Activin receptor-like kinase 1 modulates transforming growth factor-beta 1signaling in the regulation of angiogenesis

The activin receptor-like kinase 1 (ALK1) is a type I receptor for transfor ming growth factor-beta (TGF-beta) family proteins. Expression of ALK1 in b lood vessels and mutations of the ALK1 gene in human type II hereditary hem orrhagic telangiectasia patients suggest that ALK1 may have an important ro le during vascular development, To define the function of ALK1 during devel opment, we inactivated the ALK1 gene in mice by gene targeting. The ALK1 ho mozygous embryos die at midgestation, exhibiting severe vascular abnormalit ies characterized by excessive fusion of capillary plexes into cavernous ve ssels and hyperdilation of large vessels. These vascular defects are associ ated with enhanced expression of angiogenic factors and proteases and are c haracterized by deficient differentiation and recruitment of vascular smoot h muscle cells. The blood vessel defects in ALK1-deficient mice are reminis cent of mice lacking TGF-beta 1, TGF-beta type II receptor (T beta R-II), o r endoglin, suggesting that ALK1 may mediate TGF-beta 1 signal in endotheli al cells. Consistent with this hypothesis, we demonstrate that ALK1 in endo thelial cells binds to TGF-beta 1 and T beta R-II. Furthermore, the ALK1 si gnaling pathway can inhibit TGF-beta 1-dependent transcriptional activation mediated by the known TGF-beta 1 type I receptor, ALK5. Taken together, ou r results suggest that the balance between the ALK1 and ALK5 signaling path ways in endothelial cells plays a crucial role in determining vascular endo thelial properties during angiogenesis.