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血清素诱导的血管通透性是由小鼠气道和上消化道中的瞬时受体电位香草素 4 介导的。

Serotonin-induced vascular permeability is mediated by transient receptor potential vanilloid 4 in the airways and upper gastrointestinal tract of mice.

机构信息

Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.

ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Monash University, Parkville, VIC, Australia.

出版信息

Lab Invest. 2021 Jul;101(7):851-864. doi: 10.1038/s41374-021-00593-7. Epub 2021 Apr 15.

DOI:10.1038/s41374-021-00593-7
PMID:33859334
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8047529/
Abstract

Endothelial and epithelial cells form physical barriers that modulate the exchange of fluid and molecules. The integrity of these barriers can be influenced by signaling through G protein-coupled receptors (GPCRs) and ion channels. Serotonin (5-HT) is an important vasoactive mediator of tissue edema and inflammation. However, the mechanisms that drive 5-HT-induced plasma extravasation are poorly defined. The Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel is an established enhancer of signaling by GPCRs that promote inflammation and endothelial barrier disruption. Here, we investigated the role of TRPV4 in 5-HT-induced plasma extravasation using pharmacological and genetic approaches. Activation of either TRPV4 or 5-HT receptors promoted significant plasma extravasation in the airway and upper gastrointestinal tract of mice. 5-HT-mediated extravasation was significantly reduced by pharmacological inhibition of the 5-HT receptor subtype, or with antagonism or deletion of TRPV4, consistent with functional interaction between 5-HT receptors and TRPV4. Inhibition of receptors for the neuropeptides substance P (SP) or calcitonin gene-related peptide (CGRP) diminished 5-HT-induced plasma extravasation. Supporting studies assessing treatment of HUVEC with 5-HT, CGRP, or SP was associated with ERK phosphorylation. Exposure to the TRPV4 activator GSK1016790A, but not 5-HT, increased intracellular Ca in these cells. However, 5-HT pre-treatment enhanced GSK1016790A-mediated Ca signaling, consistent with sensitization of TRPV4. The functional interaction was further characterized in HEK293 cells expressing 5-HT to reveal that TRPV4 enhances the duration of 5-HT-evoked Ca signaling through a PLA and PKC-dependent mechanism. In summary, this study demonstrates that TRPV4 contributes to 5-HT-induced plasma extravasation in the airways and upper GI tract, with evidence supporting a mechanism of action involving SP and CGRP release.

摘要

内皮细胞和上皮细胞形成物理屏障，调节液体和分子的交换。这些屏障的完整性可以通过 G 蛋白偶联受体 (GPCR) 和离子通道的信号传递来影响。血清素 (5-HT) 是组织水肿和炎症的重要血管活性介质。然而，驱动 5-HT 诱导的血浆外渗的机制尚未完全确定。瞬时受体电位香草醛 4 型 (TRPV4) 离子通道是促进炎症和内皮屏障破坏的 GPCR 信号增强剂。在这里，我们使用药理学和遗传学方法研究了 TRPV4 在 5-HT 诱导的血浆外渗中的作用。TRPV4 或 5-HT 受体的激活均可促进小鼠气道和上消化道的显著血浆外渗。5-HT 介导的外渗通过 5-HT 受体亚型的药理学抑制、TRPV4 的拮抗或缺失显著减少，这与 5-HT 受体和 TRPV4 之间的功能相互作用一致。神经肽 P 物质 (SP) 或降钙素基因相关肽 (CGRP) 受体的抑制减少了 5-HT 诱导的血浆外渗。支持研究评估用 5-HT、CGRP 或 SP 处理 HUVEC 与 ERK 磷酸化有关。暴露于 TRPV4 激活剂 GSK1016790A，但不是 5-HT，增加了这些细胞内的 Ca2+。然而，5-HT 预处理增强了 GSK1016790A 介导的 Ca2+信号，这与 TRPV4 的敏化一致。在表达 5-HT 的 HEK293 细胞中进一步表征了这种功能相互作用，结果表明 TRPV4 通过 PLA 和 PKC 依赖性机制增强了 5-HT 诱导的 Ca2+信号的持续时间。总之，这项研究表明 TRPV4 有助于气道和上消化道中的 5-HT 诱导的血浆外渗，有证据支持涉及 SP 和 CGRP 释放的作用机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b7b/8047529/548f95fd5c0a/41374_2021_593_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b7b/8047529/cc478fc93e4c/41374_2021_593_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b7b/8047529/7a5ba47fc8dc/41374_2021_593_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b7b/8047529/953d424ddc95/41374_2021_593_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b7b/8047529/1cfc622578a8/41374_2021_593_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b7b/8047529/e6d7819652d4/41374_2021_593_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b7b/8047529/e7843421183a/41374_2021_593_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b7b/8047529/9d2e14b94000/41374_2021_593_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b7b/8047529/6892832652e7/41374_2021_593_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b7b/8047529/548f95fd5c0a/41374_2021_593_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b7b/8047529/cc478fc93e4c/41374_2021_593_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b7b/8047529/7a5ba47fc8dc/41374_2021_593_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b7b/8047529/953d424ddc95/41374_2021_593_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b7b/8047529/1cfc622578a8/41374_2021_593_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b7b/8047529/e6d7819652d4/41374_2021_593_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b7b/8047529/e7843421183a/41374_2021_593_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b7b/8047529/9d2e14b94000/41374_2021_593_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b7b/8047529/6892832652e7/41374_2021_593_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b7b/8047529/548f95fd5c0a/41374_2021_593_Fig9_HTML.jpg

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