Lack of a 2-antiplasmin promotes endothelial healing via over-release of VEGF after vascular injury in mice

Abstract number: P1219

Matsuno^* H., Kozawa^* O., Okada† K., Ueshima† S., Matsuo† O.

^*Department of Pharmacology Gifu University School of Medical, Japan; †Department of Phisiology II Kinki University School of Medical, Japan

The search for a novel therapy by vascular remodeling is an area of intensive investigation. We here report that the carotid arterial blood flow after endothelial injury in mice deficient in a 2-antiplasmin (a 2-AP-/– mice) was well maintained as compared with that of wild type mice. Moreover, the development of neointima 4 weeks after injury in a 2-AP-/– mice was significantly decreased as compared with that of wild type mice. Histological observations showed a prompt healing of endothelial cells in a 2-AP-/– mice 24 h after injury and the proliferating index obtained by using BrdU was much higher in repaired endothelial cells of a 2-AP-/– mice than in those of wild type mice. The amount of secreted vascular endothelial cell growth factor (VEGF) by explanted vascular smooth muscle cells from a 2-AP-/– mice was significantly increased as compared with that from wild type mice. In separate experiments using a human endothelial cell (EC) line (TKM-33), we could demonstrated that plasminogen binds to ECs and that this binding can be prevented by a 2-AP. Finally, an injection of either an anti-VEGF receptor -1 (Flt-1) antibody or a 2-AP reduced the prompt endothelial healing after injury in a 2-AP-/– mice. Plasmin cleaves extracellular matrix-bound VEGF to release a diffusible proteolytic fragment and is mainly inactivated by a 2-AP. Therefore, lack of a 2-AP could markedly result in local over-release of VEGF by the continuous activation of plasmin in the injured area and by this may result in a prompt endothelial healing after vascular injury. Our results provide new insight on the role of a 2-AP and VEGF in the pathogenesis of vascular remodeling.