Endothelial dysfunction in pulmonary vascular disorders

The pulmonary endothelium produces a variety of potent vasoactive factors which regulate vascular tone and structure, including vasodilator and anti-proliferative mediators, such as nitric oxide and vasoconstrictor-growth factors, such as endothelin-1. Evidence is presented that in pulmonary hypertension there is an alteration in the endothelial cell activation state resulting in an increased production and expression of endothelin-1 in the pulmonary vasculature, specifically correlated with functional severity of vascular abnormalities in patients with primary disease. As well, the pulmonary vasodilator response to infusions of L-arginine, the substrate for nitric oxide production by nitric oxide synthase, was used as a marker of abnormal endothelium-dependent dilation. Patients with primary vascular disease were unresponsive to substrate loading, consistent with a lack of ability to metabolize L-arginine by the nitric oxide synthase pathway. However, patients with secondary causes of pulmonary hypertension exhibited substantial pulmonary vasodilation in response to substrate loading, equivalent to that seen in response to prostacyclin. These findings are consistent with a major contribution of abnormalities in endothelial cell synthetic function to pulmonary vascular disorders in patients with pulmonary hypertension.