Abstract 814: Trpv4 Deletion in Endothelium Protects Heart Against Pressure Overload Induced Hypertrophy

Coronary microvascular dysfunction has been identified as one of the underlying causes for progression of heart failure following hypertrophy or myocardial infarction. However, the mechanisms underlying microvascular dysfunction during the progression of heart failure are unknown. Recently, we found that transient receptor potential vanilloid 4 (TRPV4) channel acts as mechanosensor in endothelial cells and negatively regulates angiogenesis. Therefore, to determine the role of TRPV4 in coronary microvascular function during pathological hypertrophy, we have induced pressure-overload in WT and TRPV4KO mice via transverse aortic constriction (TAC). We found that TAC-induced cardiomyocyte hypertrophy and reduced cardiac function in WT mice, after 28 days. In contrast, both myocyte structure and cardiac function were preserved in TRPV4KO-TAC compared to WT-TAC mice. Notably, WT-TAC hearts exhibited increased ECM deposition and reduced microvascular density compared to TRPV4KO-TAC hearts, suggesting that the absence of TRPV4 may protect myocardium from pressure-overload-induced stress. To evaluate the specific role of endothelial TRPV4 in coronary microvascular function, endothelial specific TRPV4KO (TRPV4 ECKO ) mice were generated by crossing TRPV4 lox/lox mice with Tie2-Cre mice. After confirming endothelial deletion of TRPV4 through RT-PCR and immunostaining, we have subjected TRPV4 lox/lox and TRPV4 ECKO mice to TAC. Immuno-histological analysis revealed that TRPV4 ECKO hearts exhibited increased microvascular density compared to TRPV4 lox/lox mice, 28 days post TAC. Further, we found preserved cardiac structure (myocyte cross sectional area) and cardiac function (% ejection fraction and fractional shortening) with reduced cardiac fibrosis in TRPV4 ECKO mice compared to TRPV4 lox/lox , post TAC. Thus, our results suggest that endothelial TRPV4 channels are key regulators of coronary microvasculature function and deletion of endothelial TRPV4 offers cardio-protection via increased coronary angiogenesis following pressure overload-induced by TAC.