| First Author | Li QF | Year | 2018 |
| Journal | Cell Rep | Volume | 24 |
| Issue | 11 | Pages | 2869-2882 |
| PubMed ID | 30208313 | Mgi Jnum | J:270794 |
| Mgi Id | MGI:6278730 | Doi | 10.1016/j.celrep.2018.08.025 |
| Citation | Li QF, et al. (2018) Activation of Ras in the Vascular Endothelium Induces Brain Vascular Malformations and Hemorrhagic Stroke. Cell Rep 24(11):2869-2882 |
| abstractText | 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-beta 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. |
