Evaluation of the pro-angiogenic effect of factor XIII in heterotopic mouse heart allografts and FXIII-deficient mice.
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.
Dardik
Rima
R
Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel.
Leor
Jonathan
J
Skutelsky
Ehud
E
Castel
David
D
Holbova
Radka
R
Schiby
Ginette
G
Shaish
Aviv
A
Dickneite
Gerhard
G
Loscalzo
Joseph
J
Inbal
Aida
A
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D003094:Collagen; D003331:Coronary Vessels / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004431:Ear, External; D005176:Factor XIII / Q000235:genetics; D005177:Factor XIII Deficiency / Q000235:genetics*; D026122:Factor XIIIa / Q000494:pharmacology*; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D007797:Laminin; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011509:Proteoglycans; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D016042:Transplantation, Heterotopic
D043925:Angiogenesis Inducing Agents; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D019700:Thrombospondin 1; C059485:matrigel; D003094:Collagen; D005176:Factor XIII; D026122:Factor XIIIa