Lack of α2-antiplasmin promotes re-endothelialization via over-release of VEGF after vascular injury in mice

Abstract

We here report that the arterial blood flow after endothelial injury in mice deficient in α2-antiplasmin (α2-AP-/- mice) was well maintained compared with that of wild-type mice. Moreover, the development of neointima 4 weeks after injury in α2-AP-/- mice was significantly decreased. Histologic observations showed a prompt recovery of endothelial cells with a much higher proliferating index in repaired endothelium in α2-AP-/- mice. The amount of secreted vascular endothelial growth factor (VEGF) by explanted vascular smooth muscle cells (SMCs) from α2-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 α2-AP. Finally, an injection of either an anti-VEGF receptor-1 antibody or α2-AP reduced the prompt endothelial healing. α2-AP is the main inactivator of plasmin, which cleaves extracellular matrix-bound VEGF to release a diffusible proteolytic fragment. Lack of α2-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 α2-AP and VEGF in the pathogenesis of re-endothelialization following vascular injury. © 2003 by The American Society of Hematology.