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

Department

Internal Medicine

Document Type

Article

Publication Title

JCI Insight

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.

First Page

e195681

DOI

10.1172/jci.insight.195681

Volume

11

Issue

12

Publication Date

6-22-2026

Medical Subject Headings

Animals; Aortic Aneurysm, Abdominal; Extracellular Matrix; Humans; Mice; Transcription Factor 7-Like 2 Protein; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Male; Disease Models, Animal; Mice, Knockout; Angiotensin II; Aminopropionitrile

PubMed ID

42060473

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