Tissue Factor Regulates Microvessel Formation and Stabilization by Induction of Chemokine (C-C motif) Ligand 2 Expression
Tissue Factor Regulates Microvessel Formation and Stabilization by Induction of Chemokine (C-C motif) Ligand 2 Expression
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DOI：
10.1161/atvbaha.111.233536
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发表时间：
2011-11-01
影响因子：
8.7
通讯作者：
Badimon, Lina
中科院分区：
文献类型：
--
作者：
Arderiu, Gemma;Pena, Esther;Badimon, Lina
组织因子（TF）触发动脉血栓形成。TF还能够启动导致血管生成的细胞信号传导机制。由于高心血管风险的动脉粥样硬化斑块显示出显著的血管生成，我们的目的是研究TF是否能够触发和稳定动脉粥样硬化斑块新血管形成。方法和结果-在这项研究中，我们通过实时共聚焦显微镜在三维基底膜共培养中显示，人微血管内皮细胞（HMEC-1）和人血管平滑肌细胞（HVSMCs）中的TF在毛细血管样网络的形成中起重要作用。内皮细胞和平滑肌细胞中的TF沉默抑制具有稳定表型的管状结构的形成。使用体内模型，我们观察到TF抑制HMEC-1或HVSMC降低了它们形成新毛细血管的共同能力。TF沉默诱导的表型变化与内皮细胞中趋化因子（C-C基序）配体2（CCL 2）表达减少有关。伤口愈合和趋化实验表明，TF诱导的CCL 2释放刺激HVSMC迁移到HMEC-1。结论内源性TF调节内皮细胞CCL 2的产生。分泌的CCL 2通过向内皮细胞募集平滑肌细胞来介导TF的血管生成作用，并促进新形成的微血管的成熟。（Arterioscler Thromb Vasc Biol.2011;31：2607-2615.）
Objective-Tissue factor (TF) triggers arterial thrombosis. TF is also able to initiate cellular signaling mechanisms leading to angiogenesis. Because high cardiovascular risk atherosclerotic plaques show significant angiogenesis, our objective was to investigate whether TF is able to trigger and stabilize atherosclerotic plaque neovessel formation.Methods and Results-In this study, we showed, by real-time confocal microscopy in 3-dimensional basement membrane cocultures, that TF in human microvascular endothelial cells (HMEC-1) and in human vascular smooth muscle cells (HVSMCs) plays an important role in the formation of capillary-like networks. TF silencing in endothelial cells and smooth muscle cells inhibits the formation of tube-like structures with stable phenotype. Using an in vivo model, we observed that TF inhibition in either HMEC-1 or HVSMCs reduced their shared ability to form new capillaries. The phenotypic changes induced by TF silencing were linked to reduced chemokine (C-C motif) ligand 2 (CCL2) expression in endothelial cells. Wound healing and chemotactic assays demonstrated that TF-induced release of CCL2 stimulated HVSMC migration to HMEC-1.Conclusion-Endogenous TF regulates CCL2 production in endothelial cells. Secreted CCL2 mediates the angiogenic effect of TF by recruiting smooth muscle cells toward endothelial cells and facilitates the maturation of newly formed microvessels. (Arterioscler Thromb Vasc Biol. 2011;31:2607-2615.)