LAUSR

Pulmonary hypertension (PH) is characterized by progressive obstruction of pulmonary arteries due to inflammatory processes, cellular proliferation, and extracellular matrix deposition and vasoconstriction. As treatment options are limited, we studied gene transfer of an inducible nitric oxide synthase (iNOS) using adeno-associated virus (AAV) vectors specifically targeted to endothelial cells of pulmonary vessels in a murine model of PH. Adult mice were intravenously injected with AAV vectors expressing iNOS. Mice were subjected to hypoxia for three weeks and sacrificed afterwards. We found elevated levels of iNOS both in lung tissue and pulmonary endothelial cells in hypoxic controls which could be further increased by AAV-mediated iNOS gene transfer. This additional increase in iNOS was associated with decreased wall thickness of pulmonary vessels, less macrophage infiltration, and reduced molecular markers of fibrosis. Taken together, using a tissue-targeted approach, we show that AAV-mediated iNOS overexpression in endothelial cells of the pulmonary vasculature significantly decreases vascular remodeling in a murine model of PH, suggesting upregulation of iNOS as promising target for treatment of PH.