Dual role of the L-arginine-ADMA-NO pathway in systemic hypoxic vasodilation and pulmonary hypoxic vasoconstriction
Dual role of the L-arginine-ADMA-NO pathway in systemic hypoxic vasodilation and pulmonary hypoxic vasoconstriction
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DOI：
10.1177/2045894020918850
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发表时间：
2020-07-01
影响因子：
2.6
通讯作者：
Hannemann, Juliane
中科院分区：
文献类型：
--
作者：
Boeger, Rainer;Hannemann, Juliane
在健康血管内皮中，一氧化氮作为邻近平滑肌细胞的血管扩张剂旁分泌介质。通过激活可溶性鸟苷环化酶，一氧化氮刺激环鸟苷单磷酸（cGMP），引起血管平滑肌松弛（血管舒张）和血小板聚集抑制。这一机制在体循环和肺循环中都很活跃。在体循环中，缺氧导致局部血管舒张，这是由缺氧诱导因子-1 α (HIF1 α)的稳定和内皮型一氧化氮合酶的上调引起的。相反，肺循环对缺氧的生理反应是血管收缩。肺缺氧主要是由于肺周围通气不足引起的，如支气管阻塞或炎症浸润。因此，低氧肺血管收缩是一种阻止血液分布到肺部低通气区域，从而维持血液最大氧合的机制。缺氧肺血管收缩的确切分子机制还不如体循环中的缺氧血管扩张清楚。肺泡上皮细胞可能是感知低氧浓度的关键细胞，而肺血管平滑肌细胞显然是血管收缩的效应器，肺血管内皮作为这些细胞类型之间的中介起着至关重要的作用。事实上，在暴露于急性缺氧的人类中观察到内皮细胞一氧化氮释放功能失调，动物研究表明，一氧化氮合酶抑制可增强缺氧肺血管收缩。这可能部分由不对称二甲基精氨酸升高引起，二甲基精氨酸是一种内源性一氧化氮合成抑制剂。高不对称二甲基精氨酸水平与内皮功能障碍、血管疾病和高血压有关。
In healthy vascular endothelium, nitric oxide acts as a vasodilator paracrine mediator on adjacent smooth muscle cells. By activating soluble guanylyl cyclase, nitric oxide stimulates cyclic guanosine monophosphate (cGMP) which causes relaxation of vascular smooth muscle (vasodilation) and inhibition of platelet aggregation. This mechanism is active in both, the systemic and pulmonary circulation. In the systemic circulation, hypoxia results in local vasodilation, which has been shown to be brought about by stabilization of hypoxia-inducible factor-1 alpha (HIF1 alpha) and concomitant upregulation of endothelial nitric oxide synthase. By contrast, the physiological response to hypoxia in the pulmonary circulation is vasoconstriction. Hypoxia in the lung primarily results from hypoventilation of circumscript areas of the lung, e.g. by bronchial tree obstruction or inflammatory infiltration. Therefore, hypoxic pulmonary vasoconstriction is a mechanism preventing distribution of blood to hypoventilated areas of the lungs, thereby maintaining maximal oxygenation of blood. The exact molecular mechanism of hypoxic pulmonary vasoconstriction is less well understood than hypoxic vasodilation in the systemic circulation. While alveolar epithelial cells may be key in sensing low oxygen concentration, and pulmonary vascular smooth muscle cells obviously are the effectors of vasoconstriction, the pulmonary vascular endothelium plays a crucial role as an intermediate between these cell types. Indeed, dysfunctional endothelial nitric oxide release was observed in humans exposed to acute hypoxia, and animal studies suggest that hypoxic pulmonary vasoconstriction is enhanced by nitric oxide synthase inhibition. This may be caused, in part, by elevation of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthesis. High asymmetric dimethylarginine levels are associated with endothelial dysfunction, vascular disease, and hypertension.