Dual role of the L-arginine–ADMA–NO pathway in systemic hypoxic vasodilation and pulmonary hypoxic vasoconstriction

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.