Gene transfer of recombinant endothelial nitric oxide synthase to liver invivo and in vitro

Endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) contribu tes to hepatic vascular homeostasis. The aim of this study was to examine w hether delivery of an adenoviral vector encoding eNOS gene to liver affects vasomotor function in vivo and the mechanism of NO production in vitro. Ra ts were administered adenoviruses encoding beta -galactosidase (AdCMVLacZ) or eNOS (AdCMVeNOS) via tail vein injection and studied 1 wk later. In anim als transduced with AdCMVLacZ, beta -galactosidase activity was increased i n the liver, most prominently in hepatocytes. In AdCMVeNOS-transduced anima ls, eNOS protein levels and catalytic activity were significantly increased . Overexpression of eNOS diminished baseline perfusion pressure and constri ction in response to the alpha (1)-agonist methoxamine in the perfused live r. Transduction of cultured hepatocytes with AdCMVeNOS resulted in the targ eting of recombinant eNOS to a perinuclear distribution and binding with th e NOS-activating protein heat shock protein 90. These events were associate d with increased ionomycin-stimulated NO release. In summary, this is the f irst study to demonstrate successful delivery of the recombinant eNOS gene to liver in vivo and in vitro with ensuing NO production.