Faculty Collaboration Database

Independent endothelial functions of PIEZO1 and TRPV4 in hepatic portal vein and predominance of PIEZO1 in mechanical and osmotic stress. Liver Int 2023 Sep;43(9):2026-2038

Date

06/23/2023

Pubmed ID

37349903

Pubmed Central ID

PMC10946873

DOI

10.1111/liv.15646

Scopus ID

2-s2.0-85162721012 (requires institutional sign-in at Scopus site)   4 Citations

Abstract

BACKGROUND & AIMS: PIEZO1 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.

METHODS: Wall 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.

RESULTS: PIEZO1 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.

CONCLUSIONS: The 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.

Author List

Endesh N, Chuntharpursat-Bon E, Revill C, Yuldasheva NY, Futers TS, Parsonage G, Humphreys N, Adamson A, Morley LC, Cubbon RM, Prasad KR, Foster R, Lichtenstein L, Beech DJ

Author

Kondragunta Rajendra Prasad MBBS Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Endothelium
Ion Channels
Male
Mice
Nitric Oxide
Nitric Oxide Synthase
Osmotic Pressure
Portal Vein
TRPV Cation Channels
Vasodilation