Regulation of endothelial cell activation and angiogenesis by injectable peptide nanofibers.
Regulation of endothelial cell activation and angiogenesis by injectable peptide nanofibers.
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DOI：
10.1016/j.actbio.2011.08.029
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发表时间：
2012-01
影响因子：
9.7
通讯作者：
Narmoneva, Daria A.
中科院分区：
文献类型：
--
作者：
Cho, Hongkwan;Balaji, Swathi;Sheikh, Abdul Q.;Hurley, Jennifer R.;Tian, Ye F.;Collier, Joel H.;Crombleholme, Timothy M.;Narmoneva, Daria A.
关键词：
RAD16-II 肽纳米纤维在血管组织工程中具有广阔的应用前景，并且已被证明可以在体外和体内增强血管生成，但其机制仍不清楚。我们假设 RAD16-II 的促血管生成作用源于微血管内皮细胞 (MVEC) 与 RAD 基序的低亲和力整合素依赖性相互作用。将小鼠 MVEC 在有或没有整合素和 MAPK/ERK 通路抑制剂的 RAD16-II 上培养，并对血管生成反应进行量化。使用具有受损新生血管的小鼠糖尿病伤口愈合模型对结果进行了体内验证。 RAD16-II 刺激自发毛细血管形态发生，增加 MVEC 中 β3 整合素磷酸化和 VEGF 表达。这些反应在 β3 和 MEK 抑制剂存在或在没有 RAD 基序的对照肽上被消除。广谱整合素抑制剂 echistatin 在体外完全消除了 RAD16-II 介导的毛细血管形态发生，在体内完全消除了伤口中的新生血管形成和 VEGF 表达。将 RGD 基序添加到 RAD16-II 中不会改变纳米纤维结构或机械性能，但会导致毛细血管形态发生显着降低。总的来说，这些结果表明细胞和RAD基序之间的低亲和力非特异性相互作用可以通过β3整合素和MAPK/ERK途径的磷酸化触发血管生成反应，表明低亲和力序列可用于功能化生物相容性材料以调节细胞迁移和血管生成，从而扩大了当前可用于此类功能化的可用基序库。将 RAD 或类似基序纳入蛋白质工程或混合肽支架中可能代表了血管组织工程的新策略，并将进一步增强新支架材料的设计机会。
RAD16-II peptide nanofibers are promising for vascular tissue engineering and were shown to enhance angiogenesis in vitro and in vivo, although the mechanism remains unknown. We hypothesized that the pro-angiogenic effect of RAD16-II results from low-affinity integrin-dependent interactions of microvascular endothelial cells (MVECs) with RAD motifs. Mouse MVECs were cultured on RAD16-II with or without integrin and MAPK/ERK pathway inhibitors, and angiogenic responses were quantified. Results were validated in vivo using mouse diabetic wound healing model with impaired neovascularization. RAD16-II stimulated spontaneous capillary morphogenesis, increased β3 integrin phosphorylation and VEGF expression in MVECs. These responses were abrogated in the presence of β3 and MEK inhibitors or on the control peptide without RAD motifs. Wide-spectrum integrin inhibitor echistatin completely abolished RAD16-II-mediated capillary morphogenesis in vitro and neovascularization and VEGF expression in the wound in vivo. Addition of the RGD motif to RAD16-II did not change nanofiber architecture or mechanical properties, but resulted in significant decrease in capillary morphogenesis. Overall, these results suggest that low-affinity non-specific interactions between cells and RAD motifs can trigger angiogenic responses via phosphorylation of β3 integrin and MAPK/ERK pathway, indicating that low-affinity sequences can be used to functionalize bio-compatible materials for the regulation of cell migration and angiogenesis, thus expanding the current pool of available motifs that can be used for such functionalization. Incorporation of RAD or similar motifs into protein engineered or hybrid peptide scaffolds may represent a novel strategy for vascular tissue engineering and will further enhance design opportunities for new scaffolds materials.
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影响因子：
46.2
作者：
Collier JH;Rudra JS;Gasiorowski JZ;Jung JP
通讯作者：
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作者：
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通讯作者：
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