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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1996 Sep 3;93(18):9764–9769. doi: 10.1073/pnas.93.18.9764

Involvement of integrins alpha v beta 3 and alpha v beta 5 in ocular neovascular diseases.

M Friedlander 1, C L Theesfeld 1, M Sugita 1, M Fruttiger 1, M A Thomas 1, S Chang 1, D A Cheresh 1
PMCID: PMC38503  PMID: 8790405

Abstract

Angiogenesis underlies the majority of eye diseases that result in catastrophic loss of vision. Recent evidence has implicated the integrins alpha v beta 3 and alpha v beta 5 in the angiogenic process. We examined the expression of alpha v beta 3 and alpha v beta 5 in neovascular ocular tissue from patients with subretinal neovascularization from age-related macular degeneration or the presumed ocular histoplasmosis syndrome or retinal neovascularization from proliferative diabetic retinopathy (PDR). Only alpha v beta 3 was observed on blood vessels in ocular tissues with active neovascularization from patients with age-related macular degeneration or presumed ocular histoplasmosis, whereas both alpha v beta 3 and alpha v beta 5 were present on vascular cells in tissues from patients with PDR. Since we observed both integrins on vascular cells from tissues of patients with retinal neovascularization from PDR, we examined the effects of a systemically administered cyclic peptide antagonist of alpha v beta 3 and alpha v beta 5 on retinal angiogenesis in a murine model. This antagonist specifically blocked new blood vessel formation with no effect on established vessels. These results not only reinforce the concept that retinal and subretinal neovascular diseases are distinct pathological processes, but that antagonists of alpha v beta 3 and/or alpha v beta 5 may be effective in treating individuals with blinding eye disease associated with angiogenesis.

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Selected References

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

  1. Adamis A. P., Miller J. W., Bernal M. T., D'Amico D. J., Folkman J., Yeo T. K., Yeo K. T. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol. 1994 Oct 15;118(4):445–450. doi: 10.1016/s0002-9394(14)75794-0. [DOI] [PubMed] [Google Scholar]
  2. Aiello L. P., Avery R. L., Arrigg P. G., Keyt B. A., Jampel H. D., Shah S. T., Pasquale L. R., Thieme H., Iwamoto M. A., Park J. E. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994 Dec 1;331(22):1480–1487. doi: 10.1056/NEJM199412013312203. [DOI] [PubMed] [Google Scholar]
  3. Aiello L. P., Pierce E. A., Foley E. D., Takagi H., Chen H., Riddle L., Ferrara N., King G. L., Smith L. E. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10457–10461. doi: 10.1073/pnas.92.23.10457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Amin R., Puklin J. E., Frank R. N. Growth factor localization in choroidal neovascular membranes of age-related macular degeneration. Invest Ophthalmol Vis Sci. 1994 Jul;35(8):3178–3188. [PubMed] [Google Scholar]
  5. Bailey A. J., Sloane J. P., Trickey B. S., Ormerod M. G. An immunocytochemical study of alpha-lactalbumin in human breast tissue. J Pathol. 1982 May;137(1):13–23. doi: 10.1002/path.1711370103. [DOI] [PubMed] [Google Scholar]
  6. Brem R. B., Robbins S. G., Wilson D. J., O'Rourke L. M., Mixon R. N., Robertson J. E., Planck S. R., Rosenbaum J. T. Immunolocalization of integrins in the human retina. Invest Ophthalmol Vis Sci. 1994 Aug;35(9):3466–3474. [PubMed] [Google Scholar]
  7. Brooks P. C., Clark R. A., Cheresh D. A. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science. 1994 Apr 22;264(5158):569–571. doi: 10.1126/science.7512751. [DOI] [PubMed] [Google Scholar]
  8. Brooks P. C., Montgomery A. M., Rosenfeld M., Reisfeld R. A., Hu T., Klier G., Cheresh D. A. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell. 1994 Dec 30;79(7):1157–1164. doi: 10.1016/0092-8674(94)90007-8. [DOI] [PubMed] [Google Scholar]
  9. Brooks P. C., Strömblad S., Klemke R., Visscher D., Sarkar F. H., Cheresh D. A. Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin. J Clin Invest. 1995 Oct;96(4):1815–1822. doi: 10.1172/JCI118227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cheresh D. A. Human endothelial cells synthesize and express an Arg-Gly-Asp-directed adhesion receptor involved in attachment to fibrinogen and von Willebrand factor. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6471–6475. doi: 10.1073/pnas.84.18.6471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Drake C. J., Cheresh D. A., Little C. D. An antagonist of integrin alpha v beta 3 prevents maturation of blood vessels during embryonic neovascularization. J Cell Sci. 1995 Jul;108(Pt 7):2655–2661. doi: 10.1242/jcs.108.7.2655. [DOI] [PubMed] [Google Scholar]
  12. Elner S. G., Elner V. M. The integrin superfamily and the eye. Invest Ophthalmol Vis Sci. 1996 Apr;37(5):696–701. [PubMed] [Google Scholar]
  13. Feeney L. Lipofuscin and melanin of human retinal pigment epithelium. Fluorescence, enzyme cytochemical, and ultrastructural studies. Invest Ophthalmol Vis Sci. 1978 Jul;17(7):583–600. [PubMed] [Google Scholar]
  14. Friedlander M., Brooks P. C., Shaffer R. W., Kincaid C. M., Varner J. A., Cheresh D. A. Definition of two angiogenic pathways by distinct alpha v integrins. Science. 1995 Dec 1;270(5241):1500–1502. doi: 10.1126/science.270.5241.1500. [DOI] [PubMed] [Google Scholar]
  15. Hammes H. P., Brownlee M., Jonczyk A., Sutter A., Preissner K. T. Subcutaneous injection of a cyclic peptide antagonist of vitronectin receptor-type integrins inhibits retinal neovascularization. Nat Med. 1996 May;2(5):529–533. doi: 10.1038/nm0596-529. [DOI] [PubMed] [Google Scholar]
  16. Jiang B., Bezhadian M. A., Caldwell R. B. Astrocytes modulate retinal vasculogenesis: effects on endothelial cell differentiation. Glia. 1995 Sep;15(1):1–10. doi: 10.1002/glia.440150102. [DOI] [PubMed] [Google Scholar]
  17. Klein R., Klein B. E., Moss S. E., Cruickshanks K. J. The Wisconsin Epidemiologic Study of diabetic retinopathy. XIV. Ten-year incidence and progression of diabetic retinopathy. Arch Ophthalmol. 1994 Sep;112(9):1217–1228. doi: 10.1001/archopht.1994.01090210105023. [DOI] [PubMed] [Google Scholar]
  18. Mudhar H. S., Pollock R. A., Wang C., Stiles C. D., Richardson W. D. PDGF and its receptors in the developing rodent retina and optic nerve. Development. 1993 Jun;118(2):539–552. doi: 10.1242/dev.118.2.539. [DOI] [PubMed] [Google Scholar]
  19. Pasqualini R., Bodorova J., Ye S., Hemler M. E. A study of the structure, function and distribution of beta 5 integrins using novel anti-beta 5 monoclonal antibodies. J Cell Sci. 1993 May;105(Pt 1):101–111. doi: 10.1242/jcs.105.1.101. [DOI] [PubMed] [Google Scholar]
  20. Pe'er J., Shweiki D., Itin A., Hemo I., Gnessin H., Keshet E. Hypoxia-induced expression of vascular endothelial growth factor by retinal cells is a common factor in neovascularizing ocular diseases. Lab Invest. 1995 Jun;72(6):638–645. [PubMed] [Google Scholar]
  21. Reddy V. M., Zamora R. L., Kaplan H. J. Distribution of growth factors in subfoveal neovascular membranes in age-related macular degeneration and presumed ocular histoplasmosis syndrome. Am J Ophthalmol. 1995 Sep;120(3):291–301. doi: 10.1016/s0002-9394(14)72158-0. [DOI] [PubMed] [Google Scholar]
  22. Sehested M., Hou-Jensen K. Factor VII related antigen as an endothelial cell marker in benign and malignant diseases. Virchows Arch A Pathol Anat Histol. 1981;391(2):217–225. doi: 10.1007/BF00437598. [DOI] [PubMed] [Google Scholar]
  23. Stone J., Dreher Z. Relationship between astrocytes, ganglion cells and vasculature of the retina. J Comp Neurol. 1987 Jan 1;255(1):35–49. doi: 10.1002/cne.902550104. [DOI] [PubMed] [Google Scholar]
  24. Watanabe T., Raff M. C. Retinal astrocytes are immigrants from the optic nerve. Nature. 1988 Apr 28;332(6167):834–837. doi: 10.1038/332834a0. [DOI] [PubMed] [Google Scholar]
  25. Wayner E. A., Orlando R. A., Cheresh D. A. Integrins alpha v beta 3 and alpha v beta 5 contribute to cell attachment to vitronectin but differentially distribute on the cell surface. J Cell Biol. 1991 May;113(4):919–929. doi: 10.1083/jcb.113.4.919. [DOI] [PMC free article] [PubMed] [Google Scholar]

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