Gene transfer of the neuronal NO synthase isoform to cirrhotic fat liver ameliorates portal hypertension

Reduced production of nitric oxide (NO) in the cirrhotic liver results from a defect in hepatic endothelial cell nitric oxide synthase (ecNOS) and app ears to contribute to the high intrahepatic resistance and portal hypertens ion typical of cirrhosis. Therefore, we postulated that targeting a heterol ogous NOS isoform to sinusoidal endothelial cells or other perisinusoidal c ells, such as hepatic stellate cells, would counter the defect in NO produc tion and reduce resistance to blood flow. Recombinant adenovirus (Ad) carry ing the neuronal NOS gene (nNOS) targeted liver sinusoidal endothelial cell s, stellate cells, and hepatocytes more efficiently than the corresponding cells in cirrhotic livers, but transduction rates were substantial even in cirrhotic animals. Expression of nNOS in each liver cell type, whether from normal or injured liver, caused increased NO production and inhibited endo thelin-l-induced contractility of perisinusoidal stellate cells. Finally, i n 2 different in vivo models of cirrhosis and portal hypertension, transduc tion of livers with recombinant Ad.nNOS significantly reduced intrahepatic resistance and portal pressure. The data highlight the feasibility of gene transfer to diseased liver and hepatic cells and demonstrate the potential of a novel therapy for portal hypertension caused by cirrhosis.