Multifaceted Role of Plasminogen Activator Inhibitor-1 in Regulating Early Remodeling of Vein Bypass Grafts

Abstract

The role of plasminogen activator inhibitor-1 (PAI-1) in vein graft (VG) remodeling is undefined. We examined the effect of PAI-1 on VG intimal hyperplasia and tested the hypothesis that PAI-1 regulates VG thrombin activity. VGs from wild-type (WT), Pai1(-/-), and PAI-1-transgenic mice were implanted into WT, Pai1(-/-), or PAI-1-transgenic arteries. VG remodeling was assessed 4 weeks later. Intimal hyperplasia was significantly greater in PAI-1-deficient mice than in WT mice. The proliferative effect of PAI-1 deficiency was retained in vitronectin-deficient mice, suggesting that PAI-1's antiproteolytic function plays a key role in regulating intimal hyperplasia. Thrombin-induced proliferation of PAI-1-deficient venous smooth muscle cells (SMC) was significantly greater than that of WT SMC, and thrombin activity was significantly higher in PAI-1-deficient VGs than in WT VGs. Increased PAI-1 expression, which has been associated with obstructive VG disease, did not increase intimal hyperplasia. Decreased PAI-1 expression (1) promotes intimal hyperplasia by pathways that do not require vitronectin and (2) increases thrombin activity in VG. PAI-1 overexpression, although it promotes SMC migration in vitro, did not increase intimal hyperplasia. These results challenge the concept that PAI-1 drives nonthrombotic obstructive disease in VG and suggest that PAI-1's antiproteolytic function, including its antithrombin activity, inhibits intimal hyperplasia.