TRPV4 Dominates High Shear-Induced Initial Traction Response and Long-Term Relaxation Over Piezo1.

Area of Science:

• Endothelial mechanobiology
• Vascular physiology
• Ion channel function

Background:

• Endothelial cell responses to fluid shear stress (FSS) are vital for vascular health and atherosclerosis.
• Previous studies showed distinct traction force modulations under high and low FSS.
• The upstream mechanosensors mediating these FSS-induced traction responses were previously unknown.

Purpose of the Study:

• To investigate the roles of Piezo1 and TRPV4 ion channels in modulating endothelial cell traction forces under FSS.
• To elucidate the distinct contributions of these ion channels to endothelial mechanotransduction.

Main Methods:

• Utilized human umbilical vein endothelial cells (HUVECs) with silenced Piezo1 (siPiezo1) and TRPV4 (siTRPV4) expression.
• Measured endothelial cell traction forces under varying FSS conditions (high and low).
• Analyzed traction force magnitude, alignment, and temporal dynamics following FSS exposure.

Main Results:

• siPiezo1 partially reduced the initial traction rise under high FSS but did not affect low FSS responses or alignment.
• siTRPV4 completely abolished the initial traction rise and alignment under both high and low FSS.
• Dual inhibition of Piezo1 and TRPV4 impaired initial and long-term traction, with a notable increase in low FSS response, suggesting alternative pathways.

Conclusions:

• Both Piezo1 and TRPV4 are critical mechanosensors for endothelial cells responding to FSS.
• TRPV4 plays a more dominant role than Piezo1 in mediating initial traction responses and long-term relaxation.
• These findings highlight the distinct and critical contributions of Piezo1 and TRPV4 to endothelial mechanotransduction and vascular remodeling.