Engineered microenvironments for synergistic VEGF - integrin signalling during vascularization

Moulisová, V. , Gonzalez-Garcia, C., Cantini, M. , Rodrigo-Navarro, A. , Weaver, J., Costell, M., Sabater i Serra, R., Dalby, M. J. , García, A. J. and Salmerón-Sánchez, M. (2017) Engineered microenvironments for synergistic VEGF - integrin signalling during vascularization. Biomaterials, 126, pp. 61-74. (doi:10.1016/j.biomaterials.2017.02.024) (PMID:28279265) (PMCID:PMC5354119)

Moulisová, V. , Gonzalez-Garcia, C., Cantini, M. , Rodrigo-Navarro, A. , Weaver, J., Costell, M., Sabater i Serra, R., Dalby, M. J. , García, A. J. and Salmerón-Sánchez, M. (2017) Engineered microenvironments for synergistic VEGF - integrin signalling during vascularization. Biomaterials, 126, pp. 61-74. (doi:10.1016/j.biomaterials.2017.02.024) (PMID:28279265) (PMCID:PMC5354119)

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Abstract

We have engineered polymer-based microenvironments that promote vasculogenesis both in vitro and in vivo through synergistic integrin-growth factor receptor signalling. Poly(ethyl acrylate) (PEA) triggers spontaneous organization of fibronectin (FN) into nanonetworks which provide availability of critical binding domains. Importantly, the growth factor binding (FNIII12-14) and integrin binding (FNIII9-10) regions are simultaneously available on FN fibrils assembled on PEA. This material platform promotes synergistic integrin/VEGF signalling which is highly effective for vascularization events in vitro with low concentrations of VEGF. VEGF specifically binds to FN fibrils on PEA compared to control polymers (poly(methyl acrylate), PMA) where FN remains in a globular conformation and integrin/GF binding domains are not simultaneously available. The vasculogenic response of human endothelial cells seeded on these synergistic interfaces (VEGF bound to FN assembled on PEA) was significantly improved compared to soluble administration of VEGF at higher doses. Early onset of VEGF signalling (PLCγ1 phosphorylation) and both integrin and VEGF signalling (ERK1/2 phosphorylation) were increased only when VEGF was bound to FN nanonetworks on PEA, while soluble VEGF did not influence early signalling. Experiments with mutant FN molecules with impaired integrin binding site (FN-RGE) confirmed the role of the integrin binding site of FN on the vasculogenic response via combined integrin/VEGF signalling. In vivo experiments using 3D scaffolds coated with FN and VEGF implanted in the murine fat pad demonstrated pro-vascularization signalling by enhanced formation of new tissue inside scaffold pores. PEA-driven organization of FN promotes efficient presentation of VEGF to promote vascularization in regenerative medicine applications.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Salmeron-Sanchez, Professor Manuel and Moulisova, Dr Vladimira and Rodrigo-Navarro, Mr Aleixandre and Cantini, Dr Marco and Dalby, Professor Matthew and Gonzalez Garcia, Dr Cristina
Authors: Moulisová, V., Gonzalez-Garcia, C., Cantini, M., Rodrigo-Navarro, A., Weaver, J., Costell, M., Sabater i Serra, R., Dalby, M. J., García, A. J., and Salmerón-Sánchez, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Science and Engineering > School of Engineering > Biomedical Engineering
Journal Name:Biomaterials
Publisher:Elsevier
ISSN:0142-9612
ISSN (Online):1878-5905|
Published Online:21 February 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Biomaterials 126:61-74
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
626901HEALINSYNERGY - Material-driven fibronectin fibrillogenesis to engineer synergistic growth factor microenvironmentsManuel Salmeron-SanchezEuropean Research Council (ERC)306990ENG - BIOMEDICAL ENGINEERING
653731Synergistic microenvironments for non-union bone defectsMatthew DalbyMedical Research Council (MRC)MR/L0022710/1RI MOLECULAR CELL & SYSTEMS BIOLOGY