Semaphorin 7A aggravates abdominal aortic aneurysm through PDK1/SGK3/YTHDC1 axis-mediated phenotypic switching of vascular smooth muscle cells

Abstract Aims Semaphorin 7A (SEMA7A), a membrane-anchored glycoprotein involved in immune and vascular signaling, has been implicated in cardiovascular diseases. However, its role in the development of abdominal aortic aneurysm (AAA) has not been defined. In this study, we investigated the role of SEMA7A in AAA progression and the underlying mechanisms. Methods and results A meta-analysis of genome-wide association studies (GWASs) identified SEMA7A as a candidate gene involved in AAA formation. Global and vascular smooth muscle cell (VSMC)-specific Sema7a knockout mice were generated and subjected to a CaPO4-induced AAA model. Compared with wild-type controls, SEMA7A-deficient mice exhibited a 28.6% reduction in aortic expansion, a finding that was recapitulated in VSMC-specific Sema7a knockout mice. RNA sequencing of CaPO4-stimulated mouse VSMCs, along with immunofluorescence staining of AAA tissues, revealed that SEMA7A deficiency supressed VSMC phenotypic switching. Further mechanistic studies demonstrated that SEMA7A promotes this switching via the integrin α5β1-mediated PDK1/SGK3/YTHDC1 signaling axis. Notably, administration of a synthetic SEMA7A-mimicking small peptide, ACP, significantly inhibited VSMC phenotypic switching and attenuated AAA progression. Conclusion This study underscores the critical role of SEMA7A in regulating VSMC phenotypic switching through a novel PDK1/SGK3/YTHDC1 axis, which contributes to AAA pathogenesis, suggesting that targeting SEMA7A is a promising therapeutic strategy for AAA prevention and treatment.