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 4

TCF7L2 upregulates MMP14 expression in VSMCs and AAA lesions.

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TCF7L2 upregulates MMP14 expression in VSMCs and AAA lesions. (A) qPCR a...
(A) qPCR analysis of Mmp14 mRNA levels in abdominal aortae from PCSK9/Ang II–induced AAA mice at days 0, 3, 7, 14, and 28. (B) RNA-seq analysis of Mmp14 expression in abdominal aortae from PCSK9/Ang II–induced AAA mice at day 14, stratified into saline control, ectasia (maximal diameter < 1.2 mm), dilation (≥1.2 mm without dissection), and dissection (presence of intramural hemorrhage). (C–H) HASMCs were transfected with 20 nM siTCF7L2 and siControl (C, E, and F) or 20 MOI AdTCF7L2 and AdGFP (D, G, and H) for 48 hours, followed by serum starvation in Opti-MEM for 24 hours. mRNA levels of TCF7L2 and MMP14 (C and D) and protein abundance of TCF7L2 and MMP14 (E–H) were determined from 3 independent experiments. (I) Normalized ChIP-seq reads of TCF7L2 in the genomic region upstream of the MMP14 gene are shown in the IGV image. (J) ChIP-qPCR quantification of TCF7L2 binding at the predicted motif upstream of MMP14. (K and L) Dual-luciferase reporter assays in HASMCs pretreated with 20 nM siTCF7L2 and siControl (K) or 20 MOI AdTCF7L2 and AdGFP (L) for 24 hours, followed by transfection of a minimal CMV luciferase reporter containing the TCF7L2 ChIP-seq–identified upstream regulatory fragment of MMP14. Luciferase activity was measured 24 hours after reporter transfection. (M) Representative images of immunohistochemical staining of MMP14 of suprarenal abdominal aortae in the Ang II–induced AAA model. Scale bars: 200 μm; 20 μm (higher-magnification images). (N) Quantification of MMP14 staining intensity. P values were calculated using 1-way ANOVA followed by Tukey’s post hoc analysis for A and B or Student’s t test for C–N.