Lack of alpha 2-antiplasmin promotes re-endothelialization via over-release of VEGF after vascular injury in mice.
We here report that the arterial blood flow after endothelial injury in mice deficient in alpha 2-antiplasmin (alpha 2-AP-/- mice) was well maintained compared with that of wild-type mice. Moreover, the development of neointima 4 weeks after injury in alpha 2-AP-/- mice was significantly decreased. Histologic observations showed a prompt recovery of endothelial cells with a much higher proliferating index in repaired endothelium in alpha 2-AP-/- mice. The amount of secreted vascular endothelial growth factor (VEGF) by explanted vascular smooth muscle cells (SMCs) from alpha 2-AP-/- mice was significantly increased. In separate experiments using a human endothelial cell (EC) line, we could demonstrate that plasminogen binds to ECs and that this binding can be prevented by alpha 2-AP. Finally, an injection of either an anti-VEGF receptor-1 antibody or alpha 2-AP reduced the prompt endothelial healing. alpha 2-AP is the main inactivator of plasmin, which cleaves extracellular matrix-bound VEGF to release a diffusible proteolytic fragment. Lack of alpha 2-AP, therefore, could lead to a local over-release of VEGF by the continuously active plasmin in the injured area, which could result in a prompt re-endothelialization after vascular injury. Our results provide new insight into the role of alpha 2-AP and VEGF in the pathogenesis of re-endothelialization following vascular injury.
Matsuno
Hiroyuki
H
Department of Pharmacology, Gifu University School of Medicine, Tsukasa-machi 40, Gifu 500-8705, Japan. leuven@cc.gifu-u.ac.jp
Ishisaki
Akira
A
Nakajima
Keiichi
K
Okada
Kiyotaka
K
Ueshima
Shigeru
S
Matsuo
Osamu
O
Kozawa
Osamu
O
D000818:Animals; D001158:Arteries; D002455:Cell Division; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009389:Neovascularization, Pathologic; D010958:Plasminogen / Q000378:metabolism; D012039:Regional Blood Flow; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D014654:Vascular Patency; D000979:alpha-2-Antiplasmin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D042461:Vascular Endothelial Growth Factor A; D000979:alpha-2-Antiplasmin; D010958:Plasminogen