Aortic valve stenosis (AVS) is characterized by fibrosis, inflammation, calcification, and stiffening of the aortic valve leaflets. If left untreated, AVS can result in heart failure and death. Understanding the molecular mechanisms driving AVS is critical for developing noninvasive therapies. Matrix stiffness influences gene expression, inflammation, and cell differentiation. Myofibroblast activation of valvular interstitial cells (VICs) and matrix remodeling are central to AVS development. This study investigates the role of mechanosensitive transient receptor potential vanilloid 4 (TRPV4) ion channels in matrix stiffening, cell heterogeneity, and transcriptional dynamics in AVS. Using human aortic valve biopsies from AVS patients, we observed increased expression of TRPV4, CD68+ macrophages, and alpha-SMA+ myofibroblasts compared to healthy controls, with a strong correlation between TRPV4 expression and tissue stiffness. Double immunofluorescence staining was performed on aortic valve biopsies from AVS patients and healthy subjects to identify α-SMA-positive myofibroblasts and CD68-positive macrophages expressing TRPV4 proteins. Atomic force microscopy (AFM) analysis confirmed a 12-fold increase in aortic valve stiffness in AVS tissues compared to healthy valves. In a murine model of AVS, aortic root sections from hypercholesterolemic ApoE-/- and ApoE-/-TRPV4-/- mice were analyzed to obtain force curves. We found a 7-fold increase in aortic valve stiffness in ApoE-/- mice compared to ApoE-/-TRPV4-/- mice after 6 months on a high-fat diet (Harlan Teklad), suggesting TRPV4's role in regulating valve stiffness. Additionally, AFM analysis of VICs showed significantly higher stiffness in wild-type VICs compared to TRPV4-/- VICs, particularly when stimulated by TGF, a profibrotic factor. We used single-nucleus RNA sequencing on aortic valve tissues from ApoE-/- and ApoE-/-TRPV4-/- mice, identifying 12 cell clusters and revealing that TRPV4 deficiency drives significant transcriptional dynamics in VICs, macrophages, and vascular endothelial cells, highlighting TRPV4's key role in regulating aortic stenosis. Altogether, these findings indicate that TRPV4 contributes to cellular and tissue matrix stiffening, and modulating cell heterogeneity and transcriptional dynamics in AVS, suggesting that targeting TRPV4 could offer a novel therapeutic approach for AVS.
Rahaman et al. (Fri,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: