Figure 1.

Signaling pathways and therapeutic targets. Normally, BMP9/TGFβ1 regulates angiogenesis through binding to ALK1/ENG to phosphorylate SMAD and increase PTEN activity, which in turn reduces PI3K signaling (blue lines and arrows). BMPs can also signal through MEK/ERK. In HHT (brown lines and arrows), mutation of ALK1 or ENG reduces pSMAD and PETN, resulting in increased PI3K activity or pERK level, causing AVM development. In sporadic AVM cases (red line and arrows), activating mutation in genes in the MAPK-ERK signaling pathway, such as KRAS, BRAF, and MAP2K1, increases the level of pERK, leading to AVM development or progression. The upregulation of PI3K may enhance AVM progression through exacerbation of angiogenesis in HHT. The genes in red can be tested as therapeutic targets.