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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1472.)
© 2003 American Heart Association, Inc.

Thrombosis

Novel Proangiogenic Effect of Factor XIII Associated With Suppression of Thrombospondin 1 Expression

Rima Dardik^*; Arieh Solomon^*; Joseph Loscalzo; Regina Eskaraev; Ann Bialik; Iris Goldberg; Ginette Schiby; Aida Inbal

From the Institutes of Thrombosis and Hemostasis (R.D., R.E., A.I.), Goldschleger Eye Research (A.S.), and Pathology (I.G., G.S.), Sheba Medical Center, Tel Hashomer, and Sackler Faculty of Medicine, Tel Aviv University, Israel, and Whitaker Cardiovascular Institute and Evans Department of Medicine (J.L., A.B.), Boston University School of Medicine, Boston, Mass.

Correspondence to Aida Inbal, MD, Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel 52621. E-mail aida.inbal{at}sheba.health.gov.il

Objective— Factor XIII (FXIII), a plasma transglutaminase that stabilizes fibrin clots at the final stages of blood coagulation by crosslinking fibrin monomers, is essential for embryo implantation and participates in tissue remodeling and wound healing, processes that involve angiogenesis. The aim of our study was to analyze the effect of FXIII on angiogenesis using in vitro and in vivo models and to examine the role of FXIII in the basic steps of angiogenesis, ie, migration, proliferation, and apoptosis/cell survival.

Methods and Results— In the Matrigel tube formation model, only FXIIIa caused a dose-dependent enhancement of array formation. This proangiogenic effect was not associated with alterations in vascular endothelial growth factor (VEGF) protein levels nor VEGF or VEGFR2 mRNA levels. FXIIIa, but not nonactivated or transglutaminase-inactivated FXIII, significantly enhanced endothelial cell migration and proliferation and inhibited apoptosis. After treatment of HUVECs with FXIIIa, almost complete disappearance of mRNA of thrombospondin 1 (TSP-1) and a marked reduction in the secretion of TSP-1 protein were observed. A reduction in TSP-1 protein synthesis, although to a lesser extent, was observed on treatment of microvascular endothelial cells with FXIIIa. In a rabbit cornea model, injection of FXIIIa caused neovascularization associated with almost complete disappearance of TSP-1 in the cornea.

Conclusions— These results show that FXIIIa exhibits a novel proangiogenic activity that is associated with downregulation of TSP-1 and also involves stimulation of endothelial cell proliferation and migration and inhibition of apoptosis. These findings might shed light on the mechanism by which FXIII mediates tissue repair and remodeling.

Key Words: factor XIII • angiogenesis • thrombospondin • endothelial cells

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