EFFICIENT INHIBITION OF INTIMAL HYPERPLASIA BY ADENOVIRUS-MEDIATED INDUCIBLE NITRIC-OXIDE SYNTHASE GENE-TRANSFER TO RATS AND PIGS IN-VIVO

Background: Inadequate nitric oxide (NO) availability may underlie vas cular smooth muscle overgrowth that contributes to vascular occlusive diseases including atherosclerosis and restenosis. NO possesses a numb er of properties that should inhibit this hyperplastic healing respons e, such as promoting reendothelialization, preventing platelet and leu kocyte adherence, and inhibiting cellular proliferation. Study Design: We proposed that shortterm but sustained increases in NO synthesis ac hieved with inducible NO synthase (iNOS) gene transfer at sites of vas cular injury would prevent intimal hyperplasia. We constructed an aden oviral vector, AdiNOS, carrying the human iNOS cDNA and used it to exp ress iNOS at sites of arterial injury in vivo. Results: AdiNOS-treated cultured vascular smooth muscle cells produced up to 100-fold more NO than control cells. In vivo iNOS gene transfer, using low concentrati ons of AdiNOS (2 x 10(6) plaque forming units [PFU]/rat) to injured ra t carotid arteries, resulted in a near complete (>95%) reduction in ne ointima formation even when followed longterm out to 6 weeks postinjur y. This protective effect was reversed by the continuous administratio n of an iNOS selective inhibitor L-N-6-(1-iminoethyl)-lysine. However, iNOS gene transfer did not lead to regression of preestablished neoin timal lesions. In an animal model more relevant to human vascular heal ing, iNOS gene transfer (5 x 10(8) PFU/pig) to injured porcine iliac a rteries in vivo was also efficacious, reducing intimal hyperplasia by 51.8%. Conclusions: These results indicate that shortterm overexpressi on of the iNOS gene initiated at the time of vascular injury is an eff ective method of locally increasing NO levels to prevent intimal hyper plasia. (J Am Coll Surg 1998;187:295-306. (C) 1998 by the American Col lege of Surgeons)