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 5

TCF7L2 promotes MMP activity by upregulating MMP14 and repressing TIMP3.

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TCF7L2 promotes MMP activity by upregulating MMP14 and repressing TIMP3....
(A) For MMP activity assays, HASMCs were first transfected with 20 nM siTCF7L2 or siControl for 48 hours, then infected with either Lenti-GFP or Lenti-MMP14 for 24 hours, and subsequently serum-starved in Opti-MEM for 48 hours. Conditioned media were collected, and total MMP activity was assessed using a fluorometric assay. (B–E) HASMCs were transfected with 20 nM siTCF7L2 and siControl or 20 MOI AdTCF7L2 and AdGFP for 48 hours, followed by serum starvation in Opti-MEM for 24 hours, and mRNA levels of TCF7L2 and TIMPs (B and C) and protein abundance of TIMP3 (D and E) were determined from 3 independent experiments. (F–H) HASMCs were transfected with 20 nM siTCF7L2 and siControl, followed by serum starvation in Opti-MEM for 24 hours; gelatin zymography was performed to assess the levels of pro-MMP2 and activated MMP2 in the conditioned media; and Western blot was used to evaluate TCF7L2 knockdown efficiency in whole-cell lysates. Data are presented as mean ± SEM. P values were calculated using 2-way ANOVA followed by Holm-Šidák post hoc analysis for A–C or Student’s t test for E, G, and H.