Osteoprotegerin and RANKL differentially regulate angiogenesis and endothelial cell function
Osteoprotegerin and RANKL differentially regulate angiogenesis and endothelial cell function
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DOI：
10.1007/s10456-008-9127-z
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发表时间：
2009-03-01
期刊：
影响因子：
9.8
通讯作者：
Scatena, Marta
中科院分区：
文献类型：
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作者：
McGonigle, Joseph S.;Giachelli, Cecilia M.;Scatena, Marta
骨保护素（OPG）是一种可溶性肿瘤坏死因子受体家族分子，在体外可保护内皮细胞免于凋亡，在体内可促进新生血管形成。在这项研究中，我们评估了OPG及其配体，核因子-κ B配体受体激活剂（RANKL）和肿瘤坏死因子相关凋亡诱导配体（TRAIL），在微血管形成中的作用，使用大鼠主动脉环模型的血管生成。发现OPG促进主动脉环模型中血管生成发芽增加两倍，并且这种作用通过与5倍摩尔过量的RANKL或TRAIL预孵育来抑制。虽然TRAIL本身对血管生成没有影响，但发现RANKL可有效抑制基础和血管内皮生长因子诱导的血管生成。OPG增加了微血管中内皮细胞的增殖速率;相反，RANKL抑制增殖。在主动脉环模型中以及与人脐静脉内皮细胞（HUVEC）孵育后，发现RANKL在第6、7和10天诱导内皮细胞凋亡。信号转导研究表明，OPG诱导HUVECs中ERK 1/2和Akt磷酸化，而RANKL没有影响。我们的研究结果表明，OPG是微血管形成的正调控因子，而RANKL是一种血管生成抑制剂，由于对内皮细胞增殖，凋亡和信号转导的调节作用。
Osteoprotegerin (OPG) a soluble tumor necrosis factor receptor family molecule protects endothelial cells from apoptosis in vitro and promotes neovascularization in vivo. In this study, we assessed the role of OPG and its ligands, receptor activator of nuclear factor-kappa B ligand (RANKL) and tumor necrosis factor-related apoptosis inducing ligand (TRAIL), in microvessel formation using the rat aortic ring model of angiogenesis. OPG was found to promote a twofold increase in angiogenic sprouting in the aortic ring model, and this effect was inhibited by pre-incubation with a fivefold molar excess of either RANKL or TRAIL. While TRAIL had no effect upon angiogenesis on its own, RANKL was found to potently inhibit basal and vascular endothelial growth factor-induced angiogenesis. OPG increased the rate of endothelial cell proliferation in sprouting microvessels; in contrast, RANKL inhibited proliferation. RANKL was found to induce endothelial apoptosis at days 6, 7, and 10 in the aortic ring model and after incubation with human umbilical vein endothelial cells (HUVECs). Signaling studies showed that OPG induced ERK1/2 and Akt phosphorylation in HUVECs while RANKL had no effect. Our results indicate that OPG is a positive regulator of microvessel formation, while RANKL is an angiogenic inhibitor due to effects on regulation of endothelial cell proliferation, apoptosis, and signaling.