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. 1994 Feb;93(2):662–670. doi: 10.1172/JCI117018

Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model.

S Takeshita 1, L P Zheng 1, E Brogi 1, M Kearney 1, L Q Pu 1, S Bunting 1, N Ferrara 1, J F Symes 1, J M Isner 1
PMCID: PMC293894  PMID: 7509344

Abstract

Vascular endothelial growth factor (VEGF) is a heparin-binding, endothelial cell-specific mitogen. Previous studies have suggested that VEGF is a regulator of naturally occurring physiologic and pathologic angiogenesis. In this study we investigated the hypothesis that the angiogenic potential of VEGF is sufficient to constitute a therapeutic effect. The soluble 165-amino acid isoform of VEGF was administered as a single intra-arterial bolus to the internal iliac artery of rabbits in which the ipsilateral femoral artery was excised to induce severe, unilateral hind limb ischemia. Doses of 500-1,000 micrograms of VEGF produced statistically significant augmentation of collateral vessel development by angiography as well as the number of capillaries by histology; consequent amelioration of the hemodynamic deficit in the ischemic limb was significantly greater in animals receiving VEGF than in nontreated controls (calf blood pressure ratio, 0.75 +/- 0.14 vs. 0.48 +/- 0.19, P < 0.05). Serial angiograms disclosed progressive linear extension of the collateral artery of origin (stem artery) to the distal point of parent vessel (reentry artery) reconstitution in seven of nine VEGF-treated animals. These findings establish proof of principle for the concept that the angiogenic activity of VEGF is sufficiently potent to achieve therapeutic benefit. Such a strategy might ultimately be applicable to patients with severe limb ischemia secondary to arterial occlusive disease.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baffour R., Berman J., Garb J. L., Rhee S. W., Kaufman J., Friedmann P. Enhanced angiogenesis and growth of collaterals by in vivo administration of recombinant basic fibroblast growth factor in a rabbit model of acute lower limb ischemia: dose-response effect of basic fibroblast growth factor. J Vasc Surg. 1992 Aug;16(2):181–191. [PubMed] [Google Scholar]
  2. Berkman R. A., Merrill M. J., Reinhold W. C., Monacci W. T., Saxena A., Clark W. C., Robertson J. T., Ali I. U., Oldfield E. H. Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms. J Clin Invest. 1993 Jan;91(1):153–159. doi: 10.1172/JCI116165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Breier G., Albrecht U., Sterrer S., Risau W. Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. Development. 1992 Feb;114(2):521–532. doi: 10.1242/dev.114.2.521. [DOI] [PubMed] [Google Scholar]
  4. Brown L. F., Yeo K. T., Berse B., Yeo T. K., Senger D. R., Dvorak H. F., van de Water L. Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing. J Exp Med. 1992 Nov 1;176(5):1375–1379. doi: 10.1084/jem.176.5.1375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Conn G., Soderman D. D., Schaeffer M. T., Wile M., Hatcher V. B., Thomas K. A. Purification of a glycoprotein vascular endothelial cell mitogen from a rat glioma-derived cell line. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1323–1327. doi: 10.1073/pnas.87.4.1323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Connolly D. T., Heuvelman D. M., Nelson R., Olander J. V., Eppley B. L., Delfino J. J., Siegel N. R., Leimgruber R. M., Feder J. Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest. 1989 Nov;84(5):1470–1478. doi: 10.1172/JCI114322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Connolly D. T., Olander J. V., Heuvelman D., Nelson R., Monsell R., Siegel N., Haymore B. L., Leimgruber R., Feder J. Human vascular permeability factor. Isolation from U937 cells. J Biol Chem. 1989 Nov 25;264(33):20017–20024. [PubMed] [Google Scholar]
  8. Dvorak H. F., Sioussat T. M., Brown L. F., Berse B., Nagy J. A., Sotrel A., Manseau E. J., Van de Water L., Senger D. R. Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels. J Exp Med. 1991 Nov 1;174(5):1275–1278. doi: 10.1084/jem.174.5.1275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ferrara N., Henzel W. J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989 Jun 15;161(2):851–858. doi: 10.1016/0006-291x(89)92678-8. [DOI] [PubMed] [Google Scholar]
  10. Ferrara N., Houck K. A., Jakeman L. B., Winer J., Leung D. W. The vascular endothelial growth factor family of polypeptides. J Cell Biochem. 1991 Nov;47(3):211–218. doi: 10.1002/jcb.240470305. [DOI] [PubMed] [Google Scholar]
  11. Ferrara N., Houck K., Jakeman L., Leung D. W. Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev. 1992 Feb;13(1):18–32. doi: 10.1210/edrv-13-1-18. [DOI] [PubMed] [Google Scholar]
  12. Ferrara N., Leung D. W., Cachianes G., Winer J., Henzel W. J. Purification and cloning of vascular endothelial growth factor secreted by pituitary folliculostellate cells. Methods Enzymol. 1991;198:391–405. doi: 10.1016/0076-6879(91)98040-d. [DOI] [PubMed] [Google Scholar]
  13. Ferrara N., Winer J., Burton T., Rowland A., Siegel M., Phillips H. S., Terrell T., Keller G. A., Levinson A. D. Expression of vascular endothelial growth factor does not promote transformation but confers a growth advantage in vivo to Chinese hamster ovary cells. J Clin Invest. 1993 Jan;91(1):160–170. doi: 10.1172/JCI116166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Flanagan M. F., Fujii A. M., Colan S. D., Flanagan R. G., Lock J. E. Myocardial angiogenesis and coronary perfusion in left ventricular pressure-overload hypertrophy in the young lamb. Evidence for inhibition with chronic protamine administration. Circ Res. 1991 May;68(5):1458–1470. doi: 10.1161/01.res.68.5.1458. [DOI] [PubMed] [Google Scholar]
  15. Flaumenhaft R., Moscatelli D., Saksela O., Rifkin D. B. Role of extracellular matrix in the action of basic fibroblast growth factor: matrix as a source of growth factor for long-term stimulation of plasminogen activator production and DNA synthesis. J Cell Physiol. 1989 Jul;140(1):75–81. doi: 10.1002/jcp.1041400110. [DOI] [PubMed] [Google Scholar]
  16. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971 Nov 18;285(21):1182–1186. doi: 10.1056/NEJM197111182852108. [DOI] [PubMed] [Google Scholar]
  17. Fujita M., Mikuniya A., Takahashi M., Gaddis R., Hartley J., Mckown D., Franklin D. Acceleration of coronary collateral development by heparin in conscious dogs. Jpn Circ J. 1987 Apr;51(4):395–402. doi: 10.1253/jcj.51.395. [DOI] [PubMed] [Google Scholar]
  18. Fujita M., Sasayama S., Asanoi H., Nakajima H., Sakai O., Ohno A. Improvement of treadmill capacity and collateral circulation as a result of exercise with heparin pretreatment in patients with effort angina. Circulation. 1988 May;77(5):1022–1029. doi: 10.1161/01.cir.77.5.1022. [DOI] [PubMed] [Google Scholar]
  19. Houck K. A., Ferrara N., Winer J., Cachianes G., Li B., Leung D. W. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol. 1991 Dec;5(12):1806–1814. doi: 10.1210/mend-5-12-1806. [DOI] [PubMed] [Google Scholar]
  20. Houck K. A., Leung D. W., Rowland A. M., Winer J., Ferrara N. Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem. 1992 Dec 25;267(36):26031–26037. [PubMed] [Google Scholar]
  21. Ishikawa F., Miyazono K., Hellman U., Drexler H., Wernstedt C., Hagiwara K., Usuki K., Takaku F., Risau W., Heldin C. H. Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor. Nature. 1989 Apr 13;338(6216):557–562. doi: 10.1038/338557a0. [DOI] [PubMed] [Google Scholar]
  22. Isner J. M., Rosenfield K. Redefining the treatment of peripheral artery disease. Role of percutaneous revascularization. Circulation. 1993 Oct;88(4 Pt 1):1534–1557. doi: 10.1161/01.cir.88.4.1534. [DOI] [PubMed] [Google Scholar]
  23. Keck P. J., Hauser S. D., Krivi G., Sanzo K., Warren T., Feder J., Connolly D. T. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989 Dec 8;246(4935):1309–1312. doi: 10.1126/science.2479987. [DOI] [PubMed] [Google Scholar]
  24. Kim K. J., Li B., Winer J., Armanini M., Gillett N., Phillips H. S., Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993 Apr 29;362(6423):841–844. doi: 10.1038/362841a0. [DOI] [PubMed] [Google Scholar]
  25. LONGLAND C. J. The collateral circulation of the limb; Arris and Gale lecture delivered at the Royal College of Surgeons of England on 4th February, 1953. Ann R Coll Surg Engl. 1953 Sep;13(3):161–176. [PMC free article] [PubMed] [Google Scholar]
  26. Leung D. W., Cachianes G., Kuang W. J., Goeddel D. V., Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989 Dec 8;246(4935):1306–1309. doi: 10.1126/science.2479986. [DOI] [PubMed] [Google Scholar]
  27. Levy A. P., Tamargo R., Brem H., Nathans D. An endothelial cell growth factor from the mouse neuroblastoma cell line NB41. Growth Factors. 1989;2(1):9–19. doi: 10.3109/08977198909069077. [DOI] [PubMed] [Google Scholar]
  28. Lindner V., Lappi D. A., Baird A., Majack R. A., Reidy M. A. Role of basic fibroblast growth factor in vascular lesion formation. Circ Res. 1991 Jan;68(1):106–113. doi: 10.1161/01.res.68.1.106. [DOI] [PubMed] [Google Scholar]
  29. Lindner V., Reidy M. A. Proliferation of smooth muscle cells after vascular injury is inhibited by an antibody against basic fibroblast growth factor. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3739–3743. doi: 10.1073/pnas.88.9.3739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. MILES A. A., MILES E. M. Vascular reactions to histamine, histamine-liberator and leukotaxine in the skin of guinea-pigs. J Physiol. 1952 Oct;118(2):228–257. doi: 10.1113/jphysiol.1952.sp004789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Millauer B., Wizigmann-Voos S., Schnürch H., Martinez R., Møller N. P., Risau W., Ullrich A. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell. 1993 Mar 26;72(6):835–846. doi: 10.1016/0092-8674(93)90573-9. [DOI] [PubMed] [Google Scholar]
  32. Phillips H. S., Hains J., Leung D. W., Ferrara N. Vascular endothelial growth factor is expressed in rat corpus luteum. Endocrinology. 1990 Aug;127(2):965–967. doi: 10.1210/endo-127-2-965. [DOI] [PubMed] [Google Scholar]
  33. Plate K. H., Breier G., Weich H. A., Risau W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature. 1992 Oct 29;359(6398):845–848. doi: 10.1038/359845a0. [DOI] [PubMed] [Google Scholar]
  34. Ravindranath N., Little-Ihrig L., Phillips H. S., Ferrara N., Zeleznik A. J. Vascular endothelial growth factor messenger ribonucleic acid expression in the primate ovary. Endocrinology. 1992 Jul;131(1):254–260. doi: 10.1210/endo.131.1.1612003. [DOI] [PubMed] [Google Scholar]
  35. Shweiki D., Itin A., Neufeld G., Gitay-Goren H., Keshet E. Patterns of expression of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis. J Clin Invest. 1993 May;91(5):2235–2243. doi: 10.1172/JCI116450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Shweiki D., Itin A., Soffer D., Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992 Oct 29;359(6398):843–845. doi: 10.1038/359843a0. [DOI] [PubMed] [Google Scholar]
  37. Soker S., Svahn C. M., Neufeld G. Vascular endothelial growth factor is inactivated by binding to alpha 2-macroglobulin and the binding is inhibited by heparin. J Biol Chem. 1993 Apr 15;268(11):7685–7691. [PubMed] [Google Scholar]
  38. Terman B. I., Dougher-Vermazen M., Carrion M. E., Dimitrov D., Armellino D. C., Gospodarowicz D., Böhlen P. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun. 1992 Sep 30;187(3):1579–1586. doi: 10.1016/0006-291x(92)90483-2. [DOI] [PubMed] [Google Scholar]
  39. Tischer E., Mitchell R., Hartman T., Silva M., Gospodarowicz D., Fiddes J. C., Abraham J. A. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem. 1991 Jun 25;266(18):11947–11954. [PubMed] [Google Scholar]
  40. Unger E. F., Sheffield C. D., Epstein S. E. Heparin promotes the formation of extracardiac to coronary anastomoses in a canine model. Am J Physiol. 1991 May;260(5 Pt 2):H1625–H1634. doi: 10.1152/ajpheart.1991.260.5.H1625. [DOI] [PubMed] [Google Scholar]
  41. Yanagisawa-Miwa A., Uchida Y., Nakamura F., Tomaru T., Kido H., Kamijo T., Sugimoto T., Kaji K., Utsuyama M., Kurashima C. Salvage of infarcted myocardium by angiogenic action of basic fibroblast growth factor. Science. 1992 Sep 4;257(5075):1401–1403. doi: 10.1126/science.1382313. [DOI] [PubMed] [Google Scholar]
  42. Ziada A. M., Hudlicka O., Tyler K. R., Wright A. J. The effect of long-term vasodilatation on capillary growth and performance in rabbit heart and skeletal muscle. Cardiovasc Res. 1984 Dec;18(12):724–732. doi: 10.1093/cvr/18.12.724. [DOI] [PubMed] [Google Scholar]
  43. de Vries C., Escobedo J. A., Ueno H., Houck K., Ferrara N., Williams L. T. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science. 1992 Feb 21;255(5047):989–991. doi: 10.1126/science.1312256. [DOI] [PubMed] [Google Scholar]

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