Endothelial TRPV4 mitigates obesity-induced metabolic inflammation via Ca2+-dependent eNOS phosphorylation

Rationale: Previous studies show endothelial Ca2+ permeable channel TRPV4 (transient receptor potential channel family V isoform 4) as a vasodilator defense against endothelial dysfunction in obesity-induced hypertension. However, the role of endothelial TRPV4 in metabolic homeostasis related to obesity is unclear.Objective: We identify endothelial TRPV4 as a previously unknown regulator of obesity-induced metabolic alterations.Methods and Results:  Endothelial-specific TRPV4-deficient and overexpressed mice were generated. Endothelial TRPV4 knockout exacerbated glucose intolerance, insulin resistance, and impaired lipid metabolism induced by a high-fat diet. Conversely, endothelial TRPV4 overexpression restored glucose and lipid homeostasis. In white adipose tissue, endothelial TRPV4 not only regulated UCP1 expression but also potently suppressed multiple proinflammatory genes associated with metabolic dysfunction. Mechanistically, we demonstrated that loss of endothelial TRPV4 abolished flow-induced intracellular Ca2+ elevation and the subsequent phosphorylation of endothelial nitric oxide synthase (p-eNOS), leading to diminished nitric oxide (NO) production. In contrast, gain of endothelial TRPV4 rescued Ca2+-dependent eNOS phosphorylation and NO bioavailability in the vascular endothelial cells of obese mice. Consistently, direct knockout of eNOS recapitulated the metabolic disorders observed in TRPV4-deficient mice.Conclusions: Endothelial TRPV4 preserves metabolic homeostasis by promoting eNOS phosphorylation and NO production, thereby mitigating adipose tissue inflammation and improving metabolic fitness during the development of obesity.