Vascular Endothelial Growth Factor in Ocular Fluid of Patients with Diabetic Retinopathy and Other Retinal Disorders
Lloyd Paul Aiello, Robert L. Avery, Paul G. Arrigg, Bruce A. Keyt, Henry D. Jampel, Sabera T. Shah, Louis R. Pasquale, Hagen Thieme, Mami A. Iwamoto, John E. Park, Hung V. Nguyen, Lloyd M. Aiello, Napoleone Ferrara, and George L. King
Background Retinal ischemia induces intraocular neovascularization,which often leads to glaucoma, vitreous hemorrhage, and retinaldetachment, presumably by stimulating the release of angiogenicmolecules. Vascular endothelial growth factor (VEGF) is an endothelial-cell-specificangiogenic factor whose production is increased by hypoxia.
Methods We measured the concentration of VEGF in 210 specimensof ocular fluid obtained from 164 patients undergoing intraocularsurgery, using both radioimmunoassays and radioreceptor assays.Vitreous proliferative potential was measured with in vitroassays of the growth of retinal endothelial cells and with VEGF-neutralizingantibody.
Results VEGF was detected in 69 of 136 ocular-fluid samplesfrom patients with diabetic retinopathy, 29 of 38 samples frompatients with neovascularization of the iris, and 3 of 4 samplesfrom patients with ischemic occlusion of the central retinalvein, as compared with 2 of 31 samples from patients with noneovascular disorders (P<0.001, P<0.001, and P = 0.006,respectively). The mean (±SD) VEGF concentration in 70samples of ocular fluid from patients with active proliferativediabetic retinopathy (3.6 ±6.3 ng per milliliter) washigher than that in 25 samples from patients with nonproliferativediabetic retinopathy (0.1 ±0.1 ng per milliliter, P =0.008), 41 samples from patients with quiescent proliferativediabetic retinopathy (0.2 ±0.6 ng per milliliter, P<0.001),or 31 samples from nondiabetic patients (0.1 ±0.2 ngper milliliter, P = 0.003). Concentrations of VEGF in vitreousfluid (8.8 ±9.9 ng per milliliter) were higher than thosein aqueous fluid (5.6 ±8.6 ng per milliliter, P = 0.033)in all 10 pairs of samples obtained simultaneously from thesame patient; VEGF concentrations in vitreous fluid declinedafter successful laser photocoagulation. VEGF stimulated thegrowth of retinal endothelial cells in vitro, as did vitreousfluid containing measurable VEGF. Stimulation was inhibitedby VEGF-neutralizing antibodies.
Conclusions Our data suggest that VEGF plays a major part inmediating active intraocular neovascularization in patientswith ischemic retinal diseases, such as diabetic retinopathyand retinal-vein occlusion.
Source Information
From the Department of Ophthalmology, Beetham Eye Institute (L.P.A., P.G.A., S.T.S., L.M.A.), and the Division of Research (L.P.A., H.T., G.L.K.), Joslin Diabetes Center; the Departments of Medicine and Ophthalmology, Brigham and Women's Hospital (L.R.P., M.A.I., G.L.K.); and Harvard Medical School (L.P.A., P.G.A., S.T.S., L.R.P., H.T., M.A.I., L.M.A., G.L.K.) -- all in Boston; the Neuroscience Research Institute, University of California, Santa Barbara (R.L.A.); Genentech, Inc., San Francisco (B.A.K., J.E.P., H.V.N., N.F.); and the Department of Ophthalmology, Wilmer Ophthalmological Institute, Johns Hopkins Hospital, Baltimore (H.D.J.).
Address reprint requests to Dr. L.P. Aiello at the Beetham Eye Institute, Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215.
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(2005). Effect of Insulin on Plasma Vascular Endothelial Growth Factor in Children with New-Onset Diabetes. J. Clin. Endocrinol. Metab.
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(2005). Minocycline Reduces Proinflammatory Cytokine Expression, Microglial Activation, and Caspase-3 Activation in a Rodent Model of Diabetic Retinopathy. Diabetes
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