FHL2-RhoA Signalling Mediates Mechanical Regulation of Aortic Valve Interstitial Cell Osteogenic Differentiation
Calcific aortic valve disease (CAVD) affects 25% of senior citizens and is characterized by aortic valve stiffening and calcification. Calcific lesions often include osteoblasts and occur preferentially in the natively stiffer fibrosa side of the valve, suggesting roles for osteogenesis and matrix stiffness in CAVD. Valve interstitial cells (VICs) have osteogenic potential that is modulated by matrix stiffness in vitro and may be a source of bone formation in disease. Osteogenesis of mesenchymal stem cells is mediated by four and a half LIM protein 2 (FHL2) and modulated by substrate stiffness via ras homolog gene family, member A (RhoA). However, the connection between FHL2 and RhoA and their roles in mechanically-regulated osteogenic differentiation of VICs and CAVD have not been established.
Matrix stiffness regulates RhoA-dependent FHL2 expression to direct VIC osteogenesis.