SMAD4 and vascular malformation: Moving downstream of the signalling pathway, the critical importance of the canonical SMAD1/5/8 pathway in protecting ECs against vascular malformations is shown by the HHT-like phenotype in SMAD4 LOF mutation patients [2], and by the retinal AVMs that develop in neonatal mice with endothelial loss of either SMAD4 or SMAD1/5 [24,25].