Blood flow promotes ALK1/ENG association to increase BMP9 sensitivity. In the absence of blood flow and at low concentrations of BMP9, ALK1 is not able to phosphorylate its downstream effectors SMAD1/5/8. However, in the presence of blood flow, shear stress promotes the association of ENG with ALK1, which decreases the endothelial EC50 toward BMP9. Thus, blood flow promotes ALK1 tyrosine kinase activity and phosphorylation of SMAD1/5/8 at low concentrations of BMP9. The overall effect of the synergy between blood flow and BMP signaling is the inhibition of cell proliferation and the recruitment of mural cells, promoting vessel stabilization and quiescence. SMADs are likely the key mediators of these effects; however, this relationship is not yet firmly established.
