Fig. 8

Working model: BMP9/BMP10/ALK1/SMAD4 Signaling drives the regulation of direct and indirect pathways in ECs. Binding of BMP9 and BMP10 (BMP9/10) to ALK1 along with a type II receptor on ECs mediates the activation of ALK1, leading to the initiation of direct and indirect pathways. The direct pathway involves the SMAD cascade, where activated ALK1 phosphorylates the C-terminus of SMAD1 and SMAD5, allowing the recruitment of SMAD4, forming a trimeric SMAD complex. This trimeric SMAD complex subsequently translocated to the nucleus, where it binds to the promoters of target genes with the assistance of other transcription factors (TFs), thereby regulating their expression levels. Among these, BMP9/10 induce the expression of ID1, SMAD6 and GADD45β (newly identified target). The indirect pathway involves the expression of GADD45β, an activator of MEKK4, which mediates activation of P38/MK2 signaling axis by these ligands. In this cascade, P38 phosphorylates Eps15-Ser796, while P38/MK2 phosphorylates HSP27-Ser78/82, which have been described to play important roles in endocytosis and cytoskeleton organization, respectively. BMP9 and BMP10 also induce the differential phosphorylation of the transcription factor ERG via an uncharacterized mechanism. Additionally, P38 activation regulates a subset of BMP9/10-induced genes, including SELE, HAS2, and PTGS2. On the other hand, BMP9/10 downregulates the CDK4/6 pathway leading to inhibition of G1/S transition and cell cycle arrest