Novel proangiogenic effect of factor XIII associated with suppression of thrombospondin 1 expression
Novel proangiogenic effect of factor XIII associated with suppression of thrombospondin 1 expression
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DOI：
10.1161/01.atv.0000081636.25235.c6
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发表时间：
2003-08-01
影响因子：
8.7
通讯作者：
Inbal, A
中科院分区：
文献类型：
--
作者：
Dardik, R;Solomon, A;Inbal, A
目的-因子XIII （FXIII）是一种血浆转谷氨酰胺酶，通过交联纤维蛋白单体在血液凝固的最后阶段稳定纤维蛋白凝块，对胚胎着床至关重要，并参与组织重塑和伤口愈合，这一过程涉及血管生成。我们的研究目的是通过体外和体内模型分析FXIII对血管生成的影响，并研究FXIII在血管生成的基本步骤，即迁移、增殖和细胞凋亡/细胞存活中的作用。方法和结果-在Matrigel管形成模型中，只有FXIIIa引起阵列形成的剂量依赖性增强。这种促血管生成作用与血管内皮生长因子（VEGF）蛋白水平或VEGF或VEGFR2 mRNA水平的改变无关。FXIIIa显著增强内皮细胞的迁移和增殖，抑制细胞凋亡，而非激活或转谷氨酰胺酶灭活的FXIII则无明显作用。用FXIIIa治疗HUVECs后，血小板反应蛋白1 (TSP-1) mRNA几乎完全消失，TSP-1蛋白分泌明显减少。在用FXIIIa治疗微血管内皮细胞时，观察到TSP-1蛋白合成的减少，尽管程度较小。在兔角膜模型中，注射FXIIIa引起新生血管形成，角膜中TSP-1几乎完全消失。结论-这些结果表明FXIIIa表现出一种新的促血管生成活性，这种活性与TSP-1的下调有关，还涉及刺激内皮细胞增殖和迁移以及抑制细胞凋亡。这些发现可能揭示了FXIII介导组织修复和重塑的机制。
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.