Endothelial TRPV4/Cx43 Signaling Complex Regulates Vasomotor Tone in Resistance Arteries

Area of Science:

• Cardiovascular Physiology
• Endothelial Cell Biology
• Ion Channel Function

Background:

• S-nitrosylation of connexin 43 (Cx43) gap junctions affects cell communication and hemichannel opening.
• Endothelial TRPV4 channels promote vasodilation via nitric oxide (NO) production.
• The precise role of Cx43 hemichannels in vasomotor regulation is not fully understood.

Purpose of the Study:

• To investigate the direct modulation of endothelial Cx43 hemichannels by TRPV4 channel activation.
• To elucidate the role of the TRPV4/Cx43 signaling pathway in endothelial electrical behavior and vasomotor tone.

Main Methods:

• Proximity ligation assay to detect Cx43 and TRPV4 proximity in resistance artery endothelium.
• Experiments in primary endothelial cell cultures (ECs) and ex vivo mesenteric arteries.
• Intravital microscopy in vivo to assess TRPV4-induced relaxation.

Main Results:

• TRPV4 activation in ECs enhances eNOS activity, increases NO production, and opens Cx43 hemichannels via S-nitrosylation.
• Blocking Cx43 hemichannels reduced elevated intracellular Ca2+ levels caused by TRPV4 activation.
• Inhibition of Cx43 hemichannels impaired endothelial hyperpolarization and blunted TRPV4-induced relaxation in vivo.

Conclusions:

• TRPV4 channel activation directly modulates endothelial Cx43 hemichannels through S-nitrosylation.
• The TRPV4/Cx43 signaling pathway is critical for regulating endothelial electrical behavior and vasomotor tone.
• Cx43 hemichannels play a pivotal role in TRPV4-mediated vasodilation.