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

Autor:	Li QF; Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA., Decker-Rockefeller B; Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA., Bajaj A; Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA., Pumiglia K; Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA. Electronic address: pumiglk@mail.amc.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2018 Sep 11; Vol. 24 (11), pp. 2869-2882.
DOI:	10.1016/j.celrep.2018.08.025
Abstrakt:	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 HRAS V12 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. (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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