Submitted March 7, 2003
Accepted July 13, 2003
Lack of 
2-antiplasmin promotes reendothelialization via over-release of VEGF after vascular injury in mice
Hiroyuki Matsuno*, Akira Ishisaki, Keiichi Nakajima, Kiyotaka Okada, Shigeru Ueshima, Osamu Matsuo, and Osamu Kozawa
Department of Pharmacology, Gifu University School of Medicine, Gifu, Japan; Department of Physiology II, Kinki University School of Medicine, Osaka, Japan
Department of Pharmacology, Gifu University School of Medicine, Gifu, Japan
Department of Physiology II, Kinki University School of Medicine, Osaka, Japan
* Corresponding author; email: leuven{at}cc.gifu-u.ac.jp.
We here report that the arterial blood flow after endothelial injury in mice deficient in 
2-antiplasmin (2-AP-/- mice) was well maintained as compared with that of wild type mice. Moreover, the development of neointima 4 weeks after injury in 2-AP-/- mice was significantly decreased. Histological observations showed a prompt recovery of endothelial cells with a much higher proliferating index in repaired endothelium in 2-AP-/- mice. The amount of secreted vascular endothelial growth factor (VEGF) by explanted vascular SMC from 2-AP-/- mice was significantly increased. In separate experiments using a human endothelial cell (EC) line, we could demonstrated that plasminogen binds to ECs and that this binding can be prevented by 2-AP. Finally, an injection of either an anti-VEGF receptor-1 antibody or 2-AP reduced the prompt endothelial healing. As 2-AP is the main inactivator of plasmin, that cleaves extracellular matrix-bound VEGF to release a diffusible proteolytic fragment. Lack of 2-AP, therefore, could lead to a local over-release of VEGF by the continuously active plasmin in the injured area which may result in a prompt reendothelialization after vascular injury. Our results provide new insight on the role of 2-AP and VEGF in the pathogenesis of reendothelialization following vascular injury.
