endothelial growth factor C ,Immunology ,Medicine ,lcsh:Q ,Cellular Types ,Research Article ,Developmental Biology ,Signal Transduction - Abstract
ENDOGLIN (ENG) is a co-receptor for transforming growth factor-β (TGF-β) family members that is highly expressed in endothelial cells and has a critical function in the development of the vascular system. Mutations in Eng are associated with the vascular disease known as hereditary hemorrhagic telangiectasia type l. Using mouse embryonic stem cells we observed that angiogenic factors, including vascular endothelial growth factor (VEGF), induce vasculogenesis in embryoid bodies even when Eng deficient cells or cells depleted of Eng using shRNA are used. However, ENG is required for the stem cell-derived endothelial cells to organize effectively into tubular structures. Consistent with this finding, fetal metatarsals isolated from E17.5 Eng heterozygous mouse embryos showed reduced VEGF-induced vascular network formation. Moreover, shRNA-mediated depletion and pharmacological inhibition of ENG in human umbilical vein cells mitigated VEGF-induced angiogenesis. In summary, we demonstrate that ENG is required for efficient VEGF-induced angiogenesis.
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- 2014
19. The Tissue-Specific RNA Binding Protein T-STAR Controls Regional Splicing Patterns of Neurexin Pre-mRNAs in the Brain
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Philippe Fort, Gavin J. Clowry, Lynn Overman, Caroline Dalgliesh, Julian P. Venables, Marina Danilenko, Ingrid Ehrmann, Yilei Liu, David J. Elliott, Moira Crosier, Susan Lindsay, Helen M. Arthur, Institute of Genetic Medicine [Newcastle], Newcastle University [Newcastle], Institute of Neuroscience [Newcastle] (ION), Centre de recherche en Biologie Cellulaire (CRBM), and Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)
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Cancer Research ,Anatomy and Physiology ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Exonic splicing enhancer ,Gene Expression ,Biochemistry ,Gene Splicing ,Exon ,0302 clinical medicine ,Nucleic Acids ,Gene Duplication ,RNA Precursors ,Genetics (clinical) ,Genetics ,0303 health sciences ,Brain ,RNA-Binding Proteins ,Genomics ,Exons ,Functional Genomics ,RNA splicing ,Research Article ,lcsh:QH426-470 ,RNA Splicing ,Biology ,Molecular Genetics ,03 medical and health sciences ,Splicing factor ,SR protein ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Animals ,Humans ,Gene Regulation ,Gene Networks ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Evolutionary Developmental Biology ,Alternative splicing ,Intron ,Reproductive System ,Molecular Development ,Comparative Genomics ,lcsh:Genetics ,Neuroanatomy ,Alternative Splicing ,[SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis ,RNA ,Gene Function ,Genome Expression Analysis ,Animal Genetics ,030217 neurology & neurosurgery ,Minigene ,Developmental Biology ,Neuroscience - Abstract
The RNA binding protein T-STAR was created following a gene triplication 520–610 million years ago, which also produced its two parologs Sam68 and SLM-1. Here we have created a T-STAR null mouse to identify the endogenous functions of this RNA binding protein. Mice null for T-STAR developed normally and were fertile, surprisingly, given the high expression of T-STAR in the testis and the brain, and the known infertility and pleiotropic defects of Sam68 null mice. Using a transcriptome-wide search for splicing targets in the adult brain, we identified T-STAR protein as a potent splicing repressor of the alternatively spliced segment 4 (AS4) exons from each of the Neurexin1-3 genes, and exon 23 of the Stxbp5l gene. T-STAR protein was most highly concentrated in forebrain-derived structures like the hippocampus, which also showed maximal Neurexin1-3 AS4 splicing repression. In the absence of endogenous T-STAR protein, Nrxn1-3 AS4 splicing repression dramatically decreased, despite physiological co-expression of Sam68. In transfected cells Neurexin3 AS4 alternative splicing was regulated by either T-STAR or Sam68 proteins. In contrast, Neurexin2 AS4 splicing was only regulated by T-STAR, through a UWAA-rich response element immediately downstream of the regulated exon conserved since the radiation of bony vertebrates. The AS4 exons in the Nrxn1 and Nrxn3 genes were also associated with distinct patterns of conserved UWAA repeats. Consistent with an ancient mechanism of splicing control, human T-STAR protein was able to repress splicing inclusion of the zebrafish Nrxn3 AS4 exon. Although Neurexin1-3 and Stxbp5l encode critical synaptic proteins, T-STAR null mice had no detectable spatial memory deficits, despite an almost complete absence of AS4 splicing repression in the hippocampus. Our work identifies T-STAR as an ancient and potent tissue-specific splicing regulator that uses a concentration-dependent mechanism to co-ordinately regulate regional splicing patterns of the Neurexin1-3 AS4 exons in the mouse brain., Author Summary Alternative splicing plays a key role in animal development and is largely controlled by the expression of RNA binding proteins. Most RNA binding proteins exist as families of sister proteins called paralogs, which result from gene amplification, including T-STAR, which is closely related to Sam68 and SLM-1. T-STAR, Sam68, and SLM-1 usually behave identically in splicing control in transfected cells. Here we report the physiological functions of T-STAR protein by knocking its parent gene out in the mouse. Surprisingly we observed no defects in germ cell maturation without T-STAR protein, an unexpected result given T-STAR protein is mainly expressed in the testis and its paralog Sam68 is essential for male fertility. Instead, we find T-STAR controls a panel of splicing targets that encode important synaptic proteins. T-STAR acts as a potent splicing repressor to establish regional splicing patterns of these target exons in the brain. Forebrain-derived structures like the hippocampus strongly express T-STAR protein to repress these target exons. Some T-STAR regulated splicing targets overlap with Sam68, but T-STAR also regulates its own distinct targets. Comparative genomic analyses are consistent with an ancient mechanism of splicing control by T-STAR that has been conserved since the radiation of bony vertebrates.
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- 2013
20. Nonsynonymous variants in the SMAD6 gene predispose to congenital cardiovascular malformation
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Richard J. Lewis, Peter ten Dijke, Judith A. Goodship, Bernard Keavney, Huay Lin Tan, Ana Töpf, Linda Sneddon, Elise Glen, Peter Avery, John O'Sullivan, Christopher Wren, Darroch Hall, and Helen M. Arthur
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Nonsynonymous substitution ,Smad6 Protein ,Cardiovascular Abnormalities ,SMAD ,Biology ,Bone morphogenetic protein ,Bone Morphogenetic Protein Receptors, Type II ,rare genetic variants ,Cell Line ,Mice ,Gene Frequency ,Genetic variation ,Genetics ,Animals ,Humans ,BMP ,Genetic Predisposition to Disease ,Gene ,Genetics (clinical) ,Bone Morphogenetic Protein Receptors, Type I ,Research Articles ,Alkaline Phosphatase ,Phenotype ,congenital heart defects ,BMPR1A ,United Kingdom ,BMPR2 ,Bone Morphogenetic Proteins ,Mutation ,Signal Transduction - Abstract
Congenital cardiovascular malformation (CVM) exhibits familial predisposition, but most of the specific genetic factors involved are unknown. Postulating that rare variants in genes in critical cardiac developmental pathways predispose to CVM, we systematically surveyed three genes of the bone morphogenetic protein (BMP) signaling pathway for novel variants. Exonic, splice site, and untranslated regions of BMPR1A, BMPR2, and SMAD6 genes were sequenced in 90 unrelated sporadic cases of CVM. One nonsynonymous variant (p.C484F) with predicted functional impact was found in the MAD homology 2 domain of SMAD6, an intracellular inhibitor of BMP signaling. Sequencing this domain in an additional 346 cases of CVM yielded two further nonsynonymous variants (p.P415L and p.A325T). Functional effects of all three SMAD6 mutations were investigated using BMP signaling assays in vitro. Two SMAD6 variants (p.C484F and p.P415L) had significantly (P < 0.05) lower activity than wild-type SMAD6 in inhibiting BMP signaling in a transcriptional reporter assay. In addition, the p.C484F variant had a significantly (P < 0.05) lower capacity to inhibit an osteogenic response to BMP signaling. We conclude that low-frequency deleterious variants in SMAD6 predispose to CVM. This is the first report of a human disease phenotype related to genetic variation in SMAD6. Hum Mutat 33:720–727, 2012. © 2012 Wiley Periodicals, Inc.
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- 2012
21. 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 H, McCarty, Joseph, McCarty, and Helen M, Arthur
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Central Nervous System ,Vascular smooth muscle ,Angiogenesis ,Organogenesis ,lcsh:Medicine ,Signal transduction ,Cardiovascular ,Mice ,0302 clinical medicine ,Molecular cell biology ,lcsh:Science ,Mice, Knockout ,0303 health sciences ,Multidisciplinary ,biology ,Tight junction ,Signaling cascades ,Animal Models ,Cell biology ,Vascular endothelial growth factor B ,medicine.anatomical_structure ,Inner nuclear layer ,Medicine ,Cellular Types ,Research Article ,Protein Serine-Threonine Kinases ,Retina ,Adherens junction ,03 medical and health sciences ,Model Organisms ,Vascular Biology ,medicine ,Genetics ,Animals ,Biology ,030304 developmental biology ,lcsh:R ,Receptor, Transforming Growth Factor-beta Type II ,Endothelial Cells ,Transforming growth factor beta ,Mice, Inbred C57BL ,TGF-beta signaling cascade ,Immunology ,biology.protein ,lcsh:Q ,Gene Function ,Receptors, Transforming Growth Factor beta ,Organism Development ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
TGFβ signalling in endothelial cells is important for angiogenesis in early embryonic development, but little is known about its role in early postnatal life. To address this we used a tamoxifen inducible Cre-LoxP strategy in neonatal mice to deplete the TypeII TGFβ receptor (Tgfbr2) specifically in endothelial cells. This resulted in multiple micro-haemorrhages, and glomeruloid-like vascular tufts throughout the cerebral cortices and hypothalamus of the brain as well as in retinal tissues. A detailed examination of the retinal defects in these mutants revealed that endothelial adherens and tight junctions were in place, pericytes were recruited and there was no failure of vascular smooth muscle differentiation. However, the deeper retinal plexus failed to form in these mutants and the angiogenic sprouts stalled in their progress towards the inner nuclear layer. Instead the leading endothelial cells formed glomerular tufts with associated smooth muscle cells. This evidence suggests that TGFβ signalling is not required for vessel maturation, but is essential for the organised migration of endothelial cells as they begin to enter the deeper layers of the retina. Thus, TGFβ signalling is essential in vascular endothelial cells for maintaining vascular integrity at the angiogenic front as it migrates into developing neural tissues in early postnatal life.
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- 2012
22. Endoglin expression in early development is associated with vasculogenesis and angiogenesis
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Leon Jonker and Helen M. Arthur
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medicine.medical_specialty ,Embryology ,Angiogenesis ,Neovascularization, Physiologic ,Vascular Cell Adhesion Molecule-1 ,Mice, Transgenic ,Receptors, Cell Surface ,Biology ,Dorsal aorta ,Mice ,Vasculogenesis ,Antigens, CD ,Genes, Reporter ,Internal medicine ,hemic and lymphatic diseases ,medicine ,otorhinolaryngologic diseases ,Animals ,Yolk sac ,Z721 ,Heart development ,Embryogenesis ,Endoglin ,Gene Expression Regulation, Developmental ,Allantois ,Z72 ,Mice, Mutant Strains ,Cell biology ,medicine.anatomical_structure ,Endocrinology ,Lac Operon ,embryonic structures ,Blood Vessels ,Developmental Biology - Abstract
Endoglin is an auxiliary receptor for the transforming growth factor-beta family of cytokines and is required for angiogenesis and heart development. Endoglin expression during mouse embryogenesis was analysed by monitoring beta-galactosidase expression from a lacZ reporter cassette inserted downstream of the endoglin promoter. Expression was first detected at 6.5 days post-coitum (dpc) in the amniotic fold and developing allantois. Between 7.5 and 8.5 dpc, endoglin was expressed in endothelial cells of the yolk sac, dorsal aorta and primitive heart tube, and from 9.5 to 13.5 dpc in endothelial cells throughout the developing vasculature. Interestingly, this pattern of endoglin expression is almost identical to that reported for Alk1.
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- 2001
23. Angiogenesis regulation by TGFβ signalling: clues from an inherited vascular disease.
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Marwa Mahmoud, Paul D. Upton, and Helen M. Arthur
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CELLULAR signal transduction ,NEOVASCULARIZATION ,TRANSFORMING growth factors ,ENDOTHELIUM ,GENETIC mutation ,LABORATORY mice ,CARDIOVASCULAR system - Abstract
Studies of rare genetic diseases frequently reveal genes that are fundamental to life, and the familial vascular disorder HHT (hereditary haemorrhagic telangiectasia) is no exception. The majority of HHT patients are heterozygous for mutations in either the ENG (endoglin) or the ACVRL1 (activin receptor-like kinase 1) gene. Both genes are essential for angiogenesis during development and mice that are homozygous for mutations in Eng or Acvrl1 die in mid-gestation from vascular defects. Recent development of conditional mouse models in which the Eng or Acvrl1 gene can be depleted in later life have confirmed the importance of both genes in angiogenesis and in the maintenance of a normal vasculature. Endoglin protein is a co-receptor and ACVRL1 is a signalling receptor, both of which are expressed primarily in endothelial cells to regulate TGFβ (transforming growth factor β) signalling in the cardiovasculature. The role of ACVRL1 and endoglin in TGFβ signalling during angiogenesis is now becoming clearer as interactions between these receptors and additional ligands of the TGFβ superfamily, as well as synergistic relationships with other signalling pathways, are being uncovered. The present review aims to place these recent findings into the context of a better understanding of HHT and to summarize recent evidence that confirms the importance of endoglin and ACVRL1 in maintaining normal cardiovascular health. [ABSTRACT FROM AUTHOR]
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- 2011
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24. Biochemical correlations among the thermophilic enteric yeasts Torulopsis bovina, Torulopsis pintolopesii, Saccharomyces telluris, and Candida slooffii
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Helen M. Arthur, Kenneth Watson, and Mark Blakey
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Cytochrome ,Microbiology ,Saccharomyces ,chemistry.chemical_compound ,Oxygen Consumption ,Saccharomyces telluris ,Yeasts ,Cytochrome c oxidase ,DNA, Fungal ,Molecular Biology ,Candida ,Oxidase test ,biology ,Succinate dehydrogenase ,Spectrum Analysis ,Fatty Acids ,Temperature ,biology.organism_classification ,chemistry ,Biochemistry ,biology.protein ,Cytochromes ,Fermentation ,Ethidium bromide ,Research Article - Abstract
Spontaneous and drug-induced respiration-deficient mutants were isolated from the thermophilic enteric yeasts Torulopsis bovina and Saccharomyces telluris. The biochemical properties of these yeasts were compared with those of the two naturally occurring respiration-deficient thermophilic yeasts T. pintolopesii and Candida slooffii. Succinate dehydrogenase was not detected in mitochondrial fractions from C. slooffii, but was present in all other species. Cytochrome c oxidase, succinate oxidase, and reduced nicotinamide adenine dinucleotide oxidase were not detected in C. slooffii, T. pintolopesii, and the respiration-deficient mutants. Low-temperature cytochrome spectra revealed the presence of cytochromes aa3, b, c1, and c in T. bovina and S. telluris; cytochromes b, c1, and c in C. slooffii and T. pintolopesii; and cytochromes c1 and c in the spontaneous respiration-deficient mutants. Palmitoleic and oleic acids were the major fatty acids in all the species. It was noteworthy that T. pintolopesii was rich in lauric and myristic acids. CsCl equilibrium centrifugation experiments showed the presence in all the yeasts of a light-buoyant-density (1.6785 to 1.6837-g/cm3) deoxyribonucleic acid band which was identified as mitochondrial deoxyribonucleic acid by its selective elimination on treatment of cells with ethidium bromide. The latter result indicated that the spontaneous respiration-deficient mutants were similar to cytoplasmic petite mutants of S. cerevisiae. Although classical assimilation and fermentation tests indicated that the spontaneous respiration-deficient mutants were strains of T. pintolopesii, it was concluded, on the basis of marked physiological and biochemical differences, that this was not the case.
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- 1980
25. Clearance of senescent cells during cardiac ischemia–reperfusion injury improves recovery
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Ioakim Spyridopoulos, João F. Passos, W. Andrew Owens, Leticia Donastorg Sosa, Pawel Palmowski, Anna Walaszczyk, Oliver E Yausep, Yohan Santin, David J. Grieve, Emily Dookun, Eduard Jirkovsky, Rachael Redgrave, Averina Suwana, Helen M. Arthur, James Chapman, Simon Tual-Chalot, Jeanne Mialet-Perez, Gavin D. Richardson, Michael J. Taggart, Eleanor K Gill, Mialet-Perez, Jeanne, Newcastle University [Newcastle], Charles University [Prague] (CU), Queen's University [Belfast] (QUB), Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), and Mayo Clinic [Rochester]
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0301 basic medicine ,Senescence ,Male ,Aging ,senescence ,cardiac ,[SDV]Life Sciences [q-bio] ,Inflammation ,Biology ,Pharmacology ,ischemia–reperfusion ,medicine.disease_cause ,ischemia-reperfusion ,senolytic ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Fibrosis ,medicine ,Humans ,Myocardial infarction ,cardiovascular diseases ,Senolytic ,Cellular Senescence ,remodeling ,Original Paper ,Navitoclax ,Cell Biology ,medicine.disease ,[SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,[SDV] Life Sciences [q-bio] ,Ageing ,030104 developmental biology ,chemistry ,Reperfusion Injury ,Female ,medicine.symptom ,Reperfusion injury ,030217 neurology & neurosurgery ,Oxidative stress - 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 revealed 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 pro‐inflammatory, 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 the SASP plays 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., Myocardial infarction and subsequent ischemia–reperfusion injury initiate senescence in multiple cell populations in the peri‐infarct region of the myocardium. Production of the SASP drives myocardial inflammation which promotes myocardial remodeling and inhibits angiogenesis. Treatment with the senolytic navitoclax reduced myocardial senescence and the associated SASP, resulting in a reduced scar size and increased vascularization which ultimately improved cardiac function.
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26. 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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Calinda K E Dingenouts, Wineke Bakker, Kirsten Lodder, Karien C Wiesmeijer, Asja T Moerkamp, Janita A Maring, Helen M Arthur, Anke M Smits, and Marie-José Goumans
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Medicine ,Science - 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.
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- 2017
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27. Mice Lacking Endoglin in Macrophages Show an Impaired Immune Response.
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Luisa Ojeda-Fernández, Lucía Recio-Poveda, Mikel Aristorena, Pedro Lastres, Francisco J Blanco, Francisco Sanz-Rodríguez, Eunate Gallardo-Vara, Mateo de las Casas-Engel, Ángel Corbí, Helen M Arthur, Carmelo Bernabeu, and Luisa M Botella
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Genetics ,QH426-470 - Abstract
Endoglin is an auxiliary receptor for members of the TGF-β superfamily and plays an important role in the homeostasis of the vessel wall. Mutations in endoglin gene (ENG) or in the closely related TGF-β receptor type I ACVRL1/ALK1 are responsible for a rare dominant vascular dysplasia, the Hereditary Hemorrhagic Telangiectasia (HHT), or Rendu-Osler-Weber syndrome. Endoglin is also expressed in human macrophages, but its role in macrophage function remains unknown. In this work, we show that endoglin expression is triggered during the monocyte-macrophage differentiation process, both in vitro and during the in vivo differentiation of blood monocytes recruited to foci of inflammation in wild-type C57BL/6 mice. To analyze the role of endoglin in macrophages in vivo, an endoglin myeloid lineage specific knock-out mouse line (Eng(fl/fl)LysMCre) was generated. These mice show a predisposition to develop spontaneous infections by opportunistic bacteria. Eng(fl/fl)LysMCre mice also display increased survival following LPS-induced peritonitis, suggesting a delayed immune response. Phagocytic activity is impaired in peritoneal macrophages, altering one of the main functions of macrophages which contributes to the initiation of the immune response. We also observed altered expression of TGF-β1 target genes in endoglin deficient peritoneal macrophages. Overall, the altered immune activity of endoglin deficient macrophages could help to explain the higher rate of infectious diseases seen in HHT1 patients.
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- 2016
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28. ENDOGLIN is dispensable for vasculogenesis, but required for vascular endothelial growth factor-induced angiogenesis.
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Zhen Liu, Franck Lebrin, Janita A Maring, Sander van den Driesche, Stieneke van der Brink, Maarten van Dinther, Midory Thorikay, Sabrina Martin, Kazuki Kobayashi, Lukas J A C Hawinkels, Laurens A van Meeteren, Evangelia Pardali, Jeroen Korving, Michelle Letarte, Helen M Arthur, Charles Theuer, Marie-José Goumans, Christine Mummery, and Peter ten Dijke
- Subjects
Medicine ,Science - Abstract
ENDOGLIN (ENG) is a co-receptor for transforming growth factor-β (TGF-β) family members that is highly expressed in endothelial cells and has a critical function in the development of the vascular system. Mutations in Eng are associated with the vascular disease known as hereditary hemorrhagic telangiectasia type l. Using mouse embryonic stem cells we observed that angiogenic factors, including vascular endothelial growth factor (VEGF), induce vasculogenesis in embryoid bodies even when Eng deficient cells or cells depleted of Eng using shRNA are used. However, ENG is required for the stem cell-derived endothelial cells to organize effectively into tubular structures. Consistent with this finding, fetal metatarsals isolated from E17.5 Eng heterozygous mouse embryos showed reduced VEGF-induced vascular network formation. Moreover, shRNA-mediated depletion and pharmacological inhibition of ENG in human umbilical vein cells mitigated VEGF-induced angiogenesis. In summary, we demonstrate that ENG is required for efficient VEGF-induced angiogenesis.
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- 2014
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29. Endothelial depletion of Acvrl1 in mice leads to arteriovenous malformations associated with reduced endoglin expression.
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Simon Tual-Chalot, Marwa Mahmoud, Kathleen R Allinson, Rachael E Redgrave, Zhenhua Zhai, S Paul Oh, Marcus Fruttiger, and Helen M Arthur
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Medicine ,Science - Abstract
Rare inherited cardiovascular diseases are frequently caused by mutations in genes that are essential for the formation and/or function of the cardiovasculature. Hereditary Haemorrhagic Telangiectasia is a familial disease of this type. The majority of patients carry mutations in either Endoglin (ENG) or ACVRL1 (also known as ALK1) genes, and the disease is characterized by arteriovenous malformations and persistent haemorrhage. ENG and ACVRL1 encode receptors for the TGFβ superfamily of ligands, that are essential for angiogenesis in early development but their roles are not fully understood. Our goal was to examine the role of Acvrl1 in vascular endothelial cells during vascular development and to determine whether loss of endothelial Acvrl1 leads to arteriovenous malformations. Acvrl1 was depleted in endothelial cells either in early postnatal life or in adult mice. Using the neonatal retinal plexus to examine angiogenesis, we observed that loss of endothelial Acvrl1 led to venous enlargement, vascular hyperbranching and arteriovenous malformations. These phenotypes were associated with loss of arterial Jag1 expression, decreased pSmad1/5/8 activity and increased endothelial cell proliferation. We found that Endoglin was markedly down-regulated in Acvrl1-depleted ECs showing endoglin expression to be downstream of Acvrl1 signalling in vivo. Endothelial-specific depletion of Acvrl1 in pups also led to pulmonary haemorrhage, but in adult mice resulted in caecal haemorrhage and fatal anaemia. We conclude that during development, endothelial Acvrl1 plays an essential role to regulate endothelial cell proliferation and arterial identity during angiogenesis, whilst in adult life endothelial Acvrl1 is required to maintain vascular integrity.
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- 2014
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30. Novel brain arteriovenous malformation mouse models for type 1 hereditary hemorrhagic telangiectasia.
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Eun-Jung Choi, Wanqiu Chen, Kristine Jun, Helen M Arthur, William L Young, and Hua Su
- Subjects
Medicine ,Science - Abstract
Endoglin (ENG) is a causative gene of type 1 hereditary hemorrhagic telangiectasia (HHT1). HHT1 patients have a higher prevalence of brain arteriovenous malformation (AVM) than the general population and patients with other HHT subtypes. The pathogenesis of brain AVM in HHT1 patients is currently unknown and no specific medical therapy is available to treat patients. Proper animal models are crucial for identifying the underlying mechanisms for brain AVM development and for testing new therapies. However, creating HHT1 brain AVM models has been quite challenging because of difficulties related to deleting Eng-floxed sequence in Eng(2fl/2fl) mice. To create an HHT1 brain AVM mouse model, we used several Cre transgenic mouse lines to delete Eng in different cell-types in Eng(2fl/2fl) mice: R26CreER (all cell types after tamoxifen treatment), SM22α-Cre (smooth muscle and endothelial cell) and LysM-Cre (lysozyme M-positive macrophage). An adeno-associated viral vector expressing vascular endothelial growth factor (AAV-VEGF) was injected into the brain to induce focal angiogenesis. We found that SM22α-Cre-mediated Eng deletion in the embryo caused AVMs in the postnatal brain, spinal cord, and intestines. Induction of Eng deletion in adult mice using R26CreER plus local VEGF stimulation induced the brain AVM phenotype. In both models, Eng-null endothelial cells were detected in the brain AVM lesions, and formed mosaicism with wildtype endothelial cells. However, LysM-Cre-mediated Eng deletion in the embryo did not cause AVM in the postnatal brain even after VEGF stimulation. In this study, we report two novel HHT1 brain AVM models that mimic many phenotypes of human brain AVM and can thus be used for studying brain AVM pathogenesis and testing new therapies. Further, our data indicate that macrophage Eng deletion is insufficient and that endothelial Eng homozygous deletion is required for HHT1 brain AVM development.
- Published
- 2014
- Full Text
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31. The tissue-specific RNA binding protein T-STAR controls regional splicing patterns of neurexin pre-mRNAs in the brain.
- Author
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Ingrid Ehrmann, Caroline Dalgliesh, Yilei Liu, Marina Danilenko, Moira Crosier, Lynn Overman, Helen M Arthur, Susan Lindsay, Gavin J Clowry, Julian P Venables, Philippe Fort, and David J Elliott
- Subjects
Genetics ,QH426-470 - Abstract
The RNA binding protein T-STAR was created following a gene triplication 520-610 million years ago, which also produced its two parologs Sam68 and SLM-1. Here we have created a T-STAR null mouse to identify the endogenous functions of this RNA binding protein. Mice null for T-STAR developed normally and were fertile, surprisingly, given the high expression of T-STAR in the testis and the brain, and the known infertility and pleiotropic defects of Sam68 null mice. Using a transcriptome-wide search for splicing targets in the adult brain, we identified T-STAR protein as a potent splicing repressor of the alternatively spliced segment 4 (AS4) exons from each of the Neurexin1-3 genes, and exon 23 of the Stxbp5l gene. T-STAR protein was most highly concentrated in forebrain-derived structures like the hippocampus, which also showed maximal Neurexin1-3 AS4 splicing repression. In the absence of endogenous T-STAR protein, Nrxn1-3 AS4 splicing repression dramatically decreased, despite physiological co-expression of Sam68. In transfected cells Neurexin3 AS4 alternative splicing was regulated by either T-STAR or Sam68 proteins. In contrast, Neurexin2 AS4 splicing was only regulated by T-STAR, through a UWAA-rich response element immediately downstream of the regulated exon conserved since the radiation of bony vertebrates. The AS4 exons in the Nrxn1 and Nrxn3 genes were also associated with distinct patterns of conserved UWAA repeats. Consistent with an ancient mechanism of splicing control, human T-STAR protein was able to repress splicing inclusion of the zebrafish Nrxn3 AS4 exon. Although Neurexin1-3 and Stxbp5l encode critical synaptic proteins, T-STAR null mice had no detectable spatial memory deficits, despite an almost complete absence of AS4 splicing repression in the hippocampus. Our work identifies T-STAR as an ancient and potent tissue-specific splicing regulator that uses a concentration-dependent mechanism to co-ordinately regulate regional splicing patterns of the Neurexin1-3 AS4 exons in the mouse brain.
- Published
- 2013
- Full Text
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