Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, University of Louvain Medical School, 52, Avenue Mounier, B-1200 Brussels, Belgium.
Arterioscler Thromb Vasc Biol. 2012 Sep;32(9):2241-9. doi: 10.1161/ATVBAHA.112.252783. Epub 2012 Jul 19.
We investigated the impact of hypoxia-reoxygenation on endothelial relaxation and aimed to clarify the role of transient receptor potential cation channels V4 (TRPV4) and gap junctions in the protective effect associated with hypoxic preconditioning on the vascular function.
By mimicking ischemia-reperfusion in C57BL/6 male mice in vivo, we documented a reduced NO-mediated relaxation and an increased endothelium-derived hyperpolarization (EDH[F])-mediated relaxation. Hypoxic preconditioning, however, restored NO relaxation and further improved the EDH(F) response. We also examined specifically 2 major effectors of the EDH(F) pathway, transient receptor potential cation channels V4 and connexins. We found that in endothelial cells, expression and activity of transient receptor potential cation channels V4 were increased by hypoxic stimuli independently of preconditioning which was interestingly associated with an increase of structural caveolar component caveolin-1 at membrane locations. Gap junctions, however, seemed to directly support EDH(F)-driven preconditioning as connexin 40 and connexin 43 expression increased and as in vivo carbenoxolone treatment completely inhibited the EDH(F) pathway and significantly reduced the protection afforded by preconditioning for the concomitant NO-mediated relaxation.
Our work provides evidence on how transient receptor potential cation channels V4 and connexins might participate in preserving vasorelaxation under hypoxia and restoring the NO-mediated pathway in hypoxic preconditioning conditions pointing out caveolae as a common signaling location.
我们研究了缺氧复氧对内皮松弛的影响，并旨在阐明瞬时受体电位阳离子通道 V4（TRPV4）和缝隙连接在与低氧预处理相关的血管功能保护作用中的作用。
通过在体内模拟 C57BL/6 雄性小鼠的缺血再灌注，我们记录到 NO 介导的松弛减少和内皮衍生的超极化（EDH[F]）介导的松弛增加。然而，低氧预处理恢复了 NO 松弛，并进一步改善了 EDH(F)反应。我们还专门研究了 EDH(F)途径的 2 个主要效应子，瞬时受体电位阳离子通道 V4 和连接蛋白。我们发现，在内皮细胞中，瞬时受体电位阳离子通道 V4 的表达和活性被低氧刺激增加，而与预处理无关，这与膜位置处结构空泡蛋白-1 的增加有关。然而，缝隙连接似乎直接支持 EDH(F)驱动的预处理，因为连接蛋白 40 和连接蛋白 43 的表达增加，并且体内 carbenoxolone 处理完全抑制了 EDH(F)途径，并显著降低了预处理对同时发生的 NO 介导的松弛的保护作用。
我们的工作提供了证据，证明瞬时受体电位阳离子通道 V4 和连接蛋白如何参与在低氧下保存血管松弛，并在低氧预处理条件下恢复 NO 介导的途径，指出空泡作为一个共同的信号位置。
