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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:526.)
© 2005 American Heart Association, Inc.

Vascular Biology

Molecular Mechanisms Underlying the Proangiogenic Effect of Factor XIII

Rima Dardik; Joseph Loscalzo; Regina Eskaraev; Aida Inbal

From the Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine (R.D., R.E., A.I.), Tel Aviv University, Israel; and the Whitaker Cardiovascular Institute and Evans Department of Medicine (J.L.), Boston University School of Medicine, 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— Coagulation Factor XIII (FXIII) was previously shown by us to induce angiogenesis. The aim of this study was to elucidate the molecular events underlying the proangiogenic effects of activated FXIII (FXIIIa) on human umbilical vein endothelial cells (HUVECs).

Methods and Results— As shown by coimmunoprecipitation studies, FXIIIa crosslinked _vß₃ with vascular endothelial growth factor receptor 2 (VEGFR-2) and enhanced the noncovalent interaction between the 2 receptors. In addition, FXIIIa induced tyrosine phosphorylation of VEGFR-2 in both the crosslinked high-molecular-weight and the noncovalent VEGFR-2/_vß₃ complexes. These effects as well as FXIIIa-induced proliferation and migration of HUVECs were abolished by iodoacetamide treatment of FXIIIa (I-FXIII) or by PTKI, an inhibitor of VEGFR-2. FXIIIa induced upregulation of c-Jun and Egr-1 as revealed by quantitative RT-PCR. Electrophoretic mobility-shift assay experiments showed that FXIIIa treatment of HUVECs enhanced binding of Wilm’s tumor-1 (WT-1) but not of early growth response (Egr)-1 to the thrombospondin-1 (TSP-1) promoter sequence, suggesting that WT-1 but not Egr-1 is involved in downregulation of TSP-1 expression.

Conclusions— The proangiogenic effect of FXIIIa is mediated by (1) enhancement of crosslinked and noncovalent _vß₃/VEGFR-2 complex formation; (2) tyrosine phosphorylation and activation of VEGFR-2; (3) upregulation of c-Jun and Egr-1; and (4) downregulation of TSP-1 induced indirectly by c-Jun through WT-1. These processes may clarify FXIII role in vascular remodeling and tissue repair.

Factor XIIIa (FXIIIa) was previously shown by us to induce angiogenesis. In the present work we show that the proangiogenic effect of FXIIIa is mediated by (1) enhancement of crosslinked and noncovalent _vß₃/vascular endothelial growth factor 2 (VEGFR-2) complex formation; (2) activation of VEGFR-2; (3) upregulation of cyclin D-1, Egr-1, and c-Jun; and (4) downregulation of thrombospondin-1 by WT-1.

Key Words: Factor XIII • angiogenesis • vascular endothelial growth factor receptor 2 • cJun • early growth response-1

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