Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy.
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.
Watanabe
Daisuke
D
Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Suzuma
Kiyoshi
K
Matsui
Shigeyuki
S
Kurimoto
Masafumi
M
Kiryu
Junichi
J
Kita
Mihori
M
Suzuma
Izumi
I
Ohashi
Hirokazu
H
Ojima
Tomonari
T
Murakami
Tomoaki
T
Kobayashi
Toshihiro
T
Masuda
Seiji
S
Nagao
Masaya
M
Yoshimura
Nagahisa
N
Takagi
Hitoshi
H
D000818:Animals; D016022:Case-Control Studies; D002417:Cattle; D049109:Cell Proliferation; D002478:Cells, Cultured; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016326:Extracellular Matrix Proteins; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D051379:Mice; D008875:Middle Aged; D018995:Myosin Heavy Chains; D024501:Nonmuscle Myosin Type IIB; D011506:Proteins / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000502:physiology; D012160:Retina / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D015861:Retinal Neovascularization / Q000473:pathology* / Q000503:physiopathology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014822:Vitreous Body / Q000737:chemistry*
D016326:Extracellular Matrix Proteins; D011506:Proteins; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; D024501:Nonmuscle Myosin Type IIB; C103815:nonmuscle myosin type IIB heavy chain; D018995:Myosin Heavy Chains