Multiple versions of TGF-β signaling pathways in endothelial and smooth muscle cells. During the activation phase of angiogenesis, endothelial cells degrade their vascular basement membranes, migrate into extracellular spaces, proliferate, and form vascular lumens. During the resolution phase, endothelial cells cease to migrate and to proliferate and instead reconstitute their basement membranes. The maturation and remodeling of the vessels also occur in this phase, as mesenchymal cells are recruited for endothelial tube ensheathment. (A,B) It has been reported that both ALK1 and ALK5 are TGF-β subfamily type I receptors in ECs: that is, they are both activated by TGF-β subfamily ligands binding to TGFBR2. As ALK1 and ALK5 signal through different SMAD proteins, it has been suggested that the opposing activities of these 2 type I receptors regulate angiogenesis. However, whereas some studies have suggested a role or ALK1 in resolution and ALK5 in activation,^14,17  others have suggested opposite roles, with ALK5 being necessary for ALK1 function.^16,20  (C) Both balance models (A,B) are called into question by an expression study in mice showing that, whereas Alk1 is endothelial-specific, Alk5 is expressed not in the endothelium but in neighboring smooth muscle cells.²¹  (D) Data presented do not support a role for TGF-β subfamily ligands and TGFBR2 in ALK1 function, suggesting that TGF-β superfamily ligands outside of the TGF-β subfamily may be physiologic ligands for ALK1 in endothelial cells. This hypothesis is supported by recent biochemical data demonstrating that BMP9 serves as an ALK1 ligand.^12,13