Summary
The release of growth factors from ischaemic retina has been hypothesized as the central stimulus for retinal neovascularization in proliferative diabetic retinopathy. Two of the growth factors implicated are insulin-like growth factor-I and basic fibroblast growth factor. We examined the effect of insulin-like growth factor-I on in vivo neovascularization using the established angiogenic model of the rabbit cornea (n=30), and also compared the effects of insulin-like growth factor-I and basic fibroblast growth factor using two new in vivo systems. Either supraphysiologic concentrations of each growth factor (600 μg) were injected intravitreally into pigmented rabbits (n=21) or porous polyfluorotetraethylene chambers filled with an emulsion containing collagen and growth factor (500 ng) were placed on the retina surface (n=8). Our results demonstrate that when insulin-like growth factor-I was implanted together with a slow release carrier into the pocket of the normally avascular cornea, insulin-like growth factor-I (10 μg/pellet) induced angiogenesis in all rabbits. This degree of angiogenesis was comparable to that previously shown for basic fibroblast growth factor. For the intravitreal studies, the fibrotic component was greater in the basic fibroblast growth factor injected eyes, whereas the vascular component was accentuated in the eyes injected with insulin-like growth factor-I. Light and electron microscopy demonstrated areas of vascular proliferation in both groups. Porous polyfluorotetraethylene chamber studies with insulin-like growth factor-I and basic fibroblast growth factor demonstrated vascular proliferation in the vicinity of the chamber similar to the intravitreal injected eyes, but to a lesser degree than the injected eyes. Our experiments overall support the angiogenic potential of both insulin-like growth factor-I and basic fibroblast growth factor and support distinct but complimentary roles for each growth factor in the pathogenesis of proliferative diabetic retinopathy.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Poulsen JE (1953) The Houssay phenomenon in man: recovery from retinopathy in a case of diabetes with Simmons disease. Diabetes 2: 7–12
Kohner EM, Joplin GF, Cheng H, Blach RK, Fraser TR (1972) Pituitary ablation in the treatment of diabetic retinopathy. Trans Ophthalmol Soc UK 92: 79–90
Lundback K, Malmros R, Anderson HC (1969) Hypophysectomy for diabetic angiopathy: a controlled clinical trial. In: Goldberg MF, Fine SL (eds) Symposium on the treatment of diabetic retinopathy. Public Health Service, Publ No 1890, Washington, DC, pp 291–312
Tamborlane WV, Hintz RL, Bergman M, Gene LM, Felig P, Sherwin RS (1981) Insulin-infusion-pump treatment of diabetes: influence of improved metabolic control on plasma somatomedin levels. N Engl J Med 305: 303–307
Merimee TJ, Zapf J, Froesch ER (1983) Insulin-like growth factors: studies in diabetics with and without retinopathy. N Engl J Med 309: 527–530
Dills DG, Moss SE, Klein R, Klein BEK (1991) Association of elevated IGF-I levels with increased retinopathy in late-onset diabetes. Diabetes 40: 1725–1730
Hyer SL, Sharp PS, Brooks RA, Burrin JM, Kohner EM (1989) A two-year follow-up study of serum insulin-like growth factor-I in diabetics with retinopathy. Metabolism 38: 586–589
Grant MB, Russell B, Fitzgerald C, Merimee TJ (1986) Insulin-like growth factors in vitreous: studies in controls and diabetics with neovascularization. Diabetes 35: 416–420
King GL, Goodman AD, Buzney S, Moses A, Kahn CR (1985) Receptors and growth promoting effects of insulin and insulin-like growth factors on cells from bovine retinal capillaries and aorta. J Clin Invest 75: 1028–1036
Grant MB, Jerdan J, Merimee TJ (1987) Insulin-like growth factor I modulates endothelial cell chemotaxis. J Clin Endocrinol Metab 65: 370–371
Grant MB, Guay C (1991) Plasminogen activator production by human retinal endothelial cells of non-diabetic and diabetic origin. Invest Ophthalmol Vis Sci 32: 53–64
Bauer PI, Machoric R, Bokikg C, Sanka E, Koch SA, Horvath I (1984) Interaction of plasmin with endothelial cells. Biochem J 218: 119–124
Moscatelli D, Jaffe E, Rifkin DB (1980) Tetradecanoyl pharbol acetate stimulates latent collagenase production by cultured human-endothelial cells. Cell 20: 343–351
Gaudric A, Falquerho F, Clement G et al. (1988) Fibroblast growth factors, transforming growth factor-beta in human vitreous from patients with proliferative diabetic retinopathy. Invest Ophthalmol Vis Sci 29 [Suppl]: 221 (Abstract)
Sivalingam A, Kenney J, Brown GC, Benson WE, Donoso L (1990) Basic fibroblast growth factor levels in the vitreous of patients with proliferative diabetic retinopathy. Arch Ophthalmol 108: 869–872
Hanneken A, deJuan E, Hutty GA, Fox GM, Schiffer S, Hjelmeland HL (1991) Altered distribution of basic fibroblast growth factor in diabetic retinopathy. Arch Ophthalmol 109: 1005–1011
Gospodarowicz D (1974) Localization of a fibroblast growth factor and its effect alone and with hydrocortisone on 3T3 cell growth. Nature 249: 123–127
Gospodarowicz D (1976) Humoral control of cell proliferation: the role of fibroblast growth factor in regeneration, angiogenesis, wound healing and neoplastic growth. Prog Clin Biol Res 9: 1–19
D'Amore P, Klagsbrun M (1984) Endothelial cell mitogens derived from retina and hypothalamus: biochemical and biological similarities. J Cell Biol 99: 1545–1549
Herman IM, D'Amore P (1984) Capillary endothelial cell migration: loss of stress fibers in response to retinal-derived growth factor. J Muscle Res Cell Motil 5: 697–709
Presta M, Moscatelli D, Joseph-Silverstein J, Rifkin DB (1986) Purification from a human hepatoma cell line of a basic fibroblast growth factor-like molecule that stimulates capillary endothelial cell plasminogen activator production, DNA synthesis, and migration. Mol Cell Biol 6: 4060–4066
Risau W (1986) Developing brain produces an angiogenic factor. Proc Natl Acad Sci USA 83: 3855–3859
Gospodarowitz D, Bialecki H, Thakral TK (1979) The angiogenic activity of the fibroblast and epidermal growth factor. Exp Eye Res 28: 501–514
Langer R, Folkman J (1976) Polymers for the sustained release of proteins and other macromolecules. Nature 263: 797–800
Gimbrone MA, Ramzi SC, Leapman SB, Folkman J (1974) Tumor growth and neovascularization: an experimental model using the rabbit cornea. J Natl Cancer Inst 52: 412–419
McDowell EM, Trump BF (1976) Histologic fixatives suitable for diagnostic light and electron microscopy. Arch Pathol Lab Med 100: 405–414
Reynolds ES (1963) The use of lead citrate at high pH as an electron opaque stain in electron microscopy. J Cell Biol 17: 208–212
Hansson HA, Brandsten C, Lossing C, Petruson K (1989) Transient expression of insulin-like growth factor: immunoreactivity by vascular cells during angiogenesis. Exp Mol Path 50: 125–138
Chen CH, Chen SC (1980) Angiogenic activity of vitreous and retinal extract. Invest Ophthalmol Vis Sci 6: 596–602
Felton S, Brown G, Felberg N, Federman J (1979) Vitreous inhibition of tumor neovascularization. Arch Ophthalmol 97: 1710–1713
Brem S, Preis I, Langer R, Brem H, Folkman J, Patz A (1977) Inhibition of neovascularization by an extract derived from vitreous. Am J Ophthalmol 84: 323–328
Rechler MM, Nissley SP (1990) Insulin-like growth factors. In: Sporn MB, Roberts AB (eds) Peptide growth factors and their receptors. Vol 95. Springer-Verlag, Heidelberg, pp 263–267
Arnold DR, Moshayedi P, Schoen T, Jones BE, Chader J, Waldbillig RJ (1992) Distribution of insulinlike growth factor (IGF) I and II, IGF binding proteins (IGF-BP) and IGF mRNA in ocular fluids and tissues: potential sites of synthesis of IGF-BP in aqueous and vitreous. Exp Eye Res (in press)
Engerman RL, Pfaffenback D, Davis MD (1967) Cell turnover of capillaries. Lab Invest 17: 738–743
Orlidge A, D'Amore PA (1987) Inhibition of capillary endothelial cells growth by pericytes and smooth muscle cells. J Cell Biol 105: 1455–1462
Ashton N (1961) Neovascularization in ocular disease. Trans Ophthalmo Soc (UK) 81: 145–161
Antonelli-Orlidge A, Saunders KB, Smith SR, D'Amore PA (1989) An activated form of transforming growth factor beta is produced by cocultures of endothelial cells and pericytes. Proc Natl Acad Sci USA 86: 4544–4548
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Grant, M.B., Mames, R.N., Fitzgerald, C. et al. Insulin-like growth factor I acts as an angiogenic agent in rabbit cornea and retina: comparative studies with basic fibroblast growth factor. Diabetologia 36, 282–291 (1993). https://doi.org/10.1007/BF00400229
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00400229