Activation of Ras in the Vascular Endothelium Induces Brain Vascular Malformations and Hemorrhagic Stroke

Abstract

Summary: Cerebrovascular malformations (CVMs) affect approximately 3% of the population, risking hemorrhagic stroke, seizures, and neurological deficits. Recently Ras mutations have been identified in a majority of brain arterio-venous malformations. We generated an endothelial-specific, inducible HRASV12 mouse model, which results in dilated, proliferative blood vessels in the brain, blood-brain barrier breakdown, intracerebral hemorrhage, and rapid lethality. Organoid morphogenesis models revealed abnormal cessation of proliferation, abnormalities in expression of tip and stalk genes, and a failure to properly form elongating tubes. These defects were influenced by both hyperactive PI-3′ kinase signaling and altered TGF-β signaling. Several phenotypic changes predicted by the in vitro morphogenesis analysis were validated in the mouse model. These data provide a model of brain vascular malformations induced by mutant Ras and reveal insights into intersecting molecular mechanisms in the pathogenesis of brain vascular malformations. : Li et al. generate a mouse model of vascular malformations induced by Ras mutation. Vascular anomalies arise in the brain and involve a failure in proper tip or stalk cell definition and elongation. These changes are linked to PI3K and TGF-β signaling, revealing molecular intersections with other genetically defined malformations. Keywords: HRAS, vascular malformation, endothelial, proliferation, angiogenesis, ERK, PI-3′ kinase, TGF-β, ALK1, ALK5