Skip to main navigation menu Skip to main content Skip to site footer

Review article: Biomedical intelligence

Vol. 149 No. 0304 (2019)

Vascular endothelial growth factor biology for regenerative angiogenesis

  • Andrea Uccelli
  • Thomas Wolff
  • Paolo Valente
  • Nunzia Di Maggio
  • Matteo Pellegrino
  • Lorenz Gürke
  • Andrea Banfi
  • Roberto Gianni-Barrera
DOI
https://doi.org/10.4414/smw.2019.20011
Cite this as:
Swiss Med Wkly. 2019;149:w20011
Published
27.01.2019

Summary

Despite major advances in medical, catheter-based or surgical treatment, cardiovascular diseases such as peripheral artery disease and coronary artery disease still cause significant morbidity and mortality. Furthermore, many patients do not qualify for catheter-based treatment or bypass surgery because of advanced disease or surgical risk. There is therefore an urgent need for novel treatment strategies. Therapeutic angiogenesis aims to restore blood flow to ischaemic tissue by stimulating the growth of new blood vessels through the local delivery of angiogenic factors, and may thus be an attractive treatment alternative for these patients. Angiogenesis is a complex process and the growth of normal, stable and functional vasculature depends on the coordinated interplay of different cell types and growth factors. Vascular endothelial growth factor-A (VEGF) is the fundamental regulator of vascular growth and the key target of therapeutic angiogenesis approaches. However, first-generation clinical trials of VEGF gene therapy have been disappointing, and a clear clinical benefit has yet to be established. In particular, VEGF delivery (a) appears to have a very limited therapeutic window in vivo: low doses are safe but mostly inefficient, whereas higher doses become rapidly unsafe; and (b) requires a sustained expression in vivo of at least about four weeks to achieve stable vessels that persist after cessation of the angiogenic stimulus. Here we will review the current understanding of how VEGF induces the growth of normal or pathological blood vessels, what limitations for the controlled induction of safe and efficient angiogenesis are intrinsically linked to the biological properties of VEGF, and how this knowledge can guide the design of more effective strategies for therapeutic angiogenesis.

References

  1. Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, et al.; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association. Circulation. 2018;137(12):e67–492. doi:.https://doi.org/10.1161/CIR.0000000000000558
  2. Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989;246(4935):1309–12. doi:.https://doi.org/10.1126/science.2479987
  3. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246(4935):1306–9. doi:.https://doi.org/10.1126/science.2479986
  4. Isner JM, Pieczek A, Schainfeld R, Blair R, Haley L, Asahara T, et al. Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb. Lancet. 1996;348(9024):370–4. doi:.https://doi.org/10.1016/S0140-6736(96)03361-2
  5. Losordo DW, Vale PR, Symes JF, Dunnington CH, Esakof DD, Maysky M, et al. Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation. 1998;98(25):2800–4. doi:.https://doi.org/10.1161/01.CIR.98.25.2800
  6. Gupta R, Tongers J, Losordo DW. Human studies of angiogenic gene therapy. Circ Res. 2009;105(8):724–36. doi:.https://doi.org/10.1161/CIRCRESAHA.109.200386
  7. Rubanyi GM. Mechanistic, technical, and clinical perspectives in therapeutic stimulation of coronary collateral development by angiogenic growth factors. Mol Ther. 2013;21(4):725–38. doi:.https://doi.org/10.1038/mt.2013.13
  8. Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell. 2011;146(6):873–87. doi:.https://doi.org/10.1016/j.cell.2011.08.039
  9. Ylä-Herttuala S, Bridges C, Katz MG, Korpisalo P. Angiogenic gene therapy in cardiovascular diseases: dream or vision? Eur Heart J. 2017;38(18):1365–71. doi:.https://doi.org/10.1093/eurheartj/ehw547
  10. Cai W, Schaper W. Mechanisms of arteriogenesis. Acta Biochim Biophys Sin (Shanghai). 2008;40(8):681–92. doi:.https://doi.org/10.1093/abbs/40.8.681
  11. Persson AB, Buschmann IR. Vascular growth in health and disease. Front Mol Neurosci. 2011;4:14. doi:.https://doi.org/10.3389/fnmol.2011.00014
  12. Annex BH. Therapeutic angiogenesis for critical limb ischaemia. Nat Rev Cardiol. 2013;10(7):387–96. doi:.https://doi.org/10.1038/nrcardio.2013.70
  13. Pries AR, Höpfner M, le Noble F, Dewhirst MW, Secomb TW. The shunt problem: control of functional shunting in normal and tumour vasculature. Nat Rev Cancer. 2010;10(8):587–93. doi:.https://doi.org/10.1038/nrc2895
  14. Rissanen TT, Korpisalo P, Markkanen JE, Liimatainen T, Ordén MR, Kholová I, et al. Blood flow remodels growing vasculature during vascular endothelial growth factor gene therapy and determines between capillary arterialization and sprouting angiogenesis. Circulation. 2005;112(25):3937–46. doi:.https://doi.org/10.1161/CIRCULATIONAHA.105.543124
  15. Baumgartner I, Pieczek A, Manor O, Blair R, Kearney M, Walsh K, et al. Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation. 1998;97(12):1114–23. doi:.https://doi.org/10.1161/01.CIR.97.12.1114
  16. Mäkinen K, Manninen H, Hedman M, Matsi P, Mussalo H, Alhava E, et al. Increased vascularity detected by digital subtraction angiography after VEGF gene transfer to human lower limb artery: a randomized, placebo-controlled, double-blinded phase II study. Mol Ther. 2002;6(1):127–33. doi:.https://doi.org/10.1006/mthe.2002.0638
  17. Tsurumi Y, Takeshita S, Chen D, Kearney M, Rossow ST, Passeri J, et al. Direct intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor augments collateral development and tissue perfusion. Circulation. 1996;94(12):3281–90. doi:.https://doi.org/10.1161/01.CIR.94.12.3281
  18. Lähteenvuo J, Ylä-Herttuala S. Advances and Challenges in Cardiovascular Gene Therapy. Hum Gene Ther. 2017;28(11):1024–32. doi:.https://doi.org/10.1089/hum.2017.129
  19. Ogawa S, Oku A, Sawano A, Yamaguchi S, Yazaki Y, Shibuya M. A novel type of vascular endothelial growth factor, VEGF-E (NZ-7 VEGF), preferentially utilizes KDR/Flk-1 receptor and carries a potent mitotic activity without heparin-binding domain. J Biol Chem. 1998;273(47):31273–82. doi:.https://doi.org/10.1074/jbc.273.47.31273
  20. Yamazaki Y, Tokunaga Y, Takani K, Morita T. C-terminal heparin-binding peptide of snake venom VEGF specifically blocks VEGF-stimulated endothelial cell proliferation. Pathophysiol Haemost Thromb. 2005;34(4-5):197–9. doi:.https://doi.org/10.1159/000092423
  21. Ferrara N. Binding to the extracellular matrix and proteolytic processing: two key mechanisms regulating vascular endothelial growth factor action. Mol Biol Cell. 2010;21(5):687–90. doi:.https://doi.org/10.1091/mbc.e09-07-0590
  22. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983;219(4587):983–5. doi:.https://doi.org/10.1126/science.6823562
  23. Koch S, Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med. 2012;2(7):a006502. doi:.https://doi.org/10.1101/cshperspect.a006502
  24. Grünewald FS, Prota AE, Giese A, Ballmer-Hofer K. Structure-function analysis of VEGF receptor activation and the role of coreceptors in angiogenic signaling. Biochim Biophys Acta. 2010;1804(3):567–80. doi:.https://doi.org/10.1016/j.bbapap.2009.09.002
  25. Ito N, Wernstedt C, Engström U, Claesson-Welsh L. Identification of vascular endothelial growth factor receptor-1 tyrosine phosphorylation sites and binding of SH2 domain-containing molecules. J Biol Chem. 1998;273(36):23410–8. doi:.https://doi.org/10.1074/jbc.273.36.23410
  26. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76. doi:.https://doi.org/10.1038/nm0603-669
  27. Cudmore MJ, Hewett PW, Ahmad S, Wang KQ, Cai M, Al-Ani B, et al. The role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis. Nat Commun. 2012;3(1):972. doi:.https://doi.org/10.1038/ncomms1977
  28. Haiko P, Makinen T, Keskitalo S, Taipale J, Karkkainen MJ, Baldwin ME, et al. Deletion of vascular endothelial growth factor C (VEGF-C) and VEGF-D is not equivalent to VEGF receptor 3 deletion in mouse embryos. Mol Cell Biol. 2008;28(15):4843–50. doi:.https://doi.org/10.1128/MCB.02214-07
  29. Takahashi H, Shibuya M. The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin Sci (Lond). 2005;109(3):227–41. doi:.https://doi.org/10.1042/CS20040370
  30. Krilleke D, Ng YS, Shima DT. The heparin-binding domain confers diverse functions of VEGF-A in development and disease: a structure-function study. Biochem Soc Trans. 2009;37(6):1201–6. doi:.https://doi.org/10.1042/BST0371201
  31. Harper SJ, Bates DO. VEGF-A splicing: the key to anti-angiogenic therapeutics? Nat Rev Cancer. 2008;8(11):880–7. doi:.https://doi.org/10.1038/nrc2505
  32. Park JE, Keller GA, Ferrara N. The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol Biol Cell. 1993;4(12):1317–26. doi:.https://doi.org/10.1091/mbc.4.12.1317
  33. Ruhrberg C, Gerhardt H, Golding M, Watson R, Ioannidou S, Fujisawa H, et al. Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev. 2002;16(20):2684–98. doi:.https://doi.org/10.1101/gad.242002
  34. De Spiegelaere W, Casteleyn C, Van den Broeck W, Plendl J, Bahramsoltani M, Simoens P, et al. Intussusceptive angiogenesis: a biologically relevant form of angiogenesis. J Vasc Res. 2012;49(5):390–404. doi:.https://doi.org/10.1159/000338278
  35. Gianni-Barrera R, Bartolomeo M, Vollmar B, Djonov V, Banfi A. Split for the cure: VEGF, PDGF-BB and intussusception in therapeutic angiogenesis. Biochem Soc Trans. 2014;42(6):1637–42. doi:.https://doi.org/10.1042/BST20140234
  36. Blanco R, Gerhardt H. VEGF and Notch in tip and stalk cell selection. Cold Spring Harb Perspect Med. 2013;3(1):a006569. doi:.https://doi.org/10.1101/cshperspect.a006569
  37. Hellström M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature. 2007;445(7129):776–80. doi:.https://doi.org/10.1038/nature05571
  38. Egginton S. Invited review: activity-induced angiogenesis. Pflugers Arch. 2009;457(5):963–77. doi:.https://doi.org/10.1007/s00424-008-0563-9
  39. Makanya AN, Hlushchuk R, Djonov VG. Intussusceptive angiogenesis and its role in vascular morphogenesis, patterning, and remodeling. Angiogenesis. 2009;12(2):113–23. doi:.https://doi.org/10.1007/s10456-009-9129-5
  40. Gianni-Barrera R, Trani M, Fontanellaz C, Heberer M, Djonov V, Hlushchuk R, et al. VEGF over-expression in skeletal muscle induces angiogenesis by intussusception rather than sprouting. Angiogenesis. 2013;16(1):123–36. doi:.https://doi.org/10.1007/s10456-012-9304-y
  41. Bentley K, Gerhardt H, Bates PA. Agent-based simulation of notch-mediated tip cell selection in angiogenic sprout initialisation. J Theor Biol. 2008;250(1):25–36. doi:.https://doi.org/10.1016/j.jtbi.2007.09.015
  42. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996;380(6573):435–9. doi:.https://doi.org/10.1038/380435a0
  43. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O’Shea KS, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996;380(6573):439–42. doi:.https://doi.org/10.1038/380439a0
  44. Miquerol L, Langille BL, Nagy A. Embryonic development is disrupted by modest increases in vascular endothelial growth factor gene expression. Development. 2000;127(18):3941–6.
  45. Schwarz ER, Speakman MT, Patterson M, Hale SS, Isner JM, Kedes LH, et al. Evaluation of the effects of intramyocardial injection of DNA expressing vascular endothelial growth factor (VEGF) in a myocardial infarction model in the rat--angiogenesis and angioma formation. J Am Coll Cardiol. 2000;35(5):1323–30. doi:.https://doi.org/10.1016/S0735-1097(00)00522-2
  46. Springer ML, Chen AS, Kraft PE, Bednarski M, Blau HM. VEGF gene delivery to muscle: potential role for vasculogenesis in adults. Mol Cell. 1998;2(5):549–58. doi:.https://doi.org/10.1016/S1097-2765(00)80154-9
  47. Lee RJ, Springer ML, Blanco-Bose WE, Shaw R, Ursell PC, Blau HM. VEGF gene delivery to myocardium: deleterious effects of unregulated expression. Circulation. 2000;102(8):898–901. doi:.https://doi.org/10.1161/01.CIR.102.8.898
  48. Ozawa CR, Banfi A, Glazer NL, Thurston G, Springer ML, Kraft PE, et al. Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant angiogenesis. J Clin Invest. 2004;113(4):516–27. doi:.https://doi.org/10.1172/JCI18420
  49. von Degenfeld G, Banfi A, Springer ML, Wagner RA, Jacobi J, Ozawa CR, et al. Microenvironmental VEGF distribution is critical for stable and functional vessel growth in ischemia. FASEB J. 2006;20(14):2657–9. doi:.https://doi.org/10.1096/fj.06-6568fje
  50. Sacchi V, Mittermayr R, Hartinger J, Martino MM, Lorentz KM, Wolbank S, et al. Long-lasting fibrin matrices ensure stable and functional angiogenesis by highly tunable, sustained delivery of recombinant VEGF164. Proc Natl Acad Sci USA. 2014;111(19):6952–7. doi:.https://doi.org/10.1073/pnas.1404605111
  51. Dor Y, Djonov V, Abramovitch R, Itin A, Fishman GI, Carmeliet P, et al. Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy. EMBO J. 2002;21(8):1939–47. doi:.https://doi.org/10.1093/emboj/21.8.1939
  52. Tafuro S, Ayuso E, Zacchigna S, Zentilin L, Moimas S, Dore F, et al. Inducible adeno-associated virus vectors promote functional angiogenesis in adult organisms via regulated vascular endothelial growth factor expression. Cardiovasc Res. 2009;83(4):663–71. doi:.https://doi.org/10.1093/cvr/cvp152
  53. Benjamin LE, Golijanin D, Itin A, Pode D, Keshet E. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest. 1999;103(2):159–65. doi:.https://doi.org/10.1172/JCI5028
  54. Benjamin LE, Hemo I, Keshet E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development. 1998;125(9):1591–8.
  55. Hellström M, Kalén M, Lindahl P, Abramsson A, Betsholtz C. Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development. 1999;126(14):3047–55.
  56. Lindahl P, Johansson BR, Levéen P, Betsholtz C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science. 1997;277(5323):242–5. doi:.https://doi.org/10.1126/science.277.5323.242
  57. Gaengel K, Genové G, Armulik A, Betsholtz C. Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol. 2009;29(5):630–8. doi:.https://doi.org/10.1161/ATVBAHA.107.161521
  58. Goumans MJ, Valdimarsdottir G, Itoh S, Rosendahl A, Sideras P, ten Dijke P. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J. 2002;21(7):1743–53. doi:.https://doi.org/10.1093/emboj/21.7.1743
  59. van Meeteren LA, ten Dijke P. Regulation of endothelial cell plasticity by TGF-β. Cell Tissue Res. 2012;347(1):177–86. doi:.https://doi.org/10.1007/s00441-011-1222-6
  60. Zacchigna S, Pattarini L, Zentilin L, Moimas S, Carrer A, Sinigaglia M, et al. Bone marrow cells recruited through the neuropilin-1 receptor promote arterial formation at the sites of adult neoangiogenesis in mice. J Clin Invest. 2008;118(6):2062–75. doi:.https://doi.org/10.1172/JCI32832
  61. Groppa E, Brkic S, Bovo E, Reginato S, Sacchi V, Di Maggio N, et al. VEGF dose regulates vascular stabilization through Semaphorin3A and the Neuropilin-1+ monocyte/TGF-β1 paracrine axis. EMBO Mol Med. 2015;7(10):1366–84. doi:.https://doi.org/10.15252/emmm.201405003
  62. Kivelä R, Bry M, Robciuc MR, Räsänen M, Taavitsainen M, Silvola JM, et al. VEGF-B-induced vascular growth leads to metabolic reprogramming and ischemia resistance in the heart. EMBO Mol Med. 2014;6(3):307–21. doi:.https://doi.org/10.1002/emmm.201303147
  63. Lähteenvuo JE, Lähteenvuo MT, Kivelä A, Rosenlew C, Falkevall A, Klar J, et al. Vascular endothelial growth factor-B induces myocardium-specific angiogenesis and arteriogenesis via vascular endothelial growth factor receptor-1- and neuropilin receptor-1-dependent mechanisms. Circulation. 2009;119(6):845–56. doi:.https://doi.org/10.1161/CIRCULATIONAHA.108.816454
  64. Rissanen TT, Markkanen JE, Gruchala M, Heikura T, Puranen A, Kettunen MI, et al. VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Circ Res. 2003;92(10):1098–106. doi:.https://doi.org/10.1161/01.RES.0000073584.46059.E3
  65. Hartikainen J, Hassinen I, Hedman A, Kivelä A, Saraste A, Knuuti J, et al. Adenoviral intramyocardial VEGF-DΔNΔC gene transfer increases myocardial perfusion reserve in refractory angina patients: a phase I/IIa study with 1-year follow-up. Eur Heart J. 2017;38(33):2547–55. doi:.https://doi.org/10.1093/eurheartj/ehx352
  66. Banfi A, von Degenfeld G, Gianni-Barrera R, Reginato S, Merchant MJ, McDonald DM, et al. Therapeutic angiogenesis due to balanced single-vector delivery of VEGF and PDGF-BB. FASEB J. 2012;26(6):2486–97. doi:.https://doi.org/10.1096/fj.11-197400
  67. Gianni-Barrera R, Butschkau A, Uccelli A, Certelli A, Valente P, Bartolomeo M, et al. PDGF-BB regulates splitting angiogenesis in skeletal muscle by limiting VEGF-induced endothelial proliferation. Angiogenesis. 2018;21(4):883–900. doi:.https://doi.org/10.1007/s10456-018-9634-5
  68. Kupatt C, Hinkel R, Pfosser A, El-Aouni C, Wuchrer A, Fritz A, et al. Cotransfection of vascular endothelial growth factor-A and platelet-derived growth factor-B via recombinant adeno-associated virus resolves chronic ischemic malperfusion role of vessel maturation. J Am Coll Cardiol. 2010;56(5):414–22. doi:.https://doi.org/10.1016/j.jacc.2010.03.050
  69. Groppa E, Brkic S, Uccelli A, Wirth G, Korpisalo-Pirinen P, Filippova M, et al. EphrinB2/EphB4 signaling regulates non-sprouting angiogenesis by VEGF. EMBO Rep. 2018;19(5):e45054. doi:.https://doi.org/10.15252/embr.201745054

Most read articles by the same author(s)