TCF7L2 promotes abdominal aortic aneurysm through smooth muscle cell–mediated extracellular matrix remodeling
Yongjie Deng, Yaozhong Liu, Yang Zhao, Hongyu Liu, Guizhen Zhao, Zhenguo Wang, Xu Zhang, Chao Xue, Wei Huang, Tianqing Zhu, Haocheng Lu, Yanhong Guo, Lin Chang, Ida Surakka, Y. Eugene Chen, Jifeng Zhang
Yongjie Deng, Yaozhong Liu, Yang Zhao, Hongyu Liu, Guizhen Zhao, Zhenguo Wang, Xu Zhang, Chao Xue, Wei Huang, Tianqing Zhu, Haocheng Lu, Yanhong Guo, Lin Chang, Ida Surakka, Y. Eugene Chen, Jifeng Zhang
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Research Article Cardiology Cell biology Vascular biology

TCF7L2 promotes abdominal aortic aneurysm through smooth muscle cell–mediated extracellular matrix remodeling

Abstract

Abdominal aortic aneurysm (AAA) lacks effective pharmacological therapies. Here, we investigate transcription factor 7–like 2 (TCF7L2), a genetic locus associated with both thoracic and abdominal aortic aneurysms, to elucidate its role in AAA pathogenesis. Integrating summary data–based Mendelian randomization (SMR) with single-cell RNA sequencing of human and mouse aortae, we identify TCF7L2 as a gene enriched in vascular smooth muscle cells (VSMCs) and causally linked to AAA development. Smooth muscle cell–specific TCF7L2 knockout significantly attenuates AAA formation across 3 distinct murine models (AAA induced by angiotensin II infusion, by β-aminopropionitrile/angiotensin II coadministration, and by elastase), independent of systemic blood pressure or lipid levels. Mechanistic studies reveal that TCF7L2 directly upregulates MMP14 and downregulates TIMP3 expression in vitro and in vivo, driving MMP2-mediated extracellular matrix (ECM) degradation. Concurrently, TCF7L2 represses integrin β1 (ITGB1) expression, reducing VSMC adhesion to the ECM. Collectively, these findings identify TCF7L2 as a key driver of pathological vascular remodeling in AAA, suggesting that targeting TCF7L2 may offer a novel therapeutic strategy for limiting AAA progression.

Authors

Yongjie Deng, Yaozhong Liu, Yang Zhao, Hongyu Liu, Guizhen Zhao, Zhenguo Wang, Xu Zhang, Chao Xue, Wei Huang, Tianqing Zhu, Haocheng Lu, Yanhong Guo, Lin Chang, Ida Surakka, Y. Eugene Chen, Jifeng Zhang

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Figure 2

VSMC-TCF7L2 deficiency attenuates Ang II and BAPN/Ang II–induced AAA in mice.

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VSMC-TCF7L2 deficiency attenuates Ang II and BAPN/Ang II–induced AAA in ...
(A–F) In the angiotensin II–induced (Ang II–induced) AAA model, 12-week-old male Tcf7l2fl/fl Apoe–/– (n = 8) and Tcf7l2SMKO Apoe–/– (n = 7) mice were infused with Ang II (1,000 ng/kg/min) for 4 weeks. (A) Schematic of Ang II–induced AAA model. (B) Representative morphology of aortae at the endpoint. (C) Maximum diameter of the suprarenal abdominal aortae. (D) Incidence of AAA formation. (E) Representative images of H&E and VVG staining of suprarenal abdominal aortae; red arrows indicate elastin degradation. Scale bars: 200 μm; 20 μm (higher-magnification images). (F) Grade of elastin degradation. (G–K) In the BAPN/Ang II–induced AAA model, 16-week-old male Tcf7l2fl/fl (n = 13) and Tcf7l2SMKO (n = 14) mice were infused with both Ang II (1,000 ng/kg/min, 4 weeks) and BAPN (150 mg/kg/d, the first 2 weeks). (G) Schematic of BAPN/Ang II–induced AAA model. (H) Representative morphology of aortae at the endpoint. (I) Survival curve. (J) Incidence of AAA formation. (K) Representative H&E and VVG staining of suprarenal abdominal aortae; red arrows indicate elastin degradation. Scale bars: 200 μm; 20 μm (higher-magnification images). Data are presented as mean ± SEM. P values were calculated using Mann-Whitney U test (C and F), Mantel-Cox method (I), and χ2 test (J).