Arteriovenous malformations in mice lacking activin receptor-like kinase-1

The mature circulatory system is comprised of two parallel, yet distinct, v ascular networks that carry blood to and from the heart. Studies have sugge sted that endothelial tubes are specified as arteries and veins at the earl iest stages of angiogenesis, before the onset of circulation(1-4). To under stand the molecular basis for arterial-venous identity, we have focused our studies on a human vascular dysplasia, hereditary haemorrhagic telangiecta sia (HHT), wherein arterial and venous beds fail to remain distinct. Geneti c studies have demonstrated that HHT can be caused by loss-of-function muta tions in the gene encoding activin receptor-like kinase-1 (ACVRL1; ref. 5). ACVRL1 encodes a type I receptor for the TGF-P superfamily of growth facto rs(6-8). At the earliest stage of vascular development, mice lacking Acvrl1 develop large shunts between arteries and veins, downregulate arterial Efn b2 and fail to confine intravascular haematopoiesis to arteries. These mice die by mid-gestation with severe arteriovenous malformations resulting fro m fusion of major arteries and veins. The early loss of anatomical, molecul ar and functional distinctions between arteries and Veins indicates that Ac vrl1 is required for developing distinct arterial and venous vascular beds.