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Cell-Demanded VEGF Release via Nanocapsules Elicits Different Receptor Activation Dynamics and Enhanced Angiogenesis

  • Emerging Trends in Biomaterials Research
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Abstract

Although the delivery of vascular endothelial growth factor (VEGF) with extended release profiles has consistently shown beneficial therapeutic effects compared with bolus delivery, [Martino, M. M., F. Tortelli, M. Mochizuki, S. Traub, D. Ben-David, G. A. Kuhn, R. Muller, E. Livne, S. A. Eming, and J. A. Hubbell. Sci. Transl. Med. 3(100):100ra189, 2011; Martino, M. M., P. S. Briquez, A. Ranga, M. P. Lutolf, and J. A. Hubbell. Proc. Natl. Acad. Sci. USA. 110(12):4563–4568, 2013; Amiram, M., K. M. Luginbuhl, X. Li, M. N. Feinglos, and A. Chilkoti. Proc. Natl. Acad. Sci. USA. 110(8):2792–2797, 2013] it remains unclear if the reason is solely due to the physical availability and the reduced degradation of the protein. Here we studied the activation of VEGF receptor 2 (VR-2) by sustained released VEGF compared with bolus delivered VEGF to unveil that sustained delivery system alters the dynamics of receptor activation and affects the actions of cells between sprouting and proliferation. We utilized a protein nanocapsule delivery strategy that releases VEGF as mediated by extracellular proteases. These protein nanocapsules were synthesized through an aqueous assembly of a nanogel-peptide shell around the protein, leading to one to two proteins encapsulated per nanocapsule. Receptor activation studies revealed differential dynamics of receptor activation for slowly released VEGF compared with bolus delivered VEGF. As expected sustained released VEGF via nanocapsules resulted in enhanced vascular sprouting in vitro and in vivo. These studies demonstrate the physical presentation of VEGF, in this case of a slow release with time, can affect its molecular mechanism of actions and cause alterations in cellular responses and therapeutic outcomes.

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Acknowledgments

The authors would like to thank Dr. Talar Tokatlian, Dr. Sean Anderson, Shannon Stephens and Angela Wong for their support. The authors would also like to thank Genentech for generously providing us with VEGF. This work was funded by the American Heart Association 11GRNT7630021AHA and the National Institutes of Health R01HL110592 and R01NS079691. We also acknowledge NSF IGERT: Materials Creation Training Program (MCTP)—DGE-0654431, the California NanoSystems Institute (CNSI), and the use of instruments at the Electron Imaging Center for NanoMachines supported by NIH (1S10RR23057 to ZHZ) and CNSI at UCLA.

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  1. Department of Chemical & Biomolecular Engineering, University of California Los Angeles, 420 Westwood Plaza, 5531 Boelter Hall, Los Angeles, CA, 90095, USA

    Suwei Zhu & Tatiana Segura

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  1. Suwei Zhu
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  2. Tatiana Segura
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Correspondence to Tatiana Segura.

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Associate Editor Akhilesh K Gaharwar oversaw the review of this article.

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Zhu, S., Segura, T. Cell-Demanded VEGF Release via Nanocapsules Elicits Different Receptor Activation Dynamics and Enhanced Angiogenesis. Ann Biomed Eng 44, 1983–1992 (2016). https://doi.org/10.1007/s10439-016-1581-y

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  • DOI: https://doi.org/10.1007/s10439-016-1581-y

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