Independent endothelial functions of PIEZO1 and TRPV4 in hepatic portal vein and predominance of PIEZO1 in mechanical and osmotic stress

Abstract

Background & AimsPIEZO1 and TRPV4 are mechanically and osmotically regulated calcium‐permeable channels. The aim of this study was to determine the relevance and relationship of these channels in the contractile tone of the hepatic portal vein, which experiences mechanical and osmotic variations as it delivers blood to the liver from the intestines, gallbladder, pancreas and spleen.MethodsWall tension was measured in freshly dissected portal veins from adult male mice, which were genetically unmodified or modified for either a non‐disruptive tag in native PIEZO1 or endothelial‐specific PIEZO1 deletion. Pharmacological agents were used to activate or inhibit PIEZO1, TRPV4 and associated pathways, including Yoda1 and Yoda2 for PIEZO1 and GSK1016790A for TRPV4 agonism, respectively.ResultsPIEZO1 activation leads to nitric oxide synthase‐ and endothelium‐dependent relaxation of the portal vein. TRPV4 activation causes contraction, which is also endothelium‐dependent but independent of nitric oxide synthase. The TRPV4‐mediated contraction is suppressed by inhibitors of phospholipase A2 and cyclooxygenases and mimicked by prostaglandin E2, suggesting mediation by arachidonic acid metabolism. TRPV4 antagonism inhibits the effect of agonising TRPV4 but not PIEZO1. Increased wall stretch and hypo‐osmolality inhibit TRPV4 responses while lacking effects on or amplifying PIEZO1 responses.ConclusionsThe portal vein contains independently functioning PIEZO1 channels and TRPV4 channels in the endothelium, the pharmacological activation of which leads to opposing effects of vessel relaxation (PIEZO1) and contraction (TRPV4). In mechanical and osmotic strain, the PIEZO1 mechanism dominates. Modulators of these channels could present important new opportunities for manipulating liver perfusion and regeneration in disease and surgical procedures.

Effects of liraglutide on ANP secretion and cardiac dynamics

“…However, other studies have shown that piezo 1 regulates cell response to mechanical stress by controlling Ca 2+ influx, and that piezo 1 expression increases in red blood cells and hepatic portal endothelial cells when subjected to mechanical forces. Calcium ion inflow increases through calcium osmotic channels ( 42 , 46 , 47 , 48 ). Our results showed that liraglutide decreased atrial pulse pressure and piezo 1 expression.…”

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“…Yoda2 is a structurally modified version of Yoda1 with the pyrazine ring replaced by 4-benzoic acid. This substitution significantly improves Piezo1 agonist activity with concentrations similar to those of Yoda1 (Endesh et al, 2023). Like Yoda1, Yoda2 also stabilizes open conformations of Piezo1, and its enhanced efficacy is likely due to the negative charge and more desirable pharmacokinetic properties of 4-benzoic acid at physiological pH relative to neutral pyrazine rings (Parsonage et al, 2022).…”

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“…The functional coupling between PIEZO1 and TRPV4 characterized in human umbilical vein ECs is likely dependent on the vascular bed, as activation of PIEZO1 or TRPV4 in hepatic portal vein ECs have opposing independent effects promoting relaxation and contraction, respectively. 69…”