Platelet-derived growth factor receptor β F7 mutations result in and exacerbate the severity of vascular dysplasia in the brain arteriovenous malformation through enhancing angiogenesis.

Brain arteriovenous malformations (bAVMs) are tangles of abnormal vessels that shunt blood directly from arteries to veins. The reduction of pericytes is linked to hemorrhage in bAVMs. The Pdgfb/Pdgfrβ signaling pathway is crucial for regulating pericyte recruitment during angiogenesis. Here, we show that mice with Pdgfrβ F7 mutations developed cerebrovascular dysplasia in the brain’s angiogenic region, associated with increased pro-angiogenic and inflammatory signaling. Interestingly, the expression of activin receptor-like kinase 1 (Alk1) is decreased in the brain’s angiogenic region of Pdgfrβ F7 heterozygous mice. Overexpression of ALK1 in brain endothelial cells (ECs) reduces angiogenic signaling and the severity of vascular dysplasia in Pdgfrβ F7 heterozygous mice. Pdgfrβ F7 mutations also increased dysplastic vessels and reduced pericyte coverage in the bAVM in endoglin-deficient mice. Endoglin is an AVM causative gene. Our data indicate that Pdgfrβ F7 mutations result in cerebrovascular dysplasia and worsen the bAVM phenotype in endoglin mutant mice by enhancing angiogenesis and inflammation. Overexpression of ALK1 in brain ECs reduces the severity of cerebrovascular dysplasia in Pdgfrβ F7 heterozygous mice through downregulating angiogenic signaling.