Abstract
Retinopathy of prematurity (ROP) is initiated by hyperoxia–induced obliteration of newly formed blood vessels in the retina of the premature newborn. We propose that vessel regression is a consequence of hyperoxia–induced withdrawal of a critical vascular survival factor. We show that regression of retinal capillaries in neonatal rats exposed to high oxygen, is preceded by a shut–off of vascular endothelial growth factor (VEGF) production by nearby neuroglial cells. Vessel regression occurs via selective apoptosis of endothelial cells. Intraocular injection of VEGF at the onset of experimental hyperoxia prevents apoptotic death of endothelial cells and rescues the retinal vasculature. These findings provide evidence for a specific angiogenic factor acting as a vascular survival factor in vivo. The system also provides a paradigm for vascular remodelling as an adaptive response to an increase in oxygen tension and suggests a novel approach to prevention of ROP.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
£139.00 per year
only £11.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Gibson, D.L., Sheps, S.B., Uh, S.H., Schechter, M.T. & McCormick, A.Q. Retinopathy of prematurity-induced blindness: Birth weight-specific survival and the new epidemic. Pediatrics 86, 405–412 (1990).
Michaelson, I.C. The mode of development of the vascular system of the retina: With some observations on its significance for certain retinal diseases. Trans. Ophthalmol. Soc. U.K. 68, 137–80 (1948).
Ashton, N., Ward, B. & Serpell, G. Effect of oxygen on developing reinal vessels with particular reference to the problem of retrolental fibroplasia. Br. J. Ophthalmol. 38, 397–431 (1954).
Adamis, A.P. et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am. J. Ophthalmol. 118. 445–450 (1994).
Aiello, L.P. et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. New Engl. J. Med. 331, 1480–1487 (1994).
Pe'er, J. et al. Hypoxia-induced expression of vascular endothelial growth factor by retinal cells is a common factor in neovascularizing ocular diseases. Lab. Invest. 72, 638–645 (1995).
Gospodarowic, D., Abraham, J.A. & Schilling, J. Isolation and characterization of vascular endothelial mitogen produced by pituitary-derived folliculo stellate cells. Proc. natn. Acad. Sci. U.S.A. 86, 7311–7315 (1989).
Keck, P.J. et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246, 1309–1312 (1989).
Leung, D.W., Cachianes, G., Kaung, W.J., Goeddel, D.V. & Ferrara, N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246. 1306–1309 (1989).
Dvorak, H.F. et al. Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: Concentration in tumor blood vessels. J. exp. Med. 174, 1275–1278 (1991).
Shweiki, D., Itin, A., Soffer, D. & Keshet, E. Vascular endothelial growth factor induced by hypoxia mediates hypoxia-initiated angiogenesis. Nature 359, 843–845 (1992).
Plate, K.H., Breier, G., Widch, H.A. & Risau, W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359, 845–848 (1992).
Miller, J.W. et al. Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am. J. Ophthalmol. 145, 574–578 (1994).
Stone, J. et al. Development of retinal vasculature is mediated by hypoxia-induced endothelial growth factor expression by neuroglia. J. Neurosci. 15, 4738–4747 (1995).
Phelps, D.L. Oxygen and developmental retinal capillary remodeling in the kitten. Invest. Ophthalmol. Vis. Sci. 31, 2194–2200 (1990).
Ashton, N. & Blach, R. Studies on developing retinal vessels. VIII. Effect of oxygen on the retinal vessels of the ratling. Br. J. Ophthalmol. 45, 321–340 (1961).
Gavrieli, Y., Sherman, Y. & Ben-Sasson, S.A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J. Cell Biol. 119, 493–501 (1992).
Chan-Ling, T., Tout, S., Holländer, H. & Stone, J. Vascular changes and their mechanisms in the feline model of retinopathy of prematurity. Invest. Ophthal. vis. Sci. 33, 2128–2147 (1992).
Penn, J.S., Tolman, B.L. & Lowery, L.A. Variable oxygen exposure causes pre-retinal neovascularization in the newborn rat. Invest. Ophthalmol. vis. Sci. 34, 576–585 (1993).
Raff, C.M. Social controls on cell survival and cell death. Nature 356, 397–399 (1992).
Villaschi, S. & Nicosia, R.F. Angiogenic role of endogenous basic fibroblast growth factor released by rat aorta after injury. Am. J. Pathol. 143, 181–190 (1993).
Pierce, A.P., Avery, R.L., Foley, E.D., Aiello, L.P. & Smith, L.E.H. Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. Proc. natn. Acad. Sci. U.S.A. 92, 905–909 (1995).
Stone, J. et al. The role of vascular endothelial growth factor and astrocyte degeneration in the pathogenesis of retinopathy of prematurity. Vis. Sci. (in the press).
Frangakis, M.V. & Kimelberg, H.M. Dissociation of neonatal rat brain by dispase for the preparation of primary astrocyte cultures. Neurochem. Research. 9, 1689–1698 (1984).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Alon, T., Hemo, I., Itin, A. et al. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 1, 1024–1028 (1995). https://doi.org/10.1038/nm1095-1024
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nm1095-1024