Plasminogen Activator Inhibitor-1 From Bone Marrow–Derived Cells Suppresses Neointimal Formation After Vascular Injury in Mice

Abstract

Objective - To investigate the ability of bone marrow ( BM) - derived cells to modulate neointimal growth after injury by expressing plasminogen activator inhibitor-1 ( PAI-1). Methods and Results - We performed BM transplantation ( BMT) in lethally irradiated wild- type ( WT) and PAI-1-/- mice. Three weeks after carotid injury with ferric chloride, analysis of Y-chromosome DNA expression in the vessel wall of female hosts revealed that 20.8 +/- 6.0% of the cells in the neointima and 37.6 +/- 5.7% of those in the media were of BM origin. Lack of PAI-1 in either the host or the donor cells did not affect recruitment of BM-derived cells into sites of vascular injury. The neointima consisted predominantly of smooth muscle cells, and a proportion of these cells expressed PAI-1. Overall, lack of PAI-1 was associated with enhanced neointimal formation. However, importantly, BMTWT -> PAI-1-/- mice exhibited reduced neointimal area ( P = 0.05) and luminal stenosis ( P = 0.04) compared with BMTPAI-1-/--> PAI-1-/- mice. Although PAI-1-expressing cells were shown to be present in BMTWT -> PAI-1-/- lesions, these mice did not exhibit detectable levels of the inhibitor in the circulation, suggesting that local production of PAI-1 by cells in the neointima and media was sufficient to reduce luminal stenosis. Conclusions - PAI-1 from BM-derived cells appears capable of suppressing neointimal growth after vascular injury.