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Circulation. 2015 Mar 17;131(11):995-1005. doi: 10.1161/CIRCULATIONAHA.114.012568. Epub 2015 Jan 16.

Deficiency of endothelium-specific transcription factor Sox17 induces intracranial aneurysm.

Author information

1
From Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea (S.L., I.-K.K., S.S., G.Y.K., I.K.); Department of Neurological Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea (J.S.A.); Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea (D.-C.W., S.-T.K.); Department of Forensic Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea (H.-S.K.); and Department of Physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea (B.H.J.).
2
From Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea (S.L., I.-K.K., S.S., G.Y.K., I.K.); Department of Neurological Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea (J.S.A.); Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea (D.-C.W., S.-T.K.); Department of Forensic Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea (H.-S.K.); and Department of Physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea (B.H.J.). injunek@kaist.ac.kr.

Abstract

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.

KEYWORDS:

cerebrovascular disorders; endothelial cells; intracranial aneurysm; transcription factors

[Indexed for MEDLINE]

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