13-P035 Endoglin deficiency leads to arteriovenous malformations during angiogenesis

Arteriovenous malformations (AVMs) are the major cause of haemorrhagic stroke in young adults, but the causal factors leading to AVM formation are unknown. An important clue is provided by the familial human disease Hereditary Haemorrhagic Telangiectasia (HHT), which is characterised by multi-organ AVMs and bleeding. HHT is inherited in an autosomal dominant manner and most patients carry mutations in endoglin or activin receptor-like kinase 1 genes. Both genes are involved in TGFbeta family signalling in vascular endothelium and promote angiogenesis. We aimed to model HHT in mice in order to understand the aberrant molecular and cellular events that lead to AVMs. We have generated a floxed endoglin mouse and used this to investigate the phenotypic effects of inducible endoglin loss in the vascular endothelium in response to a local angiogenic stimulus. We have also made use of the neonatal retina because it has well characterised stages of physiological angiogenesis in a two dimensional plane. Endoglin deficiency in mice leads to arteriovenous malformations that model key features of HHT. An angiogenic stimulus is required for vascular malformations to occur and a dominant feature is deregulated endothelial cell proliferation resulting in arteriovenous connections with increased cellularity and abnormally large calibre. We are now investigating anomalous cell signalling events that may be responsible.