Despite extensive research, pro-angiogenic drugs have failed to translate clinically, and therapeutic angiogenesis, which has potential in the treatment of various cardiovascular diseases, remains a major challenge. Physiologically, angiogenesis — the process of blood-vessel growth from existing vasculature — is regulated by a complex interplay of biophysical and biochemical cues from the extracellular matrix (ECM), angiogenic factors and multiple cell types. The ECM can be regarded as the natural 3D material that regulates angiogenesis. Here, we leverage knowledge of ECM properties to derive design rules for engineering pro-angiogenic materials. We propose that pro-angiogenic materials should be biomimetic, incorporate angiogenic factors and mimic cooperative interactions between growth factors and the ECM. We highlight examples of material designs that demonstrate these principles and considerations for designing better angiogenic materials.
Your institute does not have access to this article
Open Access articles citing this article.
Spatiotemporal regulation of angiogenesis/osteogenesis emulating natural bone healing cascade for vascularized bone formation
Journal of Nanobiotechnology Open Access 14 December 2021
Nature Communications Open Access 10 June 2021
An injectable sulfonated reversible thermal gel for therapeutic angiogenesis to protect cardiac function after a myocardial infarction
Journal of Biological Engineering Open Access 17 January 2019
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Potente, M., Gerhardt, H. & Carmeliet, P. Basic and therapeutic aspects of angiogenesis. Cell 146, 873–887 (2011).
Carmeliet, P. Angiogenesis in life, disease and medicine. Nature 438, 932–936 (2005).
Clegg, L. E. & Mac Gabhan, F. Systems biology of the microvasculature. Integr. Biol. 7, 498–512 (2015).
Eming, S. A. & Hubbell, J. A. Extracellular matrix in angiogenesis: dynamic structures with translational potential. Exp. Dermatol. 20, 605–613 (2011).
Krock, B. L., Skuli, N. & Simon, M. C. Hypoxia-induced angiogenesis: good and evil. Genes Cancer 2, 1117–1133 (2011).
Semenza, G. L. Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiology 19, 176–182 (2004).
Herbert, S. P. & Stainier, D. Y. Molecular control of endothelial cell behaviour during blood vessel morphogenesis. Nat. Rev. Mol. Cell Biol. 12, 551–564 (2011).
Arroyo, A. G. & Iruela-Arispe, M. L. Extracellular matrix, inflammation, and the angiogenic response. Cardiovasc. Res. 86, 226–235 (2010).
Schultz, G. S. & Wysocki, A. Interactions between extracellular matrix and growth factors in wound healing. Wound Repair Regen. 17, 153–162 (2009).
Ruhrberg, C. et al. Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev. 16, 2684–2698 (2002).
Vempati, P., Popel, A. S. & Mac Gabhann, F. Extracellular regulation of VEGF: isoforms, proteolysis, and vascular patterning. Cytokine Growth Factor Rev. 25, 1–19 (2014).
Mahabeleshwar, G. H., Feng, W., Reddy, K., Plow, E. F. & Byzova, T. V. Mechanisms of integrin–vascular endothelial growth factor receptor cross-activation in angiogenesis. Circ. Res. 101, 570–580 (2007).
Somanath, P. R., Ciocea, A. & Byzova, T. V. Integrin and growth factor receptor alliance in angiogenesis. Cell Biochem. Biophys. 53, 53–64 (2008).
Streuli, C. H. & Akhtar, N. Signal co-operation between integrins and other receptor systems. Biochem. J. 418, 491–506 (2009).
Wijelath, E. S. et al. Heparin-II domain of fibronectin is a vascular endothelial growth factor-binding domain: enhancement of VEGF biological activity by a singular growth factor/matrix protein synergism. Circ. Res. 99, 853–860 (2006). This study details how fibronectin mediates synergistic signalling between VEGFR2 and the integrin α5β1, and the consequences on EC behaviour.
Martino, M. M. et al. Engineering the growth factor microenvironment with fibronectin domains to promote wound and bone tissue healing. Sci. Transl. Med. 3, 100ra89 (2011).
Kim, S. H., Turnbull, J. & Guimond, S. Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor. J. Endocrinol. 209, 139–151 (2011).
Armulik, A., Abramsson, A. & Betsholtz, C. Endothelial/pericyte interactions. Circ. Res. 97, 512–523 (2005).
Gaengel, K., Genove, G., Armulik, A. & Betsholtz, C. Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler. Thromb. Vasc. Biol. 29, 630–638 (2009).
Ribatti, D., Nico, B. & Crivellato, E. The role of pericytes in angiogenesis. Int. J. Dev. Biol. 55, 261–268 (2011).
Davis, G. E. & Senger, D. R. Endothelial extracellular matrix: biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization. Circ. Res. 97, 1093–1107 (2005).
Lee, S., Jilani, S. M., Nikolova, G. V., Carpizo, D. & Iruela-Arispe, M. L. Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. J. Cell Biol. 169, 681–691 (2005).
Roy, R., Zhang, B. & Moses, M. A. Making the cut: protease-mediated regulation of angiogenesis. Exp. Cell Res. 312, 608–622 (2006).
van Hinsbergh, V. W. & Koolwijk, P. Endothelial sprouting and angiogenesis: matrix metalloproteinases in the lead. Cardiovasc. Res. 78, 203–212 (2008).
Ehrbar, M. et al. The role of actively released fibrin-conjugated VEGF for VEGF receptor 2 gene activation and the enhancement of angiogenesis. Biomaterials 29, 1720–1729 (2008).
Martino, M. M. & Hubbell, J. A. The 12th–14th type III repeats of fibronectin function as a highly promiscuous growth factor-binding domain. FASEB J. 24, 4711–4721 (2010).
Lin, Y.-D. et al. Instructive nanofiber scaffolds with VEGF create a microenvironment for arteriogenesis and cardiac repair. Sci. Transl. Med. 4, 146ra109 (2012).
Martino, M. M., Briquez, P. S., Ranga, A., Lutolf, M. P. & Hubbell, J. A. Heparin-binding domain of fibrin(ogen) binds growth factors and promotes tissue repair when incorporated within a synthetic matrix. Proc. Natl Acad. Sci. USA 110, 4563–4568 (2013).
Phelps, E. A., Landazuri, N., Thule, P. M., Taylor, W. R. & Garcia, A. J. Bioartificial matrices for therapeutic vascularization. Proc. Natl Acad. Sci. USA 107, 3323–3328 (2010).
Silva, E. A. & Mooney, D. J. Spatiotemporal control of vascular endothelial growth factor delivery from injectable hydrogels enhances angiogenesis. J. Thromb. Haemost. 5, 590–598 (2007).
Martino, M. M. et al. Growth factors engineered for super-affinity to the extracellular matrix enhance tissue healing. Science 343, 885–888 (2014). This study demonstrates a broadly applicable growth factor-engineering strategy to control growth factor delivery through exogenous and endogenous matrices and strongly enhance tissue repair, including angiogenesis in diabetic wounds.
Sacchi, V. et al. Long-lasting fibrin matrices ensure stable and functional angiogenesis by highly tunable, sustained delivery of recombinant VEGF164 . Proc. Natl Acad. Sci. USA 111, 6952–6957 (2014).
Yoo, S. Y. & Kwon, S. M. Angiogenesis and its therapeutic opportunities. Mediators Inflamm. 2013, 127170 (2013).
Martino, M. M. et al. Extracellular matrix and growth factor engineering for controlled angiogenesis in regenerative medicine. Front. Bioeng. Biotechnol. 3, 45 (2015).
Prabhu, V. V., Chidambaranathan, N. & Gopal, V. A. Historical review on current medication and therapies for inducing and inhibiting angiogenesis. J. Chem. Pharm. Res. 2, 526–533 (2011).
Simons, M. & Ware, J. A. Therapeutic angiogenesis in cardiovascular disease. Nat. Rev. Drug Discov. 2, 863–871 (2003).
Tongers, J., Roncalli, J. G. & Losordo, D. W. Therapeutic angiogenesis for critical limb ischemia: microvascular therapies coming of age. Circulation 118, 9–16 (2008).
Ruel, M. et al. Long-term effects of surgical angiogenic therapy with fibroblast growth factor 2 protein. J. Thorac. Cardiovasc. Surg. 124, 28–34 (2002).
Briquez, P. S., Hubbell, J. A. & Martino, M. M. Extracellular matrix-inspired growth factor delivery systems for skin wound healing. Adv. Wound Care 4, 479–489 (2015).
Rhodes, J. M. & Simons, M. The extracellular matrix and blood vessel formation: not just a scaffold. J. Cell. Mol. Med. 11, 176–205 (2007).
George, E. L., Georges-Labouesse, E. N., Patel-King, R. S., Rayburn, H. & Hynes, R. O. Defects in mesoderm, neural-tube and vascular development in mouse embryos lacking fibronectin. Development 4, 1079–1091 (1993).
Edgar, L. T., Hoying, J. B. & Weiss, J. A. In silico investigation of angiogenesis with growth and stress generation coupled to local extracellular matrix density. Ann. Biomed. Eng. 43, 1531–1542 (2015).
Bordeleau, F. et al. Tissue stiffness regulates serine/arginine-rich protein-mediated splicing of the extra domain B-fibronectin isoform in tumors. Proc. Natl Acad. Sci. USA 27, 8314–8319 (2015).
Kim, S., Harris, M. & Varner, J. A. Regulation of integrin αvβ3-mediated endothelial cell migration and angiogenesis by integrin α5β1 and protein kinase A. J. Biol. Chem. 275, 33920–33928 (2000).
Davis, G. E., Bayless, K. J. & Mavila, A. Molecular basis of endothelial cell morphogenesis in three-dimensional extracellular matrices. Anat. Rec. 268, 252–275 (2002).
Grainger, S. & Putnam, A. in Mechanical and Chemical Signaling in Angiogenesis. Studies in Mechanobiology, Tissue Engineering and Biomaterials (ed. Reinhart-King, C. ) 185–209 (Springer, 2013).
Hodivala-Dilke, K. M., Reynolds, A. R. & Reynolds, L. E. Integrins in angiogenesis: multitalented molecules in a balancing act. Cell Tissue Res. 314, 131–144 (2003).
Koch, S., Tugues, S., Li, X., Gualandi, L. & Claesson-Welsh, L. Signal transduction by vascular endothelial growth factor receptors. Biochem. J. 437, 169–183 (2011).
Olsson, A. K., Dimberg, A., Kreuger, J. & Claesson-Welsh, L. VEGF receptor signalling — in control of vascular function. Nat. Rev. Mol. Cell Biol. 7, 359–371 (2006).
Hoier, B. et al. Angiogenic response to passive movement and active exercise in individuals with peripheral arterial disease. J. Appl. Physiol. 115, 1777–1787 (2013).
Hoier, B. et al. Pro- and anti-angiogenic factors in human skeletal muscle in response to acute exercise and training. J. Physiol. 590, 595–606 (2012).
Kut, C., Mac Gabhann, F. & Popel, A. S. Where is VEGF in the body? A meta-analysis of VEGF distribution in cancer. Br. J. Cancer 97, 978–985 (2007).
Vempati, P., Popel, A. S. & Mac Gabhann, F. Formation of VEGF isoform-specific spatial distributions governing angiogenesis: computational analysis. BMC Syst. Biol. 5, 59 (2011).
Mac Gabhann, F. & Popel, A. S. Systems biology of vascular endothelial growth factors. Microcirculation 15, 715–738 (2008).
Ballmer-Hofer, K., Andersson, A. E., Ratcliffe, L. E. & Berger, P. Neuropilin-1 promotes VEGFR-2 trafficking through Rab11 vesicles thereby specifying signal output. Blood 118, 816–826 (2011).
Park, J. E., Keller, G. A. & Ferrara, N. Vascular endothelial growth-factor (VEGF) isoforms - differential deposition into the subepithelial extracellular-matrix and bioactivity of extracellular matrix-bound VEGF. Mol. Biol. Cell 4, 1317–1326 (1993).
Grunstein, J., Masbad, J. J., Hickey, R., Giordano, F. & Johnson, R. S. Isoforms of vascular endothelial growth factor act in a coordinate fashion to recruit and expand tumor vasculature. Mol. Cell. Biol. 20, 7282–7291 (2000).
Cordon-Cardo, C., Vlodavsky, I., Haimovitz-Friedman, A. H. D. & Fuks, Z. Expression of basic fibroblast growth factor in normal human tissues. Lab Invest. 6, 832–840 (1990).
Jin-No, K., Tanimizu, M., Hyodo, I., Kurimoto, F. & Yamashita, T. Plasma level of basic fibroblast growth factor increases with progression of chronic liver disease. J. Gastroenterol. 1, 119–121 (1997).
Kuwabara, K. et al. Hypoxia-mediated induction of acidic/basic fibroblast growth factor and platelet-derived growth factor in mononuclear phagocytes stimulates growth of hypoxic endothelial cells. Proc. Natl Acad. Sci. USA 92, 4606–4610 (1995).
Wang, L. et al. The effect of hypoxia on expression of basic fibroblast growth factor in pulmonary vascular pericytes. J. Tongji Med. Univ. 4, 265–267 (2000).
Presta, M. et al. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev. 16, 159–178 (2005).
Forsten, K. E., Fannon, M. & Nugent, M. A. Potential mechanisms for the regulation of growth factor binding by heparin. J. Theor. Biol. 205, 215–230 (2000).
Forsten-Williams, K., Chua, C. C. & Nugent, M. A. The kinetics of FGF-2 binding to heparan sulfate proteoglycans and MAP kinase signaling. J. Theor. Biol. 233, 483–499 (2005).
Delehedde, M. et al. Fibroblast growth factor-2 stimulation of p42/44MAPK phosphorylation and IκB degradation is regulated by heparan sulfate/heparin in rat mammary fibroblasts. J. Biol. Chem. 275, 33905–33910 (2000).
Andrae, J., Gallini, R. & Betsholtz, C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 22, 1276–1312 (2008).
Cenni, E. et al. Plasma levels of platelet-derived growth factor BB and transforming growth in patients with failed hip prostheses. Acta Orthopaed. 76, 61–66 (2005).
Kelly, J. L., Sanchez, A., Brown, G. S., Chesterman, C. N. & Sleigh, M. J. Accumulation of PDGF-BB and cell-binding form of PDGF-A in the extracellular matrix. J. Cell Biol. 121, 1153–1163 (1993).
Soyombo, A. A. & Dicorleto, P. E. Stable expression of human platelet-derived growth factor-B chain by bovin aortic endothelial cells — matrix association and selective proteolytic cleavage by thrombin. J. Biol. Chem. 269, 17734–17740 (1994).
Lindblom, P. et al. Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. 17, 1835–1840 (2003).
Abramsson, A. et al. Analysis of mural cell recruitment to tumor vessels. Circulation 105, 112–117 (2002).
Carlson, T. R., Feng, Y. Z., Maisonpierre, P. C., Mrksich, M. & Morla, A. O. Direct cell adhesion to the angiopoietins mediated by integrins. J. Biol. Chem. 276, 26516–26525 (2001).
Cascone, I., Napione, L., Maniero, F., Serini, G. & Bussolino, F. Stable interaction between α5β1 integrin and Tie2 tyrosine kinase receptor regulates endothelial cell response to Ang-1. J. Cell Biol. 170, 993–1004 (2005).
Zhang, J. et al. Angiopoietin-1/Tie2 signal augments basal Notch signal controlling vascular quiescence by inducing δ-like 4 expression through AKT-mediated activation of β-catenin. J. Biol. Chem. 286, 8055–8066 (2011).
Kofler, N. M. et al. Notch signaling in developmental and tumor angiogenesis. Genes Cancer 2, 1106–1116 (2011).
Augustin, H. G., Koh, G. Y., Thurston, G. & Alitalo, K. Control of vascular morphogenesis and homeostasis through the angiopoietin–Tie system. Nat. Rev. Mol. Cell Biol. 10, 165–177 (2009).
Mosch, B., Reissenweber, B., Neuber, C. & Pietzsch, J. Eph receptors and ephrin ligands: important players in angiogenesis and tumor angiogenesis. J. Oncol. 2010, 135285–135285 (2010).
Sawamiphak, S. et al. Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis. Nature 465, 487–491 (2010).
Marston, D. J., Dickinson, S. & Nobes, C. D. Rac-dependent trans-endocytosis of ephrinBs regulates Eph–ephrin contact repulsion. Nat. Cell Biol. 5, 879–888 (2003).
Mac Gabhann, F. & Popel, A. S. Interactions of VEGF isoforms with VEGFR-1, VEGFR-2, and neuropilin in vivo: a computational model of human skeletal muscle. Am. J. Physiol. Heart Circ. Physiol. 292, H459–H474 (2007).
Filion, R. J. & Popel, A. S. Intracoronary administration of FGF-2: a computational model of myocardial deposition and retention. Am. J. Physiol. Heart Circ. Physiol. 288, H263–H279 (2005).
Fannon, M. et al. Binding inhibition of angiogenic factors by heparan sulfate proteoglycans in aqueous humor: potential mechanism for maintenance of an avascular environment. FASEB J. 17, 902–904 (2003).
Ferrara, N. et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439–442 (1996).
Carmeliet, P. et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435–439 (1996).
Stefanini, M. O., Wu, F. T., Mac Gabhann, F. & Popel, A. S. A compartment model of VEGF distribution in blood, healthy and diseased tissues. BMC Syst. Biol. 2, 77 (2008).
Anderson, S. M. et al. VEGF internalization is not required for VEGFR-2 phosphorylation in bioengineered surfaces with covalently linked VEGF. Integr. Biol. 3, 887–896 (2011).
Chen, T. T. et al. Anchorage of VEGF to the extracellular matrix conveys differential signaling responses to endothelial cells. J. Cell Biol. 188, 595–609 (2010).
Clegg, L. W. & Mac Gabhann, F. Site-specific phosphorylation of VEGFR2 is mediated by receptor trafficking: insights from a computational model. PLoS Comput. Biol. 11, e1004158 (2015). This computational study demonstrates that reduced internalization of VEGFR2 complexes formed by ECM-immobilized VEGFs can account for experimentally observed changes in VEGFR2 signalling compared with VEGFR2 complexes formed by soluble VEGFs.
Smith, J. C., Singh, J. P., Lillquist, J. S., Goon, D. S. & Stiles, C. D. Growth factors adherent to cell substrate are mitogenically active in situ. Nature 296, 154–156 (1982).
Baird, A. & Ling, N. Fibroblast growth factors are present in the extracellular-matrix produced by endothelial cells in vitro — implications for a role of heparinase-like enzymes in the neovascular response. Biochem. Biophys. Res. Commun. 142, 428–435 (1987).
Saksela, O. & Rifkin, D. B. Release of basic fibroblast growth factor–heparan sulfate complexes from endothelial cells by plasminogen activator-mediated proteolytic activity. J. Cell Biol. 110, 767–775 (1990).
Ferrara, N. Binding to the extracellular matrix and proteolytic processing: two key mechanisms regulating vascular endothelial growth factor action. Mol. Biol. Cell 21, 687–690 (2010). This paper focuses on VEGFA as a paradigm to explain how native and proteolytically processed affinities between angiogenic factors and the ECM modulate the angiogenic response.
Vempati, P., Mac Gabhann, F. & Popel, A. S. Quantifying the proteolytic release of extracellular matrix-sequestered VEGF with a computational model. PLoS ONE 5, e11860 (2010).
Miyamoto, S., Teramoto, H., Gutkind, J. S. & Yamada, K. M. Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors. J. Cell Biol. 135, 1633–1642 (1996).
Sepp, N. T. et al. Basic fibroblast growth factor increases expression of the ανβ3 integrin complex on human microvascular endothelial cells. J. Invest. Dermatol. 103, 295–299 (1994).
Masson-Gadais, B., Houle, F., Laferriere, J. & Huot, J. Integrin ανβ3 requirement for VEGFR2-mediated activation of SAPK2/p38 and for Hsp90-dependent phosphorylation of focal adhesion kinase in endothelial cells activated by VEGF. Cell Stress Chaperones 8, 37–52 (2003).
Hodivala-Dilke, K. ανβ3 integrin and angiogenesis: a moody integrin in a changing environment. Curr. Opin. Cell Biol. 20, 514–519 (2008).
Somanath, P. R., Malinin, N. L. & Byzova, T. V. Cooperation between integrin ανβ3 and VEGFR2 in angiogenesis. Angiogenesis 12, 177–185 (2009).
Francis, S. E. et al. Central roles of α5β1 integrin and fibronectin in vascular development in mouse embryos and embryoid bodies. Arterioscler. Thromb. Vasc. Biol. 22, 927–933 (2002).
Tsou, R. & Isik, F. F. Integrin activation is required for VEGF and FGF receptor protein presence on human microvascular endothelial cells. Mol. Cell. Biochem. 224, 81–89 (2001).
Enenstein, J., Waleh, N. S. & Kramer, R. H. Basic FGF and TGF-β differentially modulate integrin expression of microvascular endothelial cells. Exp. Cell Res. 203, 499–503 (1992).
Klein, S. et al. Basic fibroblast growth-factor modulates integrin expression in microvascular endothelial cells. Mol. Biol. Cell 4, 973–982 (1993).
Byzova, T. V. et al. A mechanism for modulation of cellular responses to VEGF: activation of the integrins. Mol. Cell 6, 851–860 (2000).
Valdembri, D. et al. Neuropilin-1/GIPC1 signaling regulates α5β1 integrin traffic and function in endothelial cells. PLoS Biol. 7, 115–132 (2009).
Robinson, S. D. et al. ανβ3 integrin limits the contribution of neuropilin-1 to vascular endothelial growth factor-induced angiogenesis. J. Biol. Chem. 284, 33966–33981 (2009).
Baum, O., Djonov, V., Ganster, M., Widmer, M. & Baumgartner, I. Arteriolization of capillaries and FGF-2 upregulation in skeletal muscles of patients with chronic peripheral arterial disease. Microcirculation 12, 527–537 (2005).
Kikuchi, R. et al. An antiangiogenic isoform of VEGF-A contributes to impaired vascularization in peripheral artery disease. Nat. Med. 20, 1464–1471 (2014).
Ngo, D. T. M. et al. Antiangiogenic actions of vascular endothelial growth factor-A165b, an inhibitory isoform of vascular endothelial growth factor-A, in human obesity. Circulation 130, 1072–1080 (2014).
Zisch, A. H., Lutolf, M. P. & Hubbell, J. A. Biopolymeric delivery matrices for angiogenic growth factors. Cardiovasc. Pathol. 12, 295–310 (2003).
Rice, J. J. et al. Engineering the regenerative microenvironment with biomaterials. Adv. Healthcare Mater. 2, 57–71 (2013).
Hoganson, D. M. et al. The retention of extracellular matrix proteins and angiogenic and mitogenic cytokines in a decellularized porcine dermis. Biomaterials 31, 6730–6737 (2010).
Hern, D. L. & Hubbell, J. A. Incorporation of adhesion peptide into nonadhesive hydrogels useful for tissue resurfacing. J. Biomed. Mater. Res. 39, 266–276 (1998).
Seliktar, D., Zisch, A. H., Lutolf, M. P., Wrana, J. L. & Hubbell, J. A. MMP-2 sensitive, VEGF-bearing bioactive hydrogels for promotion of vascular healing. J. Biomed. Mater. Res. A 68, 704–716 (2004).
Turturro, M. V. et al. MMP-sensitive PEG diacrylate hydrogels with spatial variations in matrix properties stimulate directional vascular sprout formation. PLoS ONE 8, e58897 (2013).
Kyburz, K. A. & Anseth, K. S. Synthetic mimics of the extracellular matrix: how simple is complex enough? Ann. Biomed. Eng. 43, 489–500 (2015).
Pompe, T., Markowski, M. & Werner, C. Modulated fibronectin anchorage at polymer substrates controls angiogenesis. Tissue Eng. 10, 841–848 (2004).
Yu, J. et al. The effect of injected RGD modified alginate on angiogenesis and left ventricular function in a chronic rat infarct model. Biomaterials 30, 751–756 (2009).
Moon, J. J. et al. Biomimetic hydrogels with pro-angiogenic properties. Biomaterials 31, 3840–3847 (2010).
Salimath, A. S. et al. Dual delivery of hepatocyte and vascular endothelial growth factors via a protease-degradable hydrogel improves cardiac function in rats. PLoS ONE 7, e50980 (2012).
Kumar, V. A. et al. Highly angiogenic peptide nanofibers. ACS Nano 9, 860–868 (2015).
Phelps, E. A., Templeman, K. L., Thule, P. M. & Garcia, A. J. Engineered VEGF-releasing PEG-MAL hydrogel for pancreatic islet vascularization. Drug Deliv. Transl. Res. 5, 125–136 (2015).
Wang, W. et al. Peptide REDV-modified polysaccharide hydrogel with endothelial cell selectivity for the promotion of angiogenesis. J. Biomed. Mater. Res. A 103, 1703–1712 (2015).
Park, K. M., Lee, Y., Son, J. Y., Bae, J. W. & Park, K. D. In situ SVVYGLR peptide conjugation into injectable gelatin-poly(ethylene glycol)-tyramine hydrogel via enzyme-mediated reaction for enhancement of endothelial cell activity and neo-vascularization. Bioconjug. Chem. 23, 2042–2050 (2012).
Mochizuki, M. et al. Angiogenic activity of syndecan-binding laminin peptide AG73 (RKRLQVQLSIRT). Arch. Biochem. Biophys. 459, 249–255 (2007).
Humphries, J. D., Byron, A. & Humphries, M. J. Integrin ligands at a glance. J. Cell Sci. 119, 3901–3903 (2006).
Pankov, R. & Yamada, K. M. Fibronectin at a glance. J. Cell Sci. 115, 3861–3863 (2002).
Wijelath, E. et al. Enhancement of capillary and cellular ingrowth in ePTFE implants with a proangiogenic recombinant construct derived from fibronectin. J. Biomed. Mater. Res. A 95, 641–648 (2010).
Najjar, M. et al. Fibrin gels engineered with pro-angiogenic growth factors promote engraftment of pancreatic islets in extrahepatic sites in mice. Biotechnol. Bioeng. 112, 1916–1926 (2015).
Brady, A. C. et al. Proangiogenic hydrogels within macroporous scaffolds enhance islet engraftment in an extrahepatic site. Tissue Eng. Part A 19, 2544–2552 (2013).
Zisch, A. H. et al. Engineered fibrin matrices for functional display of cell membrane-bound growth factor-like activities: study of angiogenic signaling by ephrin-B2. Biomaterials 25, 3245–3257 (2004).
Moon, J. J., Lee, S. H. & West, J. L. Synthetic biomimetic hydrogels incorporated with ephrin-A1 for therapeutic angiogenesis. Biomacromolecules 8, 42–49 (2007).
Mahoney, M. J. & Anseth, K. S. Three-dimensional growth and function of neural tissue in degradable polyethylene glycol hydrogels. Biomaterials 27, 2265–2274 (2006).
MacArthur, J. W. Jr et al. Sustained release of engineered stromal cell-derived factor 1-α from injectable hydrogels effectively recruits endothelial progenitor cells and preserves ventricular function after myocardial infarction. Circulation 128, S79–S86 (2013).
Boontheekul, T., Kong, H. J. & Mooney, D. J. Controlling alginate gel degradation utilizing partial oxidation and bimodal molecular weight distribution. Biomaterials 26, 2455–2465 (2005).
Kim, J. et al. Synthesis and characterization of matrix metalloprotease sensitive-low molecular weight hyaluronic acid based hydrogels. J. Mater. Sci. Mater. Med. 19, 3311–3318 (2008).
Hanjaya-Putra, D. et al. Spatial control of cell-mediated degradation to regulate vasculogenesis and angiogenesis in hyaluronan hydrogels. Biomaterials 33, 6123–6131 (2012).
Song, M. et al. Regeneration of chronic myocardial infarction by injectable hydrogels containing stem cell homing factor SDF-1 and angiogenic peptide Ac-SDKP. Biomaterials 35, 2436–2445 (2014).
Nagase, H. & Fields, G. B. Human matrix metalloproteinase specificity studies using collagen sequence-based synthetic peptides. Biopolymers 40, 399–416 (1996).
Turk, B. E., Huang, L. L., Piro, E. T. & Cantley, L. C. Determination of protease cleavage site motifs using mixture-based oriented peptide libraries. Nat. Biotechnol. 19, 661–667 (2001).
Patterson, J. & Hubbell, J. A. Enhanced proteolytic degradation of molecularly engineered PEG hydrogels in response to MMP-1 and MMP-2. Biomaterials 31, 7836–7845 (2010).
Patterson, J. & Hubbell, J. A. SPARC-derived protease substrates to enhance the plasmin sensitivity of molecularly engineered PEG hydrogels. Biomaterials 32, 1301–1310 (2011).
Sun, Q. et al. Sustained release of multiple growth factors from injectable polymeric system as a novel therapeutic approach towards angiogenesis. Pharm. Res. 27, 264–271 (2010).
Shvartsman, D. et al. Sustained delivery of VEGF maintains innervation and promotes reperfusion in ischemic skeletal muscles via NGF/GDNF signaling. Mol. Ther. 22, 1243–1253 (2014).
Sun, G. et al. Functional neovascularization of biodegradable dextran hydrogels with multiple angiogenic growth factors. Biomaterials 32, 95–106 (2011).
Peattie, R. A. et al. Stimulation of in vivo angiogenesis by cytokine-loaded hyaluronic acid hydrogel implants. Biomaterials 25, 2789–2798 (2004).
Rufaihah, A. J. et al. Enhanced infarct stabilization and neovascularization mediated by VEGF-loaded PEGylated fibrinogen hydrogel in a rodent myocardial infarction model. Biomaterials 34, 8195–8202 (2013).
Kimura, Y. & Tabata, Y. Controlled release of stromal-cell-derived factor-1 from gelatin hydrogels enhances angiogenesis. J. Biomater. Sci. Polym. Ed. 21, 37–51 (2010).
Ennett, A. B., Kaigler, D. & Mooney, D. J. Temporally regulated delivery of VEGF in vitro and in vivo. J. Biomed. Mater. Res. 79, 176–184 (2006).
Macri, L., Silverstein, D. & Clark, R. A. Growth factor binding to the pericellular matrix and its importance in tissue engineering. Adv. Drug Deliv. Rev. 59, 1366–1381 (2007).
Sarrazin, S., Lamanna, W. C. & Esko, J. D. Heparan sulfate proteoglycans. Cold Spring Harb. Perspect. Biol. 3, a004952 (2011).
Pike, D. B. et al. Heparin-regulated release of growth factors in vitro and angiogenic response in vivo to implanted hyaluronan hydrogels containing VEGF and bFGF. Biomaterials 27, 5242–5251 (2006).
Nillesen, S. T. et al. Increased angiogenesis and blood vessel maturation in acellular collagen-heparin scaffolds containing both FGF2 and VEGF. Biomaterials 28, 1123–1131 (2007).
Liu, Y., Cai, S., Shu, X. Z., Shelby, J. & Prestwich, G. D. Release of basic fibroblast growth factor from a crosslinked glycosaminoglycan hydrogel promotes wound healing. Wound Repair Regen. 15, 245–251 (2007).
Ruvinov, E., Leor, J. & Cohen, S. The effects of controlled HGF delivery from an affinity-binding alginate biomaterial on angiogenesis and blood perfusion in a hindlimb ischemia model. Biomaterials 31, 4573–4582 (2010).
Singh, S., Wu, B. M. & Dunn, J. C. The enhancement of VEGF-mediated angiogenesis by polycaprolactone scaffolds with surface cross-linked heparin. Biomaterials 32, 2059–2069 (2011).
Chow, L. W. et al. A bioactive self-assembled membrane to promote angiogenesis. Biomaterials 32, 1574–1582 (2011).
Awada, H. K., Johnson, N. R. & Wang, Y. Sequential delivery of angiogenic growth factors improves revascularization and heart function after myocardial infarction. J. Control. Release 207, 7–17 (2015).
Zieris, A. et al. Dual independent delivery of pro-angiogenic growth factors from starPEG–heparin hydrogels. J. Control. Release 156, 28–36 (2011).
Prokoph, S. et al. Sustained delivery of SDF-1α from heparin-based hydrogels to attract circulating pro-angiogenic cells. Biomaterials 33, 4792–4800 (2012).
Wang, C. et al. Engineering a vascular endothelial growth factor 165-binding heparan sulfate for vascular therapy. Biomaterials 35, 6776–6786 (2014).
Impellitteri, N. A., Toepke, M. W., Lan Levengood, S. K. & Murphy, W. L. Specific VEGF sequestering and release using peptide-functionalized hydrogel microspheres. Biomaterials 33, 3475–3484 (2012).
Belair, D. G., Khalil, A. S., Miller, M. J. & Murphy, W. L. Serum-dependence of affinity-mediated VEGF release from biomimetic microspheres. Biomacromolecules 15, 2038–2048 (2014).
Zisch, A. H. et al. Cell-demanded release of VEGF from synthetic, biointeractive cell ingrowth matrices for vascularized tissue growth. FASEB J. 17, 2260–2262 (2003).
Phelps, E. A., Headen, D. M., Taylor, W. R., Thule, P. M. & Garcia, A. J. Vasculogenic bio-synthetic hydrogel for enhancement of pancreatic islet engraftment and function in type 1 diabetes. Biomaterials 34, 4602–4611 (2013).
Ehrbar, M. et al. Cell-demanded liberation of VEGF121 from fibrin implants induces local and controlled blood vessel growth. Circul. Res. 94, 1124–1132 (2004).
Ehrbar, M. et al. Enzymatic formation of modular cell-instructive fibrin analogs for tissue engineering. Biomaterials 28, 3856–3866 (2007).
Traub, S. et al. The promotion of endothelial cell attachment and spreading using FNIII10 fused to VEGF-A165 . Biomaterials 34, 5958–5968 (2013).
Richardson, T. P., Peters, M. C., Ennett, A. B. & Mooney, D. J. Polymeric system for dual growth factor delivery. Nat. Biotechnol. 19, 1029–1034 (2001).
Hao, X. et al. Angiogenic effects of sequential release of VEGF-A165 and PDGF-BB with alginate hydrogels after myocardial infarction. Cardiovasc. Res. 75, 178–185 (2007).
Brudno, Y., Ennett-Shepard, A. B., Chen, R. R., Aizenberg, M. & Mooney, D. J. Enhancing microvascular formation and vessel maturation through temporal control over multiple pro-angiogenic and pro-maturation factors. Biomaterials 34, 9201–9209 (2013). This study mimics the complexity of physiological angiogenesis by delivering multiple growth factors through biopolymer scaffolds, highlighting the importance of temporally controlled delivery in angiogenesis.
Chen, R. R., Silva, E. A., Yuen, W. W. & Mooney, D. J. Spatio-temporal VEGF and PDGF delivery patterns blood vessel formation and maturation. Pharm. Res. 24, 258–264 (2007).
Ehrbar, M., Metters, A., Zammaretti, P., Hubbell, J. A. & Zisch, A. H. Endothelial cell proliferation and progenitor maturation by fibrin-bound VEGF variants with differential susceptibilities to local cellular activity. J. Control. Release 101, 93–109 (2005).
Moriyama, M. et al. A novel synthetic derivative of human erythropoietin designed to bind to glycosaminoglycans. Drug Deliv. 19, 202–207 (2012).
Zhang, J. et al. Collagen-targeting vascular endothelial growth factor improves cardiac performance after myocardial infarction. Circulation 119, 1776–1784 (2009).
This work was supported by a US Department of Defense (DoD) National Defense Science & Engineering Graduate (NDSEG) Fellowship to L.E.C., by NIH R01HL101200, NIH R00HL093219, and a Sloan Research Fellowship to F.M.G., and by the grant Cytrix from the European Research Council to J.A.H.
The authors declare no competing interests.
About this article
Cite this article
Briquez, P., Clegg, L., Martino, M. et al. Design principles for therapeutic angiogenic materials. Nat Rev Mater 1, 15006 (2016). https://doi.org/10.1038/natrevmats.2015.6
Spatiotemporal regulation of angiogenesis/osteogenesis emulating natural bone healing cascade for vascularized bone formation
Journal of Nanobiotechnology (2021)
Nature Communications (2021)
Nature Reviews Materials (2020)
Nature Biomedical Engineering (2020)
An injectable sulfonated reversible thermal gel for therapeutic angiogenesis to protect cardiac function after a myocardial infarction
Journal of Biological Engineering (2019)