Inserm Unite Mixte de Recherche (UMR)-S 608, Université de la Méditerranée, Unite de Formation et de Recherche Pharmacie, 13385 Marseille, France.
Blood. 2010 May 6;115(18):3843-51. doi: 10.1182/blood-2009-06-229591. Epub 2010 Feb 25.
CD146, an endothelial molecule involved in permeability and monocyte transmigration, has recently been reported to promote vessel growth. As CD146 is also detectable as a soluble form (sCD146), we hypothesized that sCD146 could stimulate angiogenesis. Experiments of Matrigel plugs in vivo showed that sCD146 displayed chemotactic activity on endogenous endothelial cells, and exogenously injected late endothelial progenitor cells (EPCs). Recruited endothelial cells participated in formation of vascular-like structures. In vitro, sCD146 enhanced angiogenic properties of EPCs, with an increased cell migration, proliferation, and capacity to establish capillary-like structures. Effects were additive with those of vascular endothelial growth factor (VEGF), and sCD146 enhanced VEGFR2 expression and VEGF secretion. Consistent with a proangiogenic role, gene expression profiling of sCD146-stimulated EPCs revealed an up-regulation of endothelial nitric oxide synthase, urokinase plasminogen activator, matrix metalloproteinase 2, and VEGFR2. Silencing membrane-bound CD146 inhibited responses. The potential therapeutic interest of sCD146 was tested in a model of hind limb ischemia. Local injections of sCD146 significantly reduced auto-amputation, tissue necrosis, fibrosis, inflammation, and increased blood flow. Together, these findings establish that sCD146 displays chemotactic and angiogenic properties and promotes efficient neovascularization in vivo. Recombinant human sCD146 might thus support novel strategies for therapeutic angiogenesis in ischemic diseases.
CD146 是一种参与通透性和单核细胞迁移的内皮分子，最近有报道称它可促进血管生长。由于 CD146 也可检测为可溶性形式（sCD146），我们假设 sCD146 可以刺激血管生成。体内 Matrigel plugs 实验表明，sCD146 对内皮细胞具有趋化活性，并能趋化外源性注射的晚期内皮祖细胞（EPCs）。募集的内皮细胞参与了血管样结构的形成。在体外，sCD146 增强了 EPC 的血管生成特性，表现为细胞迁移、增殖和形成毛细血管样结构的能力增强。其作用与血管内皮生长因子（VEGF）的作用具有加性，sCD146 增强了 VEGFR2 的表达和 VEGF 的分泌。与促血管生成作用一致，sCD146 刺激的 EPC 的基因表达谱显示内皮型一氧化氮合酶、尿激酶纤溶酶原激活物、基质金属蛋白酶 2 和 VEGFR2 的上调。沉默膜结合型 CD146 抑制了这些反应。在下肢缺血模型中测试了 sCD146 的潜在治疗作用。sCD146 的局部注射显著减少了自动截肢、组织坏死、纤维化、炎症，并增加了血流量。总之，这些发现表明 sCD146 具有趋化和血管生成特性，并在体内促进有效的血管新生。因此，重组人 sCD146 可能支持缺血性疾病中治疗性血管生成的新策略。
