Skip to main content
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1994 Sep;145(3):574–584.

Vascular Endothelial Growth Factor/Vascular Permeability Factor Is Temporally and Spatially Correlated with Ocular Angiogenesis in a Primate Model

Joan W Miller, Anthony P Adamis, David T Shima, Patricia A D'Amore, Rachel S Moulton, Michael S O'Reilly, Judah Folkman, Harold F Dvorak, Lawrence F Brown, Brygida Berse, Tet-Kin Yeo, Kiang-Teck Yeo
PMCID: PMC1890317  PMID: 7521577

Abstract

Ischemia often precedes neovascularization. Inocular neovascularization, such as occurs in diabetic retinopathy, a diffusible angiogenic factor has been postulated to be produced by ischemicretina and to lead to neovascularization of theretina, optic nerve, or iris. However, no angiogenic factor has been conclusively identified that satisfies this hypothesis. Vascular endothelial growth factor/vascular permeability factor, hereafter referred to as VEGF, is a likely candidate for an ocular angiogenic factor because it is a secreted mitogen, specific for endothelial cells, and is upregulated by hypoxia. We investigated the association of VEGF with the development of experimental iris neovascularization in the cynomolgus monkey. Following theproduction of retinal ischemia by laser occlusion of all branch retinal veins, VEGF was increased in the aqueous fluid, and the aqueous VEGF levels changed synchronously and proportionally with the severity of iris neovascularization. Northern analysis and in situ hybridization revealed that VEGF messenger RNA is upregulated in the ischemic retina. These observations support the hypothesis that ocular neovascularization is regulated by a diffusible factor and identify VEGF as a likely candidate for a retina-derived vascular permeability and angiogenesis factor in vivo.

Full text

PDF
574

Images in this article

Selected References

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

  1. ASHTON N. Retinal vascularization in health and disease: Proctor Award Lecture of the Association for Research in Ophthalmology. Am J Ophthalmol. 1957 Oct;44(4 Pt 2):7–17. doi: 10.1016/0002-9394(57)90426-9. [DOI] [PubMed] [Google Scholar]
  2. Berse B., Brown L. F., Van de Water L., Dvorak H. F., Senger D. R. Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell. 1992 Feb;3(2):211–220. doi: 10.1091/mbc.3.2.211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brown L. F., Berse B., Jackman R. W., Tognazzi K., Manseau E. J., Senger D. R., Dvorak H. F. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract. Cancer Res. 1993 Oct 1;53(19):4727–4735. [PubMed] [Google Scholar]
  4. 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]
  5. D'Amore P. A., Glaser B. M., Brunson S. K., Fenselau A. H. Angiogenic activity from bovine retina: partial purification and characterization. Proc Natl Acad Sci U S A. 1981 May;78(5):3068–3072. doi: 10.1073/pnas.78.5.3068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. D'Anna S. A., Hochheimer B. F., Joondeph H. C., Graebner K. E. Fluorescein angiography of the heavily pigmented iris and new dyes for iris angiography. Arch Ophthalmol. 1983 Feb;101(2):289–293. doi: 10.1001/archopht.1983.01040010291022. [DOI] [PubMed] [Google Scholar]
  7. Dvorak H. F., Orenstein N. S., Carvalho A. C., Churchill W. H., Dvorak A. M., Galli S. J., Feder J., Bitzer A. M., Rypysc J., Giovinco P. Induction of a fibrin-gel investment: an early event in line 10 hepatocarcinoma growth mediated by tumor-secreted products. J Immunol. 1979 Jan;122(1):166–174. [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., 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]
  10. Ffrench-Constant C., Van de Water L., Dvorak H. F., Hynes R. O. Reappearance of an embryonic pattern of fibronectin splicing during wound healing in the adult rat. J Cell Biol. 1989 Aug;109(2):903–914. doi: 10.1083/jcb.109.2.903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Jakeman L. B., Winer J., Bennett G. L., Altar C. A., Ferrara N. Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues. J Clin Invest. 1992 Jan;89(1):244–253. doi: 10.1172/JCI115568. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. 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]
  13. 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]
  14. 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]
  15. 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]
  16. Miller J. W., Stinson W. G., Folkman J. Regression of experimental iris neovascularization with systemic alpha-interferon. Ophthalmology. 1993 Jan;100(1):9–14. doi: 10.1016/s0161-6420(93)31712-4. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Pournaras C. J., Tsacopoulos M., Riva C. E., Roth A. Diffusion of O2 in normal and ischemic retinas of anesthetized miniature pigs in normoxia and hyperoxia. Graefes Arch Clin Exp Ophthalmol. 1990;228(2):138–142. doi: 10.1007/BF00935723. [DOI] [PubMed] [Google Scholar]
  19. Pournaras C. J., Tsacopoulos M., Strommer K., Gilodi N., Leuenberger P. M. Experimental retinal branch vein occlusion in miniature pigs induces local tissue hypoxia and vasoproliferative microangiopathy. Ophthalmology. 1990 Oct;97(10):1321–1328. doi: 10.1016/s0161-6420(90)32415-6. [DOI] [PubMed] [Google Scholar]
  20. Pournaras C. J., Tsacopoulos M., Strommer K., Gilodi N., Leuenberger P. M. Scatter photocoagulation restores tissue hypoxia in experimental vasoproliferative microangiopathy in miniature pigs. Ophthalmology. 1990 Oct;97(10):1329–1333. doi: 10.1016/s0161-6420(90)32414-4. [DOI] [PubMed] [Google Scholar]
  21. Senger D. R., Galli S. J., Dvorak A. M., Perruzzi C. A., Harvey V. S., Dvorak H. F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983 Feb 25;219(4587):983–985. doi: 10.1126/science.6823562. [DOI] [PubMed] [Google Scholar]
  22. Senger D. R., Van de Water L., Brown L. F., Nagy J. A., Yeo K. T., Yeo T. K., Berse B., Jackman R. W., Dvorak A. M., Dvorak H. F. Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer Metastasis Rev. 1993 Sep;12(3-4):303–324. doi: 10.1007/BF00665960. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Sioussat T. M., Dvorak H. F., Brock T. A., Senger D. R. Inhibition of vascular permeability factor (vascular endothelial growth factor) with antipeptide antibodies. Arch Biochem Biophys. 1993 Feb 15;301(1):15–20. doi: 10.1006/abbi.1993.1109. [DOI] [PubMed] [Google Scholar]
  25. Sivalingam A., Kenney J., Brown G. C., Benson W. E., Donoso L. Basic fibroblast growth factor levels in the vitreous of patients with proliferative diabetic retinopathy. Arch Ophthalmol. 1990 Jun;108(6):869–872. doi: 10.1001/archopht.1990.01070080113046. [DOI] [PubMed] [Google Scholar]
  26. Virdi P. S., Hayreh S. S. Ocular neovascularization with retinal vascular occlusion. I. Association with experimental retinal vein occlusion. Arch Ophthalmol. 1982 Feb;100(2):331–341. doi: 10.1001/archopht.1982.01030030333024. [DOI] [PubMed] [Google Scholar]
  27. Weindel K., Marmé D., Weich H. A. AIDS-associated Kaposi's sarcoma cells in culture express vascular endothelial growth factor. Biochem Biophys Res Commun. 1992 Mar 31;183(3):1167–1174. doi: 10.1016/s0006-291x(05)80313-4. [DOI] [PubMed] [Google Scholar]
  28. Yeo K. T., Sioussat T. M., Faix J. D., Senger D. R., Yeo T. K. Development of time-resolved immunofluorometric assay of vascular permeability factor. Clin Chem. 1992 Jan;38(1):71–75. [PubMed] [Google Scholar]
  29. Yeo K. T., Wang H. H., Nagy J. A., Sioussat T. M., Ledbetter S. R., Hoogewerf A. J., Zhou Y., Masse E. M., Senger D. R., Dvorak H. F. Vascular permeability factor (vascular endothelial growth factor) in guinea pig and human tumor and inflammatory effusions. Cancer Res. 1993 Jun 15;53(12):2912–2918. [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES