Abstract P2028: Uncoupling Endothelial Trpv4 Mechanotransduction Attenuates Pressure Overload-induced Cardiac Hypertrophy Via Rho/yap/vegfr2 Mediated Coronary Cngiogenesis

Abstract

Left ventricular hypertrophy (LVH) is a bipolar response, starting as an adaptive response to the hemodynamic challenge, but over time progressing towards a maladaptive pathology with a loss of ventricular function. Despite the profound influence on cardiac function, the mechanotransduction mechanisms that regulate myocardial angiogenesis, leading to heart failure, are not well known. Here, we demonstrate that endothelial-specific deletion of mechanosensitive ion channel TRPV4 preserved cardiac function and structure and reduced fibrosis via increased capillary density compared to WT mice, 28 days post-transverse aortic constriction (TAC). Interestingly, comprehensive RNA sequencing analysis revealed an upregulation of pro-angiogenic factors (FGF2, NOS3, and VEGFα) in TRPV4 ECKO hearts after TAC compared to TRPV4 lox/lox . Further, an increased expression of VEGFR2 and activation of the YAP pathway was observed in TRPV4 ECKO hearts. Mechanistically, we found that downregulation of TRPV4 in human ECs induced matrix stiffness-dependent activation of YAP and VEGFR2 via the Rho/Rho kinase/LATS pathway. Our results thus suggest that endothelial TRPV4 acts as a mechanical break for coronary angiogenesis, and uncoupling TRPV4 mechanotransduction attenuates pathological cardiac hypertrophy by enhancing coronary angiogenesis.