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Erythropoietin as a Retinal Angiogenic Factor in Proliferative Diabetic Retinopathy

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.

Article:-

Pathologic growth of new blood vessels is a common final pathway in ocular neovascular diseases, such as proliferative diabetic retinopathy, that often result in catastrophic loss of vision. Vascular endothelial growth factor (VEGF) is a primary angiogenic factor that mediates such ischemia-induced retinal neovascularization. VEGF levels are elevated in the vitreous fluid of patients with proliferative diabetic retinopathy, and VEGF induces proliferation in vascular endothelial cells in vitro.1 Although inhibition of VEGF reduces retinal neovascularization,2,3 it does not completely inhibit ischemia-driven retinal neovascularization. Thus, the involvement of other angiogenic factors in this process seems likely.

The glycoprotein erythropoietin stimulates the formation of red cells by enhancing both their proliferation and their differentiation and by preventing apoptotic death of erythropoietin-responsive erythroid precursor cells.4-6 A major signal that regulates the production of erythropoietin in these tissues is hypoxia, and the brain has a paracrine system involving erythropoietin and erythropoietin receptors, suggesting that erythropoietin contributes to the survival of neurons by protecting them from ischemic damage.7-9 Furthermore, erythropoietin shows angiogenic activity in vascular endothelial cells, stimulating proliferation, migration, and angiogenesis in vitro, probably by means of the erythropoietin receptor expressed in those cells.10,11 Such angiogenic activity involves several signal-transduction cascades such as extracellular signal-regulated kinase, Janus kinase 2 (known as JAK2), and signal transducer and activator of transcription 5 (STAT5).12-15 Moreover, the inhibition of erythropoietin by soluble erythropoietin receptor abrogates angiogenesis in vivo.16,17

Since erythropoietin is an ischemia-induced paracrine factor that promotes angiogenesis, we wished to identify its potential role during retinal angiogenesis in proliferative diabetic retinopathy. Therefore, we examined in vitro the expression and function of erythropoietin in the vitreous fluid of patients with proliferative diabetic retinopathy and evaluated the role of erythropoietin in an in vivo experimental model of retinal angiogenesis. Our data provide strong evidence that erythropoietin is a potent retinal angiogenic factor independent of VEGF and is capable of stimulating ischemia-induced retinal angiogenesis in proliferative diabetic retinopathy.



Daisuke Watanabe, M.D., Ph.D., Kiyoshi Suzuma, M.D., Ph.D., Shigeyuki Matsui, Ph.D., Masafumi Kurimoto, M.D., Junichi Kiryu, M.D., Ph.D., Mihori Kita, M.D., Ph.D., Izumi Suzuma, M.D., Ph.D., Hirokazu Ohashi, M.D., Ph.D., Tomonari Ojima, M.D., Tomoaki Murakami, M.D., Toshihiro Kobayashi, Ph.D., Seiji Masuda, Ph.D., Masaya Nagao, Ph.D., Nagahisa Yoshimura, M.D., Ph.D., and Hitoshi Takagi, M.D., Ph.D.
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August 25, 2005
N Engl J Med 2005; 353:782-792

www.nejm.com

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