Aerosol gene transfer with inducible nitric oxide synthase reduces hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats

Background - Nitric oxide (NO) is a potent vasodilator with an important role in the regulation of pulmonary vascular tone. The effects of NO synthase (NOS) gene transfer on pulmonary vascular remodeling associated with hypoxic pulmonary hypertension are unknown. Methods and Results - We aerosolized 3 x 10⁹ pfu of an adenoviral vector containing inducible NOS gene (AdNOS2), constitutive NOS3 gene (AdNOS3), or no transgene (AdRR5) into rat lungs. Exhaled NO levels, monitored with chemiluminescence, were higher in AdNOS2-infected rats than in AdNOS3- and AdRR5-infected rats (at 3 days, 33±6 ppb, n=9, versus 17±4, n=9, and 6±2 ppb, n=3, P<0.05 for both). Exposure to FIO₂ 0.10 for 7 days increased pulmonary artery pressure from 19±4 mm Hg (baseline) to 27± 1 and 26±2 mm Hg in AdNOS3- and AdRR5-infected rats, respectively, but only to 21±1 mm Hg in AdNOS2-infected animals (P<0.05). After 7 days of hypoxia, total pulmonary resistance in AdRR5- and AdNOS3-infected rats was significantly higher than in AdNOS2-infected animals (0.41±0.05 and 0.39±0.07 versus 0.35±0.03 mm Hg · mL^-1 · min^-1, respectively, P<0.05). Right ventricular hypertrophy was reduced in AdNOS2-infected rats [right ventricular/(left ventricular+septal) weight, 0.19±0.10 versus 0.28±0.10 and 0.32±0.10 in AdRR5- and AdNOS3-infected rats, respectively, P<0.05]. The percentage of muscularized precapillary pulmonary resistance vessels was also significantly decreased (18±4% versus 25±8% and 30±5% in AdRR5- and AdNOS3-infected rats, P<0.05). Conclusions - Aerosol NOS2 gene transfer increases pulmonary NO production and significantly reduces hypoxic pulmonary hypertension and pulmonary vascular remodeling. Aerosol NOS2 gene transfer may be a promising strategy to target pulmonary vascular disorders.