Department of Obstetrics, Gynecology, and Reproductive Sciences, Larner College of Medicine, University of Vermont , Burlington, Vermont.
Department of Biology, Ecology and Earth Science, University of Calabria , Cosenza , Italy.
Am J Physiol Heart Circ Physiol. 2018 Oct 1;315(4):H1019-H1026. doi: 10.1152/ajpheart.00103.2018. Epub 2018 Jul 13.
During mammalian pregnancy, the uterine circulation must undergo substantial vasodilation and growth to maintain sufficient uteroplacental perfusion. Although we and others have shown that nitric oxide (NO) is a key mediator of these processes, the mechanisms that augment uterine artery NO signaling during gestation have not been identified. We hypothesized that Piezo1, a recently discovered cation channel, may be involved in the process of shear stress mechanotransduction, as other studies have shown that it is both mechanosensitive and linked to NO production. Surprisingly, there are no studies on Piezo1 in the uterine circulation. Our aims in the present study were to determine whether this novel channel is 1) present in uterine arteries, 2) regulated by gestation, 3) functionally relevant (able to elicit rises in intracellular Ca concentration and vasodilation), and 4) linked to NO. Immunohistochemistry confirmed that Piezo1 is present in uterine arteries, primarily but not exclusively in endothelial cells. Western blot analysis showed that its protein expression was elevated during gestation. In pressurized main uterine arteries, pharmacological activation of Piezo1 by Yoda1 produced near maximal vasodilation and was associated with significant increases in intracellular Ca concentration in endothelial cell sheets. Shear stress induced by intraluminal flow produced reversible vasodilations that were inhibited >50% by GsMTx-4, a Piezo1 inhibitor, and by N-nitro-l-arginine methyl ester/ N-nitro-l-arginine, inhibitors of NO synthase. These findings are the first to implicate a functional role for Piezo1 in the uterine circulation as a mechanosensor of endothelial shear stress. Moreover, our data demonstrate that Piezo1 activation leads to vasodilation via NO and indicate that its molecular expression is upregulated during pregnancy. NEW & NOTEWORTHY This is the first study to highlight Piezo1 in the uterine circulation. As a potentially important endothelial mechanosensor of shear stress, Piezo1 may be linked to mechanisms that support increased uteroplacental perfusion during pregnancy. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/piezo1-mechanotransduction-in-the-uterine-circulation/ .
在哺乳动物妊娠期间，子宫循环必须经历显著的血管扩张和生长，以维持足够的胎盘灌注。虽然我们和其他人已经表明，一氧化氮（NO）是这些过程的关键介质，但在妊娠期间增加子宫动脉 NO 信号的机制尚未确定。我们假设 Piezo1，一种最近发现的阳离子通道，可能参与剪切力机械转导过程，因为其他研究表明它既具有机械敏感性，又与 NO 产生有关。令人惊讶的是，在子宫循环中没有关于 Piezo1 的研究。本研究的目的是确定 1）这种新型通道是否存在于子宫动脉中，2）是否受妊娠调节，3）是否具有功能相关性（能够引起细胞内 Ca 浓度升高和血管扩张），以及 4）是否与 NO 相关。免疫组织化学证实 Piezo1 存在于子宫动脉中，主要但不仅限于内皮细胞中。Western blot 分析表明，其蛋白表达在妊娠期间升高。在加压的主要子宫动脉中，Yoda1 对 Piezo1 的药理学激活产生了近乎最大的血管舒张作用，并与内皮细胞片中细胞内 Ca 浓度的显著增加相关。由腔内流动产生的剪切力引起的可逆血管舒张被 GsMTx-4（Piezo1 抑制剂）和 N-硝基-l-精氨酸甲酯/ N-硝基-l-精氨酸（NOS 抑制剂）抑制超过 50%。这些发现首次表明 Piezo1 在子宫循环中作为内皮剪切力的机械感受器具有功能作用。此外，我们的数据表明，Piezo1 激活通过 NO 导致血管舒张，并表明其分子表达在妊娠期间上调。新的和值得注意的是，这是第一项强调 Piezo1 在子宫循环中的研究。作为剪切力的潜在重要内皮机械感受器，Piezo1 可能与支持妊娠期间胎盘灌注增加的机制有关。在 https://ajpheart.podbean.com/e/piezo1-mechanotransduction-in-the-uterine-circulation/ 上收听本文相应的播客。
