Deletion of endothelial TRPV4 protects myocardium against pressure overload‐induced hypertrophy

Abstract

Left ventricular hypertrophy (LVH) starts as an adaptive response of the heart to a hemodynamic challenge, e.g., hypertension, that normalizes wall stress. However, over time this adaptive response often progresses towards a maladaptive pathology with a progressive loss of ventricular function frequently leading to heart failure which is the cause of 1 of 8 deaths in the United States. Although impaired perfusion is one of the major reasons for heart failure, the mechanisms underlying this insidious progression from adaptation to maladaptation are unknown. Importantly, the role of mechanical factors and their molecular mechanisms associated with mechanotransduction in coronary angiogenesis and heart failure are understudied. We have previously shown that transient receptor potential vanilloid 4 (TRPV4) channel is an endothelial mechanosensor and negatively regulates tumor angiogenesis. Therefore, we investigated if TRPV4 mechanotransduction regulates coronary angiogenesis during myocardial stress. To determine this, we subjected WT and global TRPV4KO mice to pressure overload‐induced hypertrophy through transverse aortic construction (TAC). 2D echocardiography analysis revealed that cardiac structure and function is preserved in TRPV4KO‐TAC mice compared to WT‐TAC. Histologically, hearts from global TRPV4KO mice exhibited decreased myocyte cross‐sectional area and fibrosis compared to WT‐TAC. Notably, we found that TRPV4KO hearts exhibited increased capillary density than WT hearts, post‐TAC suggesting that absence of TRPV4 may contribute to these protective effects. To elucidate the specific role of endothelial TRPV4 in coronary angiogenesis, we have generated the endothelial‐specific TRPV4KO (TRPV4ECKO) mice by crossing TRPV4lox/lox mice with Tie2‐Cre mice. First, we have characterized and confirmed the deletion of TRPV4 by genotyping and functional assays in isolated endothelial cells. We then subjected TRPV4ECKO and TRPV4lox/lox mice to pressure overload and assessed the cardiac function up to 28 days using echocardiography. Confocal microscopy revealed larger and properly aligned vessels in TRPV4ECKO hearts compared to TRPV4lox/lox hearts. Further, we found preserved cardiac structure (myocyte cross‐sectional area) and cardiac function (% ejection fraction and fractional shortening) with reduced cardiac fibrosis in TRPV4ECKO mice compared to TRPV4lox/lox post‐TAC, like the global TRPV4KO TAC hearts. Thus, our results suggest that deletion of endothelial TRPV4 preserves cardiac function, myocyte structure and reduces fibrosis via increased coronary angiogenesis following pressure overload‐induced by TAC.Support or Funding InformationNational Institutes of Health (NIH) (R01HL119705 and R15CA202847), American Heart Association (AHA) Grant‐in‐Aid (14GRNT20380935), and start‐up funds from NEOMED (CKT).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.