TRPV4 is Associated with a Marfan Syndrome-Related Mechanosensitive Gene Program in Aortic Smooth Muscle Cells

Marfan syndrome (MFS) aortopathy involves extracellular matrix disruption, altered mechanical cues, and maladaptive vascular smooth muscle cell (VSMC) remodeling. However, the mechanosensitive regulators associated with MFS-related VSMC dysfunction remain unclear. This study aimed to identify and validate mechanosensitive candidate genes in MFS aortopathy. Public VSMC transcriptomic data from GSE128101 were re-analyzed to identify differentially expressed genes (DEGs). Protein-protein interaction analysis, functional enrichment, and minimum redundancy maximum relevance analysis were used to prioritize mechanosensitive candidates. Candidate genes were examined in independent MFS-related datasets and validated by qRT-PCR in primary aortic medial VSMCs from MFS patients and donor controls. TRPV4 localization was assessed by immunofluorescence. TRPV4 function was evaluated in primary human aortic smooth muscle cells using overexpression and siRNA-mediated knockdown, followed by proliferation, wound-closure, inflammatory cytokine, and NF-κB pathway assays. A total of 436 DEGs were identified in MFS-derived aortic VSMCs. Functional analyses highlighted extracellular matrix remodeling, mechanotransduction-related, inflammatory, and cytoskeleton-associated pathways. TRPV4 was the top-ranked mechanosensitive candidate, with TRPM5 also identified as an overlapping candidate. qRT-PCR confirmed increased TRPV4 and TRPM5 expression in MFS-derived VSMCs. MFS-derived VSMCs also showed elevated inflammatory gene expression and enhanced membrane-associated TRPV4 localization. In vitro, TRPV4 overexpression promoted proliferation, wound closure, inflammatory cytokine secretion, and NF-κB pathway phosphorylation, whereas TRPV4 knockdown showed opposite effects. These exploratory findings identify TRPV4 as a leading mechanosensitive candidate associated with MFS-related VSMC remodeling and inflammatory activation. Larger cohorts, MFS-specific models, and direct mechanistic assays are required to determine its biomarker or therapeutic relevance.