Evaluation of the pro-angiogenic effect of factor XIII in heterotopic mouse heart allografts and FXIII-deficient mice

Rima Dardik; Jonathan Leor; Ehud Skutelsky; David Castel; Radka Holbova; Ginette Schiby; Aviv Shaish; Gerhard Dickneite; Joseph Loscalzo; Aida Inbal

doi:10.1160/TH05-06-0409

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2006; 95(03): 546-550
DOI: 10.1160/TH05-06-0409

Animal Models

Schattauer GmbH

Evaluation of the pro-angiogenic effect of factor XIII in heterotopic mouse heart allografts and FXIII-deficient mice

Autoren

Rima Dardik

¹Institute of Thrombosis and Hemostasis, Tel Hashomer, and Sackler Faculty of Medicine, Tel Aviv University, Israel
Jonathan Leor

²Neufeld Cardiac Research Institute, Tel Hashomer, and Sackler Faculty of Medicine, Tel Aviv University, Israel
Ehud Skutelsky

³Institutes of Pathology, Tel Hashomer, and Sackler Faculty of Medicine, Tel Aviv University, Israel
David Castel

²Neufeld Cardiac Research Institute, Tel Hashomer, and Sackler Faculty of Medicine, Tel Aviv University, Israel
Radka Holbova

²Neufeld Cardiac Research Institute, Tel Hashomer, and Sackler Faculty of Medicine, Tel Aviv University, Israel
Ginette Schiby

³Institutes of Pathology, Tel Hashomer, and Sackler Faculty of Medicine, Tel Aviv University, Israel
Aviv Shaish

⁴Lipid and Atherosclerosis Research, Sheba Medical Center, Tel Hashomer, and Sackler Faculty of Medicine, Tel Aviv University, Israel
Gerhard Dickneite

⁵Pharmacology and Toxicology, ZLB-Behring, Marburg, Germany
Joseph Loscalzo

⁶Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachussets, USA
Aida Inbal

¹Institute of Thrombosis and Hemostasis, Tel Hashomer, and Sackler Faculty of Medicine, Tel Aviv University, Israel

Abstract

Summary

Thrombin-activated Factor XIII (FXIIIa),a plasma transglutaminase, stabilizes fibrin clots by crosslinking fibrin chains. FXIIIa was previously shown by us to exhibit proangiogenic activity associated with downregulation of thrombospondin-1, phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR-2), and upregulation of c-Jun. In the current study, we evaluated the proangiogenic effect of FXIIIa in two murine models: a neonatal heterotopic cardiac allograft model in normal mice, and a Matrigel plug model in FXIII-deficient mice. In the neonatal cardiac allograft model, the number of new vessels as well as graft viability (contractile performance) was significantly higher in FXIIIa-injected animals than in controls. A significant increase in the level of c-Jun mRNA and a significant decrease in the level of TSP-1 mRNA were observed in heart allografts treated with FXIIIa. A marked decrease in TSP-1 protein expression was observed within the endothelial cells of hearts treated with FXIIIa. In the Matrigel plug model, FXIII-deficient mice showed a significantly decreased number of new vessels compared to that of the control mice,and the number of vessels almost reached normal levels following addition of FXIIIa. The results of this study provide substantial in vivo evidence for the proangiogenic activity of FXIIIa.

Keywords

Angiogenesis - factor XIII - thrombospondin-1

Volltext

Referenzen

References
1 Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 09: 669-76.
2 Browder T, Folkman J, Pirie-Shephered S. The hemostatic system as a regulator of angiogenesis. J Biol Chem 2000; 275: 1521-4.
3 Muszbek L, Adany R, Mikkola H. Novel aspects of blood coagulation factor XIII. I. Structure, distribution, activation, and function. Crit Rev Clin Lab Sci 1996; 33: 357-421.
4 Greenberg CS, Birckbichler PJ, Rice RH. Transglutaminases: multifunctional cross-linking enzymes that stabilize tissues. FASEB J 1991; 05: 3071-7.
5 Dardik R, Solomon A, Loscalzo J. et al. Novel proangiogenic effect of factor XIII associated with suppression of thrombospondin1 expression. Arterioscler Thromb Vasc Biol 2003; 23: 1472-7.
6 Lawler J. Thrombospondin-1 as an endogenous inhibitor of angiogenesis and tumor growth. J Cell Mol Med 2002; 06: 1-12.
7 Dardik R, Loscalzo J, Eskaraev R. et al. Molecular mechanisms underlying the proangiogenic effect of factor XIII (FXIII). Arterioscler Thromb Vasc Biol 2005; 25: 526-32.
8 Dejong V, Degeorges A, Filleur S. et al. The Wilms’ tumor gene product represses the transcription of thrombospondin 1 in response to overexpression of c-Jun. Oncogene 1999; 18: 3143-51.
9 Koseki-Kuno S, Yamakawa M, Dickneite G. et al. Factor XIII A subunit-deficient mice developed severe uterine bleeding events and subsequent spontaneous miscarriages. Blood 2003; 102: 4410-2.
10 Inbal A, Lubetsky A, Krapp T. et al. Impaired wound healing in factor XIII deficient mice. Thromb Haemost 2005; 94: 432-7.
11 Fey TA, Krause RA, Hsieh GC. et al. Improved methods for transplanting split-heart neonatal cardiac grafts into the ear pinna of mice and rats. J Pharmacol Toxicol Methods 1998; 39: 9-17.
12 Lauer P, Metzner HJ, Zettlmeissl G. et al. Targeted inactivation of the mouse locus encoding coagulation factor XIII-A: hemostatic abnormalities in mutant mice and characterization of the coagulation deficit. Thromb Haemost 2002; 88: 967-74.
13 Kim HS, Skurk C, Thomas SR. et al. Regulation of angiogenesis by glycogen synthase kinase-bbeta. J Biol Chem 2002; 277: 41888-96.
14 Kumar P, Amin MA, Harlow LA. et al. Src and phosphatidylinositol 3-kinase mediate soluble E-selectin-induced angiogenesis. Blood 2003; 101: 3960-8.
15 Iruela-Arispe ML, Lombardo M, Krutzsch HC. et al. Inhibition of angiogenesis by thrombospondin-1 is mediated by 2 independent regions within the type 1 repeats. Circulation 1999; 100: 1423-31.
16 Jimenez B, Volpert OV, Crawford SE. et al. Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat Med 2000; 06: 41-8.
17 Kilian O, Fuhrmann R, Alt V. et al. Plasma transglutaminase factor XIII induces microvessel ingrowth into biodegradable hydroxyapatite implants in rats. Biomaterials 2005; 26: 1819-27.