Mutation of platelet-derived growth factor receptor β causes and exacerbates the severity of brain arteriovenous malformation through enhancing angiogenesis

Abstract 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 mutation of Pdgfrβ causes cerebrovascular malformations in the brain's angiogenic region, associated with increased pro-angiogenic signaling. Interestingly, the expression of activin receptor-like kinase 1 (Alk1) is decreased in the brain's angiogenic region of Pdgfrβ mutant mice. Overexpression of ALK1 in brain endothelial cells (ECs) reduces angiogenic signaling and the severity of vascular malformations in Pdgfrβ mutant mice. Mutation of Pdgfrβ also increases bAVM penetrance in endoglin-deficient mice (a gene that causes AVMs), leading to an increase of dysplastic vessels and microhemorrhages in bAVMs. Our data indicate that Pdgfrβ mutation causes cerebrovascular malformations and worsens the bAVM phenotype in endoglin mutant mice by enhancing angiogenesis, EC proliferation, and inflammation. Overexpression of ALK1 in brain ECs reduces the severity of cerebrovascular malformations in Pdgfrβ mutant mice through downregulating angiogenic signaling.