School of Medicine, University of Leeds, Leeds, UK.
School of Chemistry, University of Leeds, Leeds, UK.
Liver Int. 2023 Sep;43(9):2026-2038. doi: 10.1111/liv.15646. Epub 2023 Jun 22.
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.
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.
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 A and cyclooxygenases and mimicked by prostaglandin E , 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.
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.
PIEZO1 和 TRPV4 是机械和渗透调节的钙通透性通道。本研究旨在确定这些通道在肝门静脉收缩中的相关性和关系，肝门静脉在将血液从肠道、胆囊、胰腺和脾脏输送到肝脏时会经历机械和渗透变化。
从成年雄性小鼠中分离出门静脉，测量其壁张力，这些小鼠在遗传上未进行修饰或修饰为在天然 PIEZO1 中进行非破坏性标记或内皮特异性 PIEZO1 缺失。使用药理学制剂来激活或抑制 PIEZO1、TRPV4 和相关途径，包括 Yoda1 和 Yoda2 用于 PIEZO1，GSK1016790A 用于 TRPV4 激动剂。
PIEZO1 的激活导致门静脉一氧化氮合酶和内皮依赖性舒张。TRPV4 的激活导致收缩，这也是内皮依赖性的，但独立于一氧化氮合酶。TRPV4 介导的收缩被磷脂酶 A 和环氧化酶抑制剂抑制，并被前列腺素 E 模拟，表明通过花生四烯酸代谢介导。TRPV4 拮抗剂抑制激动剂 TRPV4 的作用，但不抑制 PIEZO1。壁拉伸增加和低渗度抑制 TRPV4 反应，而对 PIEZO1 反应没有影响或增强。
门静脉内皮中含有独立作用的 PIEZO1 通道和 TRPV4 通道，其药理学激活导致血管舒张（PIEZO1）和收缩（TRPV4）的相反作用。在机械和渗透应变中，PIEZO1 机制占主导地位。这些通道的调节剂可能为在疾病和手术过程中操纵肝灌注和再生提供重要的新机会。
