期刊
ACTA BIOMATERIALIA
卷 8, 期 1, 页码 154-164出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.actbio.2011.08.029
关键词
Angiogenesis; Self-assembling peptide nanofibers; Vascular tissue engineering; Low-affinity interactions
资金
- NIH/NDDK [1R21DK078814]
- NIH/NIBIB [1R01EB009701]
- NSF [CHE-0802286]
- University of Cincinnati Department of Biomedical Engineering
- American Heart Association [11PRE7420008]
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. The results were validated in vivo using a mouse diabetic wound healing model with impaired neovascularization. RAD16-II stimulated spontaneous capillary morphogenesis, and increased beta(3) integrin phosphorylation and VEGF expression in MVECs. These responses were abrogated in the presence of beta(3) and MAPK/ERK pathway 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. The 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 beta(3) integrin and MAPK/ERK pathway, indicating that low-affinity sequences can be used to functionalize biocompatible 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 scaffold materials. (C) 2011 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
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