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  Vol. 113 No. 12, December 1995 TABLE OF CONTENTS
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Hypoxic Regulation of Vascular Endothelial Growth Factor in Retinal Cells

Lloyd Paul Aiello, MD, PhD; Jill M. Northrup; Bruce A. Keyt, PhD; Hitoshi Takagi, MD, PhD; Mami A. Iwamoto, MD

Arch Ophthalmol. 1995;113(12):1538-1544.


Abstract



Background
Vascular endothelial growth factor (VEGF) is an angiogenic protein and vasopermeability factor whose intraocular concentrations are closely correlated with active neovascularization in patients with diabetes mellitus, central retinal vein occlusion, retinopathy of prematurity, and rubeosis iridis.

Objective
To determine whether hypoxia could induce expression of VEGF in retinal cells, which then promotes retinal endothelial cell proliferation.

Methods
Retinal pigment epithelial cells, pericytes, and microvascular endothelial cells were exposed to hypoxic conditions in vitro, and RNA expression of VEGF was evaluated by Northern blot analysis. The VEGF-specific proliferative potential of the medium was measured by means of retinal endothelial cell growth assays and VEGF-neutralizing VEGF receptor IgG chimeric protein.

Results
The VEGF RNA levels increased within 4 hours and reached elevations of threefold to 30-fold after 18 hours of hypoxia (0% to 5% oxygen, 5% carbon dioxide, 90% to 95% nitrogen) in all cell types (.01<P<.03). Stimulation was dependent on oxygen concentration. The VEGF RNA levels were normalized by reinstitution of normoxia for 24 hours (P<.004). Medium conditioned by hypoxic retinal pericytes and retinal pigment epithelial cells stimulated retinal endothelial cell growth by 20% (P=.04), and this stimulation was entirely inhibited by VEGF-neutralizing receptor chimeric protein (P=.02).

Conclusion
Hypoxia increases VEGF expression in retinal cells, which promotes retinal endothelial cell proliferation, suggesting that VEGF plays a major role in mediating intraocular neovascularization resulting from ischemic retinal diseases.



Author Affiliations



From the Research Division (Drs Aiello and Tagaki and Ms Northrup) and Beetham Eye Institute (Dr Aiello), Joslin Diabetes Center, Boston, Mass; Department of Ophthalmology, Harvard Medical School, Boston (Drs Aiello and Iwamoto); Department of Cardiovascular Research, Genentech Inc, San Francisco, Calif (Dr Keyt); and Division of Ophthalmology, Brigham & Women's Hospital, Boston (Dr Iwamoto).



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