INHIBITORY ROLE OF PLASMINOGEN-ACTIVATOR INHIBITOR-1 IN ARTERIAL WOUND-HEALING AND NEOINTIMA FORMATION - A GENE TARGETING AND GENE-TRANSFERSTUDY IN MICE

Background Plasminogen-deficient mice display impaired vascular wound healing and reduced arterial neointima formation after arterial injury , suggesting that inhibition of plasmin generation might reduce arteri al neointima formation. Therefore, we studied the consequences of plas minogen activator inhibitor-1 (PAI-1) gene inactivation and adenoviral PAI-1 gene transfer on arterial neointima formation. Methods and Resu lts Neointima formation was evaluated in PAI-1-deficient (PAI-1(-/-)) mice with perivascular electric or transluminal mechanical injury. PAI -1 deficiency improved vascular wound healing in both models: the cros s-sectional neointimal area was 0.001+/-0.001 mm(2) in PAI-1(+/+) and 0.016+/-0.008 mm(2) in PAI-1(-/-) mice within 1 week after electric in jury (P<.02) and 0.055+/-0.008 mm(2) in PAI-1(+/+) and 0.126+/-0.006 m m(2) in PAI-1(-/-) mice within 3 weeks after mechanical injury (P<.001 ). Proliferation of smooth muscle cells was not affected by PAI-1 defi ciency. Topographic analysis of arterial wound healing after electric injury revealed that PAI-1(-/-) smooth muscle cells, originating from the uninjured borders, more rapidly migrated into the necrotic center of the arterial wound than wild-type smooth muscle cells. On the basis of immunostaining, PAI-1 expression was markedly upregulated during v ascular wound healing. There were no genotypic differences in reendoth elialization of the vascular wound. When PAI-1(-/-) mice were intraven ously injected with replication-defective adenovirus expressing human PAI-1 (AdCMVPAI-1), plasma PAI-1 antigen levels increased in a dose-de pendent fashion up to to 61+/-8 mu g/mL with 2x10(9) plaque-forming un its (pfu) virus. Luminal stenosis was 35+/-13% in control AdRR5-treate d (2x10(9) pfu) and suppressed to 5+/-5% in AdCMVPAI-1-treated (6x10(8 ) pfu) PAI-1(-/-) mice (P<.002). Conclusions By affecting cellular mig ration, PAI-1 plays an inhibitory role in vascular wound healing and a rterial neointima formation after injury, and adenoviral PAI-1 gene tr ansfer reduces arterial neointima formation in mice.