Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair
Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair
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DOI：
10.1073/pnas.1016546108
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发表时间：
2011-08-16
影响因子：
11.1
通讯作者：
Stupp, Samuel I.
中科院分区：
文献类型：
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作者：
Webber, Matthew J.;Tongers, Joern;Stupp, Samuel I.
缺血性心血管疾病是世界范围内发病率和死亡率的主要原因，对开发新的治疗方法有很大的需求。我们报道了一种基于多肽两亲性纳米结构的完全合成的无细胞疗法的开发，该纳米结构旨在模拟最有效的血管生成信号蛋白之一血管内皮生长因子的活性。在多肽两亲分子自组装之后，纳米级的细丝形成，在它们的表面以高密度显示出一种类似血管内皮生长因子的多肽。研究发现，血管内皮生长因子模拟纤维可诱导血管内皮细胞中血管内皮生长因子受体的磷酸化，促进内皮细胞的促血管生成行为，表现为在体外的增殖、存活和迁移。在鸡胚实验中，这些纳米结构在宿主血管系统中引发了血管生成反应。当在小鼠后肢缺血模型中进行评估时，与对照组相比，纳米纤维增加了组织灌注量、功能恢复、肢体挽救和跑步机耐力，其中包括单独的血管内皮生长因子模拟肽。免疫组织学证据还表明，缺血后肢微循环密度增加，这表明这种有希望的潜在疗法的疗效机制与这些多价类似血管内皮生长因子的纳米纤维治疗所导致的微循环血管生成增强有关。
There is great demand for the development of novel therapies for ischemic cardiovascular disease, a leading cause of morbidity and mortality worldwide. We report here on the development of a completely synthetic cell-free therapy based on peptide amphiphile nanostructures designed to mimic the activity of VEGF, one of the most potent angiogenic signaling proteins. Following self-assembly of peptide amphiphiles, nanoscale filaments form that display on their surfaces a VEGF-mimetic peptide at high density. The VEGF-mimetic filaments were found to induce phosphorylation of VEGF receptors and promote proangiogenic behavior in endothelial cells, indicated by an enhancement in proliferation, survival, and migration in vitro. In a chicken embryo assay, these nanostructures elicited an angiogenic response in the host vasculature. When evaluated in a mouse hind-limb ischemia model, the nanofibers increased tissue perfusion, functional recovery, limb salvage, and treadmill endurance compared to controls, which included the VEGF-mimetic peptide alone. Immunohistological evidence also demonstrated an increase in the density of microcirculation in the ischemic hind limb, suggesting the mechanism of efficacy of this promising potential therapy is linked to the enhanced microcirculatory angiogenesis that results from treatment with these polyvalent VEGF-mimetic nanofibers.