Angiogenic Microvascular Endothelial Cells Release Microparticles Rich in Tissue Factor That Promotes Postischemic Collateral Vessel Formation
Angiogenic Microvascular Endothelial Cells Release Microparticles Rich in Tissue Factor That Promotes Postischemic Collateral Vessel Formation
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DOI：
10.1161/atvbaha.114.303927
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发表时间：
2015-02-01
影响因子：
8.7
通讯作者：
Badimon, Lina
中科院分区：
文献类型：
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作者：
Arderiu, Gemma;Pena, Esther;Badimon, Lina
目的：治疗性血管生成是治疗缺血的一种有前景的策略。我们以前的工作表明，内源性内皮组织因子(TF)的表达诱导微血管内皮细胞(MECs)的分泌内信号和启动血管生成。我们假设活化的微血管内皮细胞可以通过释放富含Tf的微血管内皮细胞微粒(MEMP)而发挥进一步的旁分泌调节作用，并诱导缺血组织的新生血管形成。方法与结果-在这里，我们首次描述了激活的MECs能够通过释放富含Tf的微粒子来诱导缺血区修复性新生血管的形成。我们在体外和体内实验表明，野生型和Tf上调MECs释放的Memps都能诱导血管生成和侧支血管形成，而Tf沉默MECs产生的Tf缺乏Memps不能触发血管生成。在小鼠后肢缺血模型中，分离的携带转移因子的MEMP被输送到未灌流的内收肌中，增强侧支循环和毛细血管的形成，这是MRI所证明的。结论微血管内皮细胞释放的富含Tf的Memps可通过促进缺血后血管新生和组织再灌流来克服动脉闭塞和组织缺血的后果。
Objective-Therapeutic angiogenesis is a promising strategy for treating ischemia. Our previous work showed that endogenous endothelial tissue factor (TF) expression induces intracrine signaling and switches-on angiogenesis in microvascular endothelial cells (mECs). We have hypothesized that activated mECs could exert a further paracrine regulation through the release of TF-rich microvascular endothelial microparticles (mEMPs) and induce neovascularization of ischemic tissues.Approach and Results-Here, we describe for the first time that activated mECs are able to induce reparative neovascularization in ischemic zones by releasing TF-rich microparticles. We show in vitro and in vivo that mEMPs released by both wildtype and TF-upregulated-mECs induce angiogenesis and collateral vessel formation, whereas TF-poor mEMPs derived from TF-silenced mECs are not able to trigger angiogenesis. Isolated TF-bearing mEMPs delivered to nonperfused adductor muscles in a murine hindlimb ischemia model enhance collateral flow and capillary formation evidenced by MRI. TF-bearing mEMPs increase angiogenesis operating via paracrine regulation of neighboring endothelial cells, signaling through the 1-integrin pathway Rac1-ERK1/2-ETS1 and triggering CCL2 (chemokine [C-C motif] ligand 2) production to form new and competent mature neovessels.Conclusions-These findings demonstrate that TF-rich mEMPs released by microvascular endothelial cells can overcome the consequences of arterial occlusion and tissue ischemia by promoting postischemic neovascularization and tissue reperfusion.