Working model for the roles of ALK1 and ALK5 in angiogenesis. (A) BMP-4 as an angiogenic stimulus causes local induction of ALK1, which is activated by BMP-9 normally circulating in the plasma. (B) ALK1 signaling induces expression of MGP, which prevents excessive angiogenic stimulation by binding to BMP-4, and expression of ALK5. (C-D) ALK5 is activated by local TGFβ, which results in VEGF induction and stimulation of endothelial cell growth and angiogenesis.