Illustration of TGF-β family signaling in ECs. TGF-β activates both ALK1 and ALK5 type I receptor expressed by ECs, whereas BMP9 only binds ALK1. The affinity of BMP9 for ALK1 is greater than that of TGF-β, making it likely that ALK1 will predominantly bind BMP9 when both ligands are available. In addition, endoglin acts as a coreceptor modulating signaling through ALK1. Smad 1, 5, and 8 are preferentially phosphorylated and activated by ALK1, whereas Smad 2 and 3 act downstream of ALK5. Subsequently, Smads are translocated to the nucleus, where they regulate specific gene expression.