Fig. 3

Future treatments for HHT. The HHT-causing mutations of genes encoding components of the BMP9/BMP10 signaling pathway (indicated by red asterisks), result in decreased downstream signaling (indicated by thinner arrows than in Fig. 2) and increased activity of the VEGF and ANGPT2 signaling pathways (indicated by thicker arrows than in Fig. 2). Several drugs that target these pathways are already in use in clinical trials (blue boxes) or under evaluation in preclinical studies (parma boxes) for HHT treatment. Currently evaluated HHT treatments target VEGF via anti-VEGF antibodies (bevacizumab) or VEGFR2 tyrosine kinase inhibitors (VEGFR2-TKI such as pazopanib). Tacrolimus and sirolimus were identified through recent high-throughput screening of FDA-approved drugs as activators of ALK1 (and ALK3) signaling. They are under phase I/II trials as clinical treatments for HHT. Preclinical studies are investigating the beneficial effects of anti-ANGPT2 antibodies (LC-10) and PI3-kinase inhibitors (wortmannin or LY294002). As shown on this cartoon, all these treatments aim at restoring the balance between the BMP9 pathway and the VEGF/ANGPT2 pathways in order to re-establish vascular quiescence