Francis Michael, Xu Ningyong, Zhou Chun, Stevens Troy
Department of Physiology and Cell Biology, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama.
Department of Physiology and Cell Biology, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama; Department of Medicine, University of South Alabama, Mobile, Alabama.
Am J Pathol. 2016 Jun;186(6):1701-9. doi: 10.1016/j.ajpath.2016.02.002. Epub 2016 Apr 12.
The canonical transient receptor potential channel 4 (TRPC4) comprises an endothelial store-operated Ca(2+) entry channel, and TRPC4 inactivation confers a survival benefit in pulmonary arterial hypertension (PAH). Endothelial Ca(2+) signals mediated by TRPC4 enhance vascular permeability in vitro, but the contribution of TRPC4-dependent Ca(2+) signals to the regulation of endothelial permeability in PAH is poorly understood. We tested the hypothesis that TRPC4 increases vascular permeability and alters the frequency of endothelial Ca(2+) transients in PAH. We measured permeability in isolated lungs, and found that TRPC4 exaggerated permeability responses to thapsigargin in Sugen/hypoxia-treated PAH rats. We compared endothelial Ca(2+) activity of wild-type with TRPC4-knockout rats using confocal microscopy, and evaluated how Ca(2+) signals were influenced in response to thapsigargin and sequential treatment with acetylcholine. We found that thapsigargin-stimulated Ca(2+) signals were increased in PAH, and recovered by TRPC4 inactivation. Store depletion revealed bimodal Ca(2+) responses to acetylcholine, with both short- and long-duration populations. Our results show that TRPC4 underlies an exaggerated endothelial permeability response in PAH. Furthermore, TRPC4 increased the frequency of endothelial Ca(2+) transients in severe PAH, suggesting that TRPC4 provides a Ca(2+) source associated with endothelial dysfunction in the pathophysiology of PAH. This phenomenon represents a new facet of the etiology of PAH, and may contribute to PAH vasculopathy by enabling inflammatory mediator flux across the endothelial barrier.
典型瞬时受体电位通道4（TRPC4）是一种内皮储存-操作性Ca(2+)进入通道，TRPC4失活可在肺动脉高压（PAH）中带来生存益处。由TRPC4介导的内皮Ca(2+)信号在体外可增强血管通透性，但TRPC4依赖性Ca(2+)信号对PAH中内皮通透性调节的作用尚不清楚。我们检验了TRPC4增加血管通透性并改变PAH中内皮Ca(2+)瞬变频率的假说。我们测量了离体肺的通透性，发现TRPC4会夸大Sugen/低氧处理的PAH大鼠对毒胡萝卜素的通透性反应。我们使用共聚焦显微镜比较了野生型大鼠和TRPC4基因敲除大鼠的内皮Ca(2+)活性，并评估了毒胡萝卜素以及乙酰胆碱序贯处理对Ca(2+)信号的影响。我们发现毒胡萝卜素刺激的Ca(2+)信号在PAH中增加，并且通过TRPC4失活得以恢复。储存耗竭揭示了对乙酰胆碱的双峰Ca(2+)反应，包括短期和长期群体。我们的结果表明，TRPC4是PAH中内皮通透性反应过度的基础。此外，TRPC4增加了重度PAH中内皮Ca(2+)瞬变的频率，这表明TRPC4在PAH病理生理学中提供了一个与内皮功能障碍相关的Ca(2+)来源。这种现象代表了PAH病因学的一个新方面，并且可能通过使炎症介质穿过内皮屏障而导致PAH血管病变。
