FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 353:782-792 August 25, 2005 Number 8 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Editorial by Aiello, L. P. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background Although vascular endothelial growth factor (VEGF) is a primary mediator of retinal angiogenesis, VEGF inhibition alone is insufficient to prevent retinal neovascularization. Hence, it is postulated that there are other potent ischemia-induced angiogenic factors. Erythropoietin possesses angiogenic activity, but its potential role in ocular angiogenesis is not established.

Methods We measured both erythropoietin and VEGF levels in the vitreous fluid of 144 patients with the use of radioimmunoassay and enzyme-linked immunosorbent assay. Vitreous proliferative potential was measured according to the growth of retinal endothelial cells in vitro and with soluble erythropoietin receptor. In addition, a murine model of ischemia-induced retinal neovascularization was used to evaluate erythropoietin expression and regulation in vivo.

Results The median vitreous erythropoietin level in 73 patients with proliferative diabetic retinopathy was significantly higher than that in 71 patients without diabetes (464.0 vs. 36.5 mIU per milliliter, P<0.001). The median VEGF level in patients with retinopathy was also significantly higher than that in patients without diabetes (345.0 vs. 3.9 pg per milliliter, P<0.001). Multivariate logistic-regression analyses indicated that erythropoietin and VEGF were independently associated with proliferative diabetic retinopathy and that erythropoietin was more strongly associated with the presence of proliferative diabetic retinopathy than was VEGF. Erythropoietin and VEGF gene-expression levels are up-regulated in the murine ischemic retina, and the blockade of erythropoietin inhibits retinal neovascularization in vivo and endothelial-cell proliferation in the vitreous of patients with diabetic retinopathy in vitro.

Conclusions Our data suggest that erythropoietin is a potent ischemia-induced angiogenic factor that acts independently of VEGF during retinal angiogenesis in proliferative diabetic retinopathy.

Source Information

From the Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto (D.W., K.S., M. Kurimoto, J.K., M. Kita, I.S., H.O., T.O., T.M., N.Y., H.T.); the Department of Pharmacoepidemiology, Kyoto University Graduate School of Public Health, Kyoto (S. Matsui); the Laboratory of Biosignals and Response, Kyoto University Graduate School of Biostudies, Kyoto (T.K., S. Masuda, M.N.); the Department of Ophthalmology, Otsu Red Cross Hospital, Otsu (M. Kita); and the Department of Ophthalmology, Hyogo Prefectural Amagasaki Hospital, Amagasaki (H.T.) — all in Japan.

Address reprint requests to Dr. Takagi at the Department of Ophthalmology, Hyogo Prefectural Amagasaki Hospital, Higashidaimotsu-cho, 1-1-1, Amagasaki 660-0828, Japan, or at hitoshi{at}kuhp.kyoto-u.ac.jp.

Full Text of this Article

Related Letters:

Erythropoietin as a Retinal Angiogenic Factor
Manzoni P., Maestri A., Gomirato G., Takagi H., Watanabe D., Matsui S.
Extract | Full Text | PDF  
N Engl J Med 2005; 353:2190-2191, Nov 17, 2005. Correspondence

This article has been cited by other articles:

• Browning, A C, Dua, H S, Amoaku, W M (2008). The effects of growth factors on the proliferation and in vitro angiogenesis of human macular inner choroidal endothelial cells. Br. J. Ophthalmol. 92: 1003-1008 [Abstract] [Full Text]  
• Garcia-Ramirez, M., Hernandez, C., Simo, R. (2008). Expression of Erythropoietin and Its Receptor in the Human Retina: A comparative study of diabetic and nondiabetic subjects. Diabetes Care 31: 1189-1194 [Abstract] [Full Text]  
• Tong, Z., Yang, Z., Patel, S., Chen, H., Gibbs, D., Yang, X., Hau, V. S., Kaminoh, Y., Harmon, J., Pearson, E., Buehler, J., Chen, Y., Yu, B., Tinkham, N. H., Zabriskie, N. A., Zeng, J., Luo, L., Sun, J. K., Prakash, M., Hamam, R. N., Tonna, S., Constantine, R., Ronquillo, C. C., Sadda, S., Avery, R. L., Brand, J. M., London, N., Anduze, A. L., King, G. L., Bernstein, P. S., Watkins, S., Genetics of Diabetes and Diabetic Complication Stu, , Jorde, L. B., Li, D. Y., Aiello, L. P., Pollak, M. R., Zhang, K. (2008). Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications. Proc. Natl. Acad. Sci. USA 105: 6998-7003 [Abstract] [Full Text]  
• Zhang, J., Wu, Y., Jin, Y., Ji, F., Sinclair, S. H., Luo, Y., Xu, G., Lu, L., Dai, W., Yanoff, M., Li, W., Xu, G.-T. (2008). Intravitreal Injection of Erythropoietin Protects both Retinal Vascular and Neuronal Cells in Early Diabetes. IOVS 49: 732-742 [Abstract] [Full Text]  
• Shankar, A. G. (2008). The Role of Recombinant Erythropoietin in Childhood Cancer. The Oncologist 13: 157-166 [Abstract] [Full Text]  
• Nangaku, M., Izuhara, Y., Takizawa, S., Yamashita, T., Fujii-Kuriyama, Y., Ohneda, O., Yamamoto, M., van Ypersele de Strihou, C., Hirayama, N., Miyata, T. (2007). A Novel Class of Prolyl Hydroxylase Inhibitors Induces Angiogenesis and Exerts Organ Protection Against Ischemia. Arterioscler. Thromb. Vasc. Bio. 27: 2548-2554 [Abstract] [Full Text]  
• Kase, S., Saito, W., Ohgami, K., Yoshida, K., Furudate, N., Saito, A., Yokoi, M., Kase, M., Ohno, S. (2007). Expression of erythropoietin receptor in human epiretinal membrane of proliferative diabetic retinopathy. Br. J. Ophthalmol. 91: 1376-1378 [Abstract] [Full Text]  
• Forooghian, F., Razavi, R., Timms, L. (2007). Hypoxia-inducible factor expression in human RPE cells. Br. J. Ophthalmol. 91: 1406-1410 [Abstract] [Full Text]  
• Al-Kateb, H., Mirea, L., Xie, X., Sun, L., Liu, M., Chen, H., Bull, S. B., Boright, A. P., Paterson, A. D., for the DCCT/EDIC Research Group, (2007). Multiple Variants in Vascular Endothelial Growth Factor (VEGFA) Are Risk Factors for Time to Severe Retinopathy in Type 1 Diabetes: The DCCT/EDIC Genetics Study. Diabetes 56: 2161-2168 [Abstract] [Full Text]  
• Kokhaei, P., Abdalla, A. O., Hansson, L., Mikaelsson, E., Kubbies, M., Haselbeck, A., Jernberg-Wiklund, H., Mellstedt, H., Osterborg, A. (2007). Expression of Erythropoietin Receptor and In vitro Functional Effects of Epoetins in B-Cell Malignancies. Clin. Cancer Res. 13: 3536-3544 [Abstract] [Full Text]  
• Abu El-Asrar, A. M, Missotten, L., Geboes, K. (2007). Expression of hypoxia-inducible factor-1{alpha} and the protein products of its target genes in diabetic fibrovascular epiretinal membranes. Br. J. Ophthalmol. 91: 822-826 [Abstract] [Full Text]  
• Fadini, G. P., Sartore, S., Agostini, C., Avogaro, A. (2007). Significance of Endothelial Progenitor Cells in Subjects With Diabetes. Diabetes Care 30: 1305-1313 [Full Text]  
• McLeod, D. (2007). A chronic grey matter penumbra, lateral microvascular intussusception and venous peduncular avulsion underlie diabetic vitreous haemorrhage. Br. J. Ophthalmol. 91: 677-689 [Abstract] [Full Text]  
• Asaumi, Y., Kagaya, Y., Takeda, M., Yamaguchi, N., Tada, H., Ito, K., Ohta, J., Shiroto, T., Shirato, K., Minegishi, N., Shimokawa, H. (2007). Protective Role of Endogenous Erythropoietin System in Nonhematopoietic Cells Against Pressure Overload-Induced Left Ventricular Dysfunction in Mice. Circulation 115: 2022-2032 [Abstract] [Full Text]  
• Zhong, L., Bradley, J., Schubert, W., Ahmed, E., Adamis, A. P., Shima, D. T., Robinson, G. S., Ng, Y.-S. (2007). Erythropoietin Promotes Survival of Retinal Ganglion Cells in DBA/2J Glaucoma Mice. IOVS 48: 1212-1218 [Abstract] [Full Text]  
• Bunn, H. F. (2007). New agents that stimulate erythropoiesis. Blood 109: 868-873 [Abstract] [Full Text]  
• Hernandez, C., Fonollosa, A., Garcia-Ramirez, M., Higuera, M., Catalan, R., Miralles, A., Garcia-Arumi, J., Simo, R. (2006). Erythropoietin Is Expressed in the Human Retina and It Is Highly Elevated in the Vitreous Fluid of Patients With Diabetic Macular Edema.. Diabetes Care 29: 2028-2033 [Abstract] [Full Text]  
• Bierer, R., Peceny, M. C., Hartenberger, C. H., Ohls, R. K. (2006). Erythropoietin Concentrations and Neurodevelopmental Outcome in Preterm Infants. Pediatrics 118: e635-e640 [Abstract] [Full Text]  
• Satoh, K., Kagaya, Y., Nakano, M., Ito, Y., Ohta, J., Tada, H., Karibe, A., Minegishi, N., Suzuki, N., Yamamoto, M., Ono, M., Watanabe, J., Shirato, K., Ishii, N., Sugamura, K., Shimokawa, H. (2006). Important Role of Endogenous Erythropoietin System in Recruitment of Endothelial Progenitor Cells in Hypoxia-Induced Pulmonary Hypertension in Mice. Circulation 113: 1442-1450 [Abstract] [Full Text]  
• Hardee, M. E., Arcasoy, M. O., Blackwell, K. L., Kirkpatrick, J. P., Dewhirst, M. W. (2006). Erythropoietin Biology in Cancer. Clin. Cancer Res. 12: 332-339 [Abstract] [Full Text]  
• Manzoni, P., Maestri, A., Gomirato, G., Takagi, H., Watanabe, D., Matsui, S. (2005). Erythropoietin as a Retinal Angiogenic Factor. NEJM 353: 2190-2191 [Full Text]  
• Martyn, C. (2005). What's new in the other general journals. BMJ 331: 537-538 [Full Text]  
• Aiello, L. P. (2005). Angiogenic Pathways in Diabetic Retinopathy. NEJM 353: 839-841 [Full Text]