Fig. 2

BMP9 and BMP10 induce vascular quiescence by various mechanisms. Through ALK1 phosphorylation of Smad1/5/9, BMP9 or BMP10 triggers transcriptional effects that induce vascular quiescence, including repression of ANGPT2 (angiopoietin 2) and induction of VEGFR1 expressions. In parallel, BMP9 inhibits the phosphorylation of the phosphatase PTEN (which is active in its unphosphorylated form), thereby inhibiting the activity of PI3K, a downstream effector of both VEGF and ANGPT2. ANGPT2 signaling is complex: when ANGPT1 (angiopoietin 1) is present, ANGPT2 acts as an antagonist of ANGPT1 and prevents the phosphorylation of the Tie2 receptor and the activation of PI3K. When ANGPT2 is present in large excess over ANGPT1, it acts as an agonist of the Tie2 receptor and stimulates PI3 Kinase. Tie2 activation is pro-angiogenic. VEGF activates different signaling pathways (PI3K/AKT, PLCγ/ERK, src/p38MAPK) which trigger a variety of biological responses (EC (endothelial cell) survival, permeability, proliferation and migration). VEGFR1, whose expression is increased by BMP9, acts as a decoy VEGF receptor, thereby shutting down the pro-angiogenic VEGF signaling mediated by VEGFR2

Altogether, BMP9 and BMP10 maintain vascular quiescence by shutting down the pro-angiogenic VEGF and ANGPT2 signaling pathways.