Böger Rainer, Hannemann Juliane
Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Institute DECIPHER, German-Chilean Institute for Research on Pulmonary Hypoxia and its Health Sequelae, Hamburg, Germany.
Pulm Circ. 2020 Apr 9;10(2):2045894020918850. doi: 10.1177/2045894020918850. eCollection 2020 Apr-Jun.
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-1α (HIF1α) 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.
在健康的血管内皮中，一氧化氮作为一种血管舒张旁分泌介质作用于相邻的平滑肌细胞。通过激活可溶性鸟苷酸环化酶，一氧化氮刺激环磷酸鸟苷（cGMP），从而导致血管平滑肌舒张（血管扩张）并抑制血小板聚集。这一机制在体循环和肺循环中均起作用。在体循环中，缺氧会导致局部血管扩张，这已被证明是由缺氧诱导因子-1α（HIF1α）的稳定以及内皮型一氧化氮合酶的伴随上调所引起的。相比之下，肺循环中对缺氧的生理反应是血管收缩。肺部缺氧主要是由肺局部区域的通气不足导致的，例如支气管树阻塞或炎症浸润。因此，缺氧性肺血管收缩是一种防止血液流向肺部通气不足区域的机制，从而维持血液的最大氧合。与体循环中的缺氧性血管扩张相比，缺氧性肺血管收缩的确切分子机制尚不太清楚。虽然肺泡上皮细胞可能是感知低氧浓度的关键，而肺血管平滑肌细胞显然是血管收缩的效应器，但肺血管内皮在这些细胞类型之间起着至关重要的中间作用。事实上，在暴露于急性缺氧的人类中观察到内皮一氧化氮释放功能失调，动物研究表明一氧化氮合酶抑制会增强缺氧性肺血管收缩。这可能部分是由不对称二甲基精氨酸（一种一氧化氮合成的内源性抑制剂）的升高所引起的。高浓度的不对称二甲基精氨酸与内皮功能障碍、血管疾病和高血压有关。
