Gene transfer of endothelial nitric oxide synthase to the lung of the mouse in vivo - Effect on agonist-induced and flow-mediated vascular responses

The effects of transfer of the endothelial nitric oxide synthase(eNOS) gene to the lung were studied in mice, After intratracheal administration of Ad CMV beta gal, expression of the P-galactosidase reporter gene was detected in pulmonary airway cells, in alveolar cells, and in small pulmonary arteri es. Gene expression with AdCMV beta gal peaked 1 day after administration a nd decayed over a 7- to 14-day period, whereas gene expression after AdRSV beta gal transfection peaked on day 5 and was sustained over a 21- to 28-da y period. One day after administration of AdCMVeNOS, eNOS protein levels we re increased, and there was a small reduction in mean pulmonary arterial pr essure and pulmonary vascular resistance. The pressure-flow relationship in the pulmonary vascular bed was shifted to the right in animals transfected with eNOS, and pulmonary vasodepressor responses to bradykinin and the typ e V cGMP-selective phosphodiesterase inhibitor zaprinast were enhanced, whe reas systemic responses were not altered. Pulmonary vasopressor responses t o endothelin-l (ET-1), angiotensin II, and ventilatory hypoxia were reduced significantly in animals transfected with the eNOS gene, whereas presser r esponses to norepinephrine and U46619 were not changed. Systemic presser re sponses to ET-1 and angiotensin II. were similar in eNOS-transfected mice a nd in control mice. Intratracheal administration of AdRSVeNOS attenuated th e increase in pulmonary arterial pressure in mice exposed to the fibrogenic anticancer agent bleomycin. These data suggest that transfer of the eNOS g ene in vivo can selectively reduce pulmonary vascular resistance and pulmon ary presser responses to ET-1, angiotensin IT, and hypoxia; enhance pulmona ry depressor responses; and attenuate pulmonary hypertension induced by ble omycin. Moreover, these data suggest that in vivo gene transfer may be a us eful therapeutic intervention for the treatment of pulmonary hypertensive d isorders.