International immunopharmacology · 2026
Endothelial TRPV4 mitigates obesity-induced metabolic dysfunction via Ca2+-dependent eNOS phosphorylation.
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Chu Yuan, Zhang Yizhi, Chu Chu, Liu Yuan, Tang Junjian, Yu Fan, Zhu Yifei
Аннотация
RATIONALE: Previous studies have shown that the endothelial Ca2+ permeable channel TRPV4 (transient receptor potential channel family V isoform 4) acts 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 alteration.
METHODS AND RESULTS: Endothelial-specific TRPV4-deficient and overexpressing mice were generated. Endothelial TRPV4 knockout exacerbated glucose intolerance, insulin resistance, and impaired lipid metabolism. Conversely, endothelial TRPV4 overexpression restored glucose and lipid homeostasis impaired by a high-fat diet. In white adipose tissue, endothelial TRPV4 not only regulated UCP1 expression but also suppressed multiple proinflammatory genes associated with metabolic dysfunction. Mechanistically, we demonstrated that loss of endothelial TRPV4 decreased flow-induced intracellular Ca2+ influx and the subsequent phosphorylation of endothelial nitric oxide synthase (p-eNOS), leading to diminished nitric oxide (NO) production. In contrast, overexpression of endothelial TRPV4 rescued Ca2+-dependent eNOS phosphorylation and NO bioavailability. Furthermore, we identified that TRPV4 activation triggers an AMPK-eNOS signaling axis in endothelial cells, which subsequently activates the sGC/cGMP/PKG pathway in adipocytes via paracrine signaling to promote UCP1 expression. Consistently, direct global knockout of eNOS caused metabolic disorders which were similar to those observed in TRPV4-deficient mice. Importantly, a four-week in vivo rescue experiment with the NO donor DETA-NONOate effectively reversed the metabolic dysfunction and adipose tissue inflammation induced by endothelial TRPV4 deficiency.
CONCLUSIONS: Endothelial TRPV4 preserves metabolic homeostasis by promoting AMPK/eNOS-derived NO production, which subsequently activates the adipocyte cGMP/PKG signaling axis to mitigate adipose tissue inflammation and metabolic dysfunction of obesity.
OBJECTIVE: We identify endothelial TRPV4 as a previously unknown regulator of obesity-induced metabolic alteration.
METHODS AND RESULTS: Endothelial-specific TRPV4-deficient and overexpressing mice were generated. Endothelial TRPV4 knockout exacerbated glucose intolerance, insulin resistance, and impaired lipid metabolism. Conversely, endothelial TRPV4 overexpression restored glucose and lipid homeostasis impaired by a high-fat diet. In white adipose tissue, endothelial TRPV4 not only regulated UCP1 expression but also suppressed multiple proinflammatory genes associated with metabolic dysfunction. Mechanistically, we demonstrated that loss of endothelial TRPV4 decreased flow-induced intracellular Ca2+ influx and the subsequent phosphorylation of endothelial nitric oxide synthase (p-eNOS), leading to diminished nitric oxide (NO) production. In contrast, overexpression of endothelial TRPV4 rescued Ca2+-dependent eNOS phosphorylation and NO bioavailability. Furthermore, we identified that TRPV4 activation triggers an AMPK-eNOS signaling axis in endothelial cells, which subsequently activates the sGC/cGMP/PKG pathway in adipocytes via paracrine signaling to promote UCP1 expression. Consistently, direct global knockout of eNOS caused metabolic disorders which were similar to those observed in TRPV4-deficient mice. Importantly, a four-week in vivo rescue experiment with the NO donor DETA-NONOate effectively reversed the metabolic dysfunction and adipose tissue inflammation induced by endothelial TRPV4 deficiency.
CONCLUSIONS: Endothelial TRPV4 preserves metabolic homeostasis by promoting AMPK/eNOS-derived NO production, which subsequently activates the adipocyte cGMP/PKG signaling axis to mitigate adipose tissue inflammation and metabolic dysfunction of obesity.