Advances in the Cellular and Molecular Biology of Angiogenesis 1659

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. Hereditary haemorrhagic telangiectasia HHT (hereditary haemorrhagic telangiectasia) is an inherited vascular disorder associated with altered TGFβ (transforming growth factor β) signalling in endothelial cells. It is inherited in an autosomal dominant fashion and affects approximately 1 in 5000 individuals. Clinically, HHT is characterized by multiple red spots known as telangiectases that develop on the skin, in the mucocutaneous lining of the oronasal and GI (gastrointestinal) tract, and are prone to severe haemorrhage The majority of HHT patients carry mutations in one of two genes: ENG (endoglin), a co-receptor for ligands of the TGFβ superfamily [4], or ACVRL1 (activin receptor-lik