HHT occurs due to LOF mutations in ENG, ALK1, SMAD4, and, more rarely, BMP9 (respective proteins indicated with red asterisks), which are all in the same signaling pathway. On endothelial cells, BMP9 or BMP10 recruits a heterocomplex composed of two type II receptors (BMPRII or ActRIIA, which are the main type II receptors expressed on ECs, and two similar type I receptors (ALK1), and the coreceptor ENG (endoglin). Upon BMP binding, the type II receptor phosphorylates ALK1, which subsequently phosphorylates the transcription factors SMAD1/5. SMAD1/5 bind SMAD4, which is shared with the TGF-β pathway, to regulate transcription of many genes (in association with other transcription factors). BMP9 and BMP10 maintain vascular quiescence (middle panel) via repression of angiogenesis pathways (right panel). VEGF-A (red) binds to VEGFR2, which activates the ERK1/2 and P38 MAPK pathways and the PI3K/AKT/mTORC1 pathway. In turn, the PI3K/AKT/mTORC1 pathway activates the signaling cascade P70S6K/S6. VEGF can also activate the calcineurin phosphatase, which activates, via dephosphorylation, the NFAT transcription factor family. The PI3K/AKT/mTOR pathway is negatively regulated by the phosphatase PTEN, which is active when unphosphorylated. VEGF-A can also bind to VEGFR1, but this will not generate a signal. Two other members of the VEGF family, VEGF-B (yellow) and PlGF (blue), also bind to VEGFR1. BMP9 induces the expression of VEGFR1, thus inhibiting VEGF signaling. BMP9 also induces PTEN expression and phosphorylation, which inhibit AKT activity as well as the expression of SGK1 kinase, which can activate the mTORC1/P70S6K/S6 pathway. Moreover, BMP9 inhibits ERK activation and CDK4/6 kinases through not-yet-characterized mechanisms. Ang1 activates the TIE2 receptor to maintain vascular quiescence, and this pathway can be antagonized by Ang2.