Aerosol gene transfer with inducible nitric oxide synthase reduces hypoxicpulmonary 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 3X10(9) pfu of an adenoviral vector cont aining inducible NOS gene (AdNOS2), constitutive NOS3 gene (AdNOS3), or no transgene (AdRR5) into rat lungs. Exhaled NO levels, monitored with chemilu minescence, were higher in AdNOS2-infected rats than in AdNOS3- and AdRR5-i nfected 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 pulmona ry 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 pulmona ry resistance in AdRR5- and AdNOS3-infected rats was significantly higher t han in AdNOS2-infected animals (0.41+/-0.05 and 0.39+/-0.07 versus 0.35+/-0 .03 mmHg . mL(-1) . min(-1), respectively; P<0.05). Right ventricular hyper trophy was reduced in AdNOS2-infected rats [right ventricular/(left ventric ular+septal) weight, 0.19+/-0.10 versus 0.28+/-0.10 and 0.32+/-0.10 in AdRR 5- and AdNOS3-infected rats, respectively, P<0.05]. The percentage of muscu larized precapillary pulmonary resistance vessels was also significantly de creased (18+/-4% versus 25+/-8% and 30+/-5% in AdRR5- and AdNOS3-infected r ats, P<0.05). Conclusions-Aerosol NOS2 gene transfer increases pulmonary NO production an d significantly reduces hypoxic pulmonary hypertension and pulmonary vascul ar remodeling. Aerosol NOS2 gene transfer may be a promising strategy to ta rget pulmonary vascular disorders.