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 6

TCF7L2 represses ITGB1 to disrupt VSMC-ECM adhesion.

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TCF7L2 represses ITGB1 to disrupt VSMC-ECM adhesion. (A–D) HASMCs were t...
(A–D) HASMCs were transfected with 20 nM siTCF7L2 or siControl (A and B) or infected with 20 MOI AdTCF7L2 or AdGFP (C and D) for 48 hours, followed by serum starvation in Opti-MEM for 24 hours. Cells were then plated onto collagen I–coated wells and allowed to adhere at 37°C for 90 minutes. Adherent cells were visualized by crystal violet staining (A and C) and quantified (B and D). The original magnification of the images was 4×. (E–J) Under the same transfection or infection conditions as above, mRNA levels (E and H) and protein abundance (F, G, I, and J) of ITGB1 were determined from 3 independent experiments. (K and L) HASMCs were cotransfected with 20 nM siTCF7L2 or siControl and either 20 nM siITGB1 or control siRNA for 48 hours, followed by adhesion assay as in A–D. The original magnification of the images was 4×. (M) IGV browser view of ChIP-seq signal tracks showing TCF7L2 and IgG binding at the human ITGB1 locus, with aligned Hi-C (ENCSR797MWY) and ATAC-seq (ENCFF719YRB) profiles. (N) Bulk RNA-seq analysis of Itgb1 expression in abdominal aortae from PCSK9/Ang II–induced AAA mice versus saline controls at day 14. Data are presented as mean ± SEM. P values were calculated using Student’s t test for B, D, E, G, H, J and N, and 2-way ANOVA followed by Holm-Šidák post hoc analysis for L.