A murine model of hereditary hemorrhagic telangiectasia

Endoglin (CD105), an accessory protein of the TGF-beta receptor superfamily , is highly expressed on endothelial cells. Hereditary hemorrhagic telangie ctasia type 1 (HHT1) is associated with mutations in the Endoglin gene, lea ding to haploinsufficiency. To generate a disease model and ascertain the r ole of endoglin in development, we generated mice lacking 1 or both copies of the gene. Endoglin null embryos die at gestational day 10.0-10.5 due to defects in vessel and heart development. Vessel formation appears normal un til hemorrhage occurs in yolk sacs and embryos. The primitive vascular plex us of the yolk sac fails to mature into defined vessels, and vascular chann els dilate and rupture. Internal bleeding is seen in the peritoneal cavity, implying fragile vessels. Heart development is arrested at day 9.0, and th e atrioventricular canal endocardium fails to undergo mesenchymal transform ation and cushion-tissue formation. These data suggest that endoglin is cri tical for both angiogenesis and heart valve formation. Some heterozygotes, either with an inbred 123/Ola or mixed C57BL/6-129/Ola background, show sig ns of HHT, such as telangiectases or recurrent nosebleeds. In this murine m odel of HHT, it appears that epigenetic factors and modifier genes, some of which are present in 129/Ola, contribute to disease heterogeneity.