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

Area of Science:

• Cardiovascular Biology
• Metabolic Syndrome Research
• Endothelial Cell Function

Background:

• Endothelial transient receptor potential channel TRPV4 (transient receptor potential channel family V isoform 4) is a vasodilator.
• Its role in obesity-related metabolic homeostasis is not well understood.

Purpose of the Study:

• To investigate the role of endothelial TRPV4 in obesity-induced metabolic alterations.
• To identify endothelial TRPV4 as a regulator of metabolic homeostasis.

Main Methods:

• Generated endothelial-specific TRPV4-deficient and overexpressing mouse models.
• Assessed glucose tolerance, insulin resistance, and lipid metabolism.
• Investigated signaling pathways including Ca2+ influx, eNOS phosphorylation, and NO production.
• Utilized NO donors for in vivo rescue experiments.

Main Results:

• Endothelial TRPV4 deficiency worsened glucose intolerance, insulin resistance, and lipid metabolism.
• Overexpression of endothelial TRPV4 improved metabolic parameters in high-fat diet-fed mice.
• TRPV4 deficiency reduced nitric oxide (NO) production via decreased Ca2+ influx and eNOS phosphorylation.
• TRPV4 activation of AMPK-eNOS signaling axis in endothelial cells impacts adipocyte cGMP/PKG pathway, promoting UCP1 and reducing inflammation.

Conclusions:

• Endothelial TRPV4 is crucial for maintaining metabolic homeostasis during obesity.
• It preserves metabolic health by enhancing AMPK/eNOS-derived NO production.
• This NO signaling activates adipocyte cGMP/PKG pathway, mitigating inflammation and metabolic dysfunction.