Seungjoo Lee 1, Il-Kug Kim 1, Jae Sung Ahn 1, Dong-Cheol Woo 1, Sang-Tae Kim 1, Sukhyun Song 1, Gou Young Koh 1, Hyung-Seok Kim 1, Byeong Hwa Jeon 1, Injune Kim 2.
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.
Figure 1. Sox17 deletion in endothelial cells induces intracranial aneurysm (IA). A, Immunostaining of Sox17. En face endothelial layers of mouse intracerebral artery (ICA) and inferior vena cava (IVC) stained for Sox17 and vascular endothelial (VE)-cadherin (top). Cross-sectional image of mouse ICA (bottom left) stained for Sox17, platelet endothelial cell adhesion molecule, and α-smooth muscle actin and higher magnification of boxed area (bottom right). B and C, Scanning electron microscopy images of vascular casts. B, Fusiform aneurysm by Sox17 deficiency. Gross morphology of control (ctrl) and Sox17-deficient (Sox17iΔEC) ICA (top) and higher magnifications of distal ICA (bottom). Arrow indicates luminal dilation; and arrowhead, arterial tortuosity. C, Saccular aneurysms by Sox17 deficiency in anterior cerebral artery (ACA; top) and middle cerebral artery (MCA; bottom). Arrows indicate saccular aneurysms. Pseudo-coloring denotes ICAs in B and C. D, Increased IA incidence with angiotensin II (AT II) infusion (n=20). See Table I in the online-only Data Supplement for more details. E, Magnetic resonance angiography of cerebral arteries (ventral view). Arrowhead indicates a basilar artery with tortuosity. Scale bars: A, 30 μm; B, 2 mm (top) and 500 μm (bottom); C, 100 μm; and E, 2 mm. Data are mean±SD. **P<0.01 by the Fisher exact test.
Comentarios