In the last few years, several groups generated murine models for HHT and uncovered that AVMs are exclusively a pathogenic feature of canonical BMP9/10 signaling through Alk1 and Eng receptors, Smad1/5 transcriptional factors and the Smad4 transcriptional effector in endothelial cells (ECs) [1–10]. This evidence concerns the gene SMAD4 and hereditary hemorrhagic telangiectasia.