Abstract Body (Do not enter title and authors here): Introduction: Abdominal aortic aneurysm (AAA) is a major cardiovascular disease characterized by the dysregulation of vascular smooth muscle cell (VSMC) homeostasis. TCF7L2, a transcription factor involved in Wnt signaling, plays a key role in cell proliferation and differentiation. Genome-wide association studies (GWAS) have identified the gene as being positively associated with aortic aneurysms, but its specific impact and the underlying mechanisms on AAA remain unclear.
Methods and results: Two models were employed to induce AAA in VSMC-specific Tcf7l2 knockout (floxed Tcf7l2/Myh11-CreERT2) mice: elastase- and AngII/BAPN-induced AAA models. TCF7L2 deficiency in VSMCs significantly alleviated AAA formation, aorta dilation, elastin degradation, and VSMC apoptosis in both models. In primary human aortic smooth muscle cells, small interfering RNA-mediated Tcf7l2 knockdown attenuated glycolysis and lactate production, as revealed by RNA sequencing, targeted metabolomics, lactate assay, and Seahorse Glycolysis Stress Test. TCF7L2 deficiency in VSMCs also inhibited cell migration, TNFα/CHX- and FasL-induced apoptosis. Conversely, adenovirus-mediated overexpression of TCF7L2 promoted these processes. We further performed Cut&Run sequencing and ChIP sequencing analysis, the data revealed that TCF7L2 binds to the promoter regions of Ldha/b and Tp53 genes, indicating that TCF7L2 promotes VSMC glycolysis and apoptosis through direct interaction with these key genes. Additionally, TCF7L2 upregulated the mRNA and protein expression of MMP14 in VSMCs, suggesting a mechanism by which TCF7L2 regulates extracellular matrix organization.
Conclusions: Our data indicate that TCF7L2 plays a key role in AAA development by modulating VSMC glycolysis, apoptosis, migration, and extracellular matrix organization, highlighting TCF7L2 as a potential target for treating VSMC-related diseases.