The essential role of endothelial SMAD4 in the maintenance of cerebrovascular integrity has been demonstrated by the study using a brain endothelial specific Smad4 knockout mouse, which develops phenotypes partially simulating HHT patients, such as dilated vessels, increased EC proliferation, intracranial hemorrhage and BBB breakdown (Li et al., 2011). Here, SMAD4 is linked to hereditary hemorrhagic telangiectasia.