Inhibitory role of plasminogen activator inhibitor-1 in arterial wound healing and neointima formation: a gene targeting and gene transfer study in mice.

Abstract

Plasminogen-deficient mice display impaired vascular wound healing and reduced arterial neointima formation after arterial injury, suggesting that inhibition of plasmin generation might reduce arterial neointima formation. Therefore, we studied the consequences of plasminogen activator inhibitor-1 (PAI-1) gene inactivation and adenoviral PAI-1 gene transfer on arterial neointima formation. 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 cross-sectional neointimal area was 0.001+/-0.001 mm2 in PAI-1(+/+) and 0.016+/-0.008 mm2 in PAI-1(-/-) mice within 1 week after electric injury (P<.02) and 0.055+/-0.008 mm2 in PAI-1(+/+) and 0.126+/-0.006 mm2 in PAI-1(-/-) mice within 3 weeks after mechanical injury (P<.001). Proliferation of smooth muscle cells was not affected by PAI-1 deficiency. 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 vascular wound healing. There were no genotypic differences in reendothelialization of the vascular wound. When PAI-1(-/-) mice were intravenously injected with replication-defective adenovirus expressing human PAI-1 (AdCMVPAI-1), plasma PAI-1 antigen levels increased in a dose-dependent fashion up to to 61+/-8 microg/mL with 2x10(9) plaque-forming units (pfu) virus. Luminal stenosis was 35+/-13% in control AdRR5-treated (2x10(9) pfu) and suppressed to 5+/-5% in AdCMVPAI-1-treated (6x10(8) pfu) PAI-1(-/-) mice (P<.002). By affecting cellular migration, PAI-1 plays an inhibitory role in vascular wound healing and arterial neointima formation after injury, and adenoviral PAI-1 gene transfer reduces arterial neointima formation in mice.