Trpv4 Mechanosensing Mediates Valvular Interstitial Cell Differentiation to Myofibroblast

Abstract

Aortic valve stenosis (AVS) is a heart disease that gradually worsens, marked by the fibrosis, inflammation, and stiffening of the aortic valve leaflets, which results in obstructed blood flow and increased pressure on the left ventricle. This condition is associated with a significantly high risk of death. As AVS progresses, valvular interstitial cells (VICs) transform into myofibroblasts due to various soluble and physical cues, leading to detrimental changes in the surrounding cellular matrix. The transformation of VICs into myofibroblasts and the subsequent stiffening of the aortic valve are key factors in the advancement of AVS. Published work by our group and others show that Trpv4 (Transient Receptor Potential subfamily V member 4), a mechanosensitive, calcium-permeant channel/receptor, is activated by a range of soluble and physical stimuli. In mice, Trpv4 deficiency is associated with fibrosis and inflammation. In this study, we tested the hypothesis that Trpv4 regulates the transformation of VICs into myofibroblasts. Our research yielded several key findings: 1) Trpv4 is active in mouse VICs; 2) blocking Trpv4 activity in VICs prevents their transformation into myofibroblasts when exposed to TGF or matrix stiffness; 3) Trpv4 is needed for traction force generation in VICs as determined by traction force microscopy; and 4) Trpv4 residues 100 to 130 are required for myofibroblast differentiation and traction force generation. Altogether, our results highlight the crucial role of Trpv4 mechanosensing in regulating the transformation of VICs to myofibroblasts, a central process in AVS. We believe these findings could lead to novel Trpv4-targeted treatments to mitigate the effects of AVS. NIH (R01 AI172086) grant to Shaik O. Rahaman. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.