TRPV4 calcium-permeable channel contributes to valve stiffening in aortic stenosis

Abstract

Aortic valve stenosis (AVS) is a progressive disease marked by fibrosis, inflammation, calcification, and stiffening of the aortic valve leaflets, leading to disrupted blood flow and left ventricular pressure overload. AVS can result in heart failure and death within 2 to 5 years if left untreated, highlighting its high mortality rate. Understanding the molecular mechanisms of AVS is essential for developing noninvasive treatments. Emerging data suggest that extracellular and intracellular matrix stiffness influences gene expression, inflammation, and cell differentiation. Myofibroblast activation of valvular interstitial cells (VICs) along with excess extracellular matrix (ECM) accumulation and remodeling are primary drivers of AVS progression. Inflammation also plays a critical role, with macrophages accumulating in valve leaflets from AVS patients, promoting inflammation, activating VICs, and synthesizing and remodeling the ECM. Our lab and others have reported that macrophage and fibroblast activities, including migration, inflammatory gene expression, and myofibroblast activation, are sensitive to matrix stiffness, indicating that valve leaflet stiffening may regulate AVS progression via a cellular stiffness sensor. Our published work shows that mechanosensitive Ca2+-permeable transient receptor potential vanilloid 4 (TRPV4) channels regulate fibrosis in other organs and control macrophage and fibroblast activation, suggesting TRPV4 as the potential stiffness sensor in AVS. This implies that fibrosis and tissue stiffening may reinforce each other, creating a vicious cycle in AVS development, with VICs and macrophages playing central roles. Here, we identify the cellular stiffness sensor mediating the link between stiffness and AVS development using human aortic valve tissues, a murine model of aortic valve stenosis, and atomic force microscopy analysis.