on December 23, 2004
Published online before print December 23, 2004, doi: 10.1161/01.ATV.0000154137.21230.80
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on July 27, 2004
Accepted on December 3, 2004
Molecular Mechanisms Underlying the Proangiogenic Effect of Factor XIII
Rima Dardik ;
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.
* To whom correspondence should be addressed. 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 
v
3 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/v3 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 v3/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.
Key words: Factor XIII • angiogenesis • vascular endothelial growth factor receptor 2 • cJun • early growth response-1
This article has been cited by other articles:
 |
|
 |
|
  S. E. Iismaa, B. M. Mearns, L. Lorand, and R. M. Graham Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders Physiol Rev, July 1, 2009; 89(3): 991 - 1023. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Johnson, D. M. Rose, and R. A. Terkeltaub Factor XIIIA mobilizes transglutaminase 2 to induce chondrocyte hypertrophic differentiation J. Cell Sci., July 1, 2008; 121(13): 2256 - 2264. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Mitola, B. Brenchio, M. Piccinini, L. Tertoolen, L. Zammataro, G. Breier, M. T. Rinaudo, J. den Hertog, M. Arese, and F. Bussolino Type I Collagen Limits VEGFR-2 Signaling by a SHP2 Protein-Tyrosine Phosphatase-Dependent Mechanism 1 Circ. Res., January 6, 2006; 98(1): 45 - 54. [Abstract] [Full Text] [PDF]
|
|