Cardiovascular Research Center, Hospital de Sant Pau, IIB-Sant Pau, Barcelona, Spain.
Arterioscler Thromb Vasc Biol. 2011 Nov;31(11):2607-15. doi: 10.1161/ATVBAHA.111.233536.
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.
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.
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.
组织因子 (TF) 可引发动脉血栓形成。TF 还能够启动细胞信号转导机制，导致血管生成。由于心血管风险高的动脉粥样硬化斑块显示出明显的血管生成，我们的目的是研究 TF 是否能够引发和稳定动脉粥样硬化斑块新生血管形成。
在这项研究中，我们通过在 3 维基底膜共培养物中的实时共聚焦显微镜显示，TF 在人微血管内皮细胞 (HMEC-1) 和人血管平滑肌细胞 (HVSMCs) 中在形成毛细血管样网络中发挥重要作用。内皮细胞和血管平滑肌细胞中的 TF 沉默抑制了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 抑制在 HMEC-1 或 HVSMCs 中均减少了它们形成新毛细血管的共同能力。TF 沉默引起的表型变化与内皮细胞中趋化因子 (C-C 基序) 配体 2 (CCL2) 的表达减少有关。伤口愈合和趋化性测定表明，TF 诱导的 CCL2 释放刺激 HVSMC 向 HMEC-1 的迁移。
内源性 TF 调节内皮细胞中 CCL2 的产生。分泌的 CCL2 通过招募平滑肌细胞向内皮细胞并促进新形成的微血管成熟，介导 TF 的血管生成作用。
