Endoglin regulates angiogenesis: an investigation of cellular and molecular mechanisms. (360G-Wellcome-086511_B_08_Z)

Development and maintenance of an optimally functioning vasculature are essential for health. Abnormal vessel responses can result in a range of vascular problems including haemorrhage, vessel dilatation or aneurysm, which may be associated with increased morbidity and mortality, depending on the affected organ. The aim of this project is to understand the role of the essential endothelial receptor endoglin during development of the vasculature. Pathological mutations of the endoglin gene in the familial vascular disorder Hereditary Haemorrhagic Telangiectasia lead to the local formation of arteriovenous malformations and haemorrhagic, dilated and tortuous blood vessels (telangiectases) that often enlarge or become more numerous with age. The molecular mechanisms underlying these events are poorly understood, largely because of a lack of robust animal models. We have recently derived an inducible endoglin knockout mouse which, for the first time, develops arteriovenous malformations in a reproducible manner. We will use this unique model to investigate the underlying cellular and molecular mechanisms responsible for abnormal vascular remodelling. Following this, we aim to investigate repair of these vascular abnormalities. Increased understanding of the central role of endoglin in angiogenesis has wider implications for current therapies to regulate angiogenesis and vascular repair in an extensive range of pathologies.