Deficiency of Endothelium-Specific Transcription Factor Sox17 Induces Intracranial Aneurysm

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Background-Intracranial aneurysm (IA) is a common vascular disorder that frequently leads to fatal vascular rupture. Although various acquired risk factors associated with IA have been identified, the hereditary basis of IA remains poorly understood. As a result, genetically modified animals accurately modeling IA and related pathogenesis have been lacking, and subsequent drug development has been delayed. Methods and Results-The transcription factor Sox17 is robustly expressed in endothelial cells of normal intracerebral arteries. The combination of Sox17 deficiency and angiotensin II infusion in mice induces vascular abnormalities closely resembling the cardinal features of IA such as luminal dilation, wall thinning, tortuosity, and subarachnoid hemorrhages. This combination impairs junctional assembly, cell-matrix adhesion, regeneration capacity, and paracrine secretion in endothelial cells of intracerebral arteries, highlighting key endothelial dysfunctions that lead to IA pathogenesis. Moreover, human IA samples showed reduced Sox17 expression and impaired endothelial integrity, further strengthening the applicability of this animal model to clinical settings. Conclusions-Our findings demonstrate that Sox17 deficiency in mouse can induce IA under hypertensive conditions, suggesting Sox17 deficiency as a potential genetic factor for IA formation. The Sox17-deficient mouse model provides a novel platform to develop therapeutics for incurable IA.
Publisher
LIPPINCOTT WILLIAMS & WILKINS
Issue Date
2015-03
Language
English
Article Type
Article
Keywords

GENOME-WIDE ASSOCIATION; BLOOD-BRAIN-BARRIER; TERM FOLLOW-UP; CEREBRAL ANEURYSMS; MYOCARDIAL-INFARCTION; MICE; ANGIOGENESIS; RISK; MAINTENANCE; GENETICS

Citation

CIRCULATION, v.131, no.11, pp.995 - 1005

ISSN
0009-7322
DOI
10.1161/CIRCULATIONAHA.114.012568
URI
http://hdl.handle.net/10203/196070
Appears in Collection
MSE-Journal Papers(저널논문)
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