Tetrahydrobiopterin in pulmonary hypertension: pulmonary hypertension in guanosine triphosphate-cyclohydrolase-deficient mice.

The regulation of pulmonary vascular tone is a complex process and represents a balance between constrictor and dilator influences. In pulmonary hypertension, whether caused by hypoxia or flowand pressure-induced remodeling, the balance is tilted predominantly toward vasoconstriction. Despite decades of research, the initiating events in most patients with primary pulmonary hypertension remain unknown. The causes are probably diverse, and clinical recognition of the disease often occurs after the process is fairly advanced. On presentation, initiating events are obscured by the adaptations that occurred in the pulmonary circulation in response to the hypertension. Thus, the clinically evident disease may be quite distant from the initial cause(s) of pulmonary hypertension. Laboratory investigations of specific biochemical defects that can lead to pulmonary hypertension and vascular remodeling should help us understand these proximate causes. In this issue of Circulation, 2 independent studies1,2 report that a defect in the synthesis of tetrahydrobiopterin (BH4), a cofactor required for the synthesis of nitric oxide ( NO) through the catalytic activity of NO synthase (NOS), results in pulmonary hypertension. The studies confirm that a defect in endothelial NOS (eNOS) function can be an initiating event leading to both pulmonary hypertension and pulmonary vascular remodeling. Their results are consistent with observations of impaired NOS activity and NOS-dependent vasodilation in both patients and animal models with pulmonary hypertension. Such studies provide proof of concept that a specific biochemical defect can cause eNOS uncoupling to remodel the pulmonary vasculature.