SDF-1 is both necessary and sufficient to promote proliferative retinopathy
Jason M. Butler, … , Maria B. Grant, Edward W. Scott
Jason M. Butler, … , Maria B. Grant, Edward W. Scott
Published January 3, 2005
Citation Information: J Clin Invest. 2005;115(1):86-93. https://doi.org/10.1172/JCI22869.
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Article

SDF-1 is both necessary and sufficient to promote proliferative retinopathy

Abstract

Diabetic retinopathy is the leading cause of blindness in working-age adults. It is caused by oxygen starvation in the retina inducing aberrant formation of blood vessels that destroy retinal architecture. In humans, vitreal stromal cell–derived factor–1 (SDF-1) concentration increases as proliferative diabetic retinopathy progresses. Treatment of patients with triamcinolone decreases SDF-1 levels in the vitreous, with marked disease improvement. SDF-1 induces human retinal endothelial cells to increase expression of VCAM-1, a receptor for very late antigen–4 found on many hematopoietic progenitors, and reduce tight cellular junctions by reducing occludin expression. Both changes would serve to recruit hematopoietic and endothelial progenitor cells along an SDF-1 gradient. We have shown, using a murine model of proliferative adult retinopathy, that the majority of new vessels formed in response to oxygen starvation originate from hematopoietic stem cell–derived endothelial progenitor cells. We now show that the levels of SDF-1 found in patients with proliferative retinopathy induce retinopathy in our murine model. Intravitreal injection of blocking antibodies to SDF-1 prevented retinal neovascularization in our murine model, even in the presence of exogenous VEGF. Together, these data demonstrate that SDF-1 plays a major role in proliferative retinopathy and may be an ideal target for the prevention of proliferative retinopathy.

Authors

Jason M. Butler, Steven M. Guthrie, Mehmet Koc, Aqeela Afzal, Sergio Caballero, H. Logan Brooks, Robert N. Mames, Mark S. Segal, Maria B. Grant, Edward W. Scott

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Figure 6

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Anti–SDF-1 antibody prevents retinal neovascularization by HSC-derived c...
Anti–SDF-1 antibody prevents retinal neovascularization by HSC-derived circulating endothelial progenitors. All micrographs are merged confocal images of retinal flat mounts. Animals were perfused with a red fluorescent dye (RITC-dextran; Sigma-Aldrich) to delineate the vasculature. New blood vessels incorporate GFP+ HSC progeny, thereby forming areas of green/yellow fluorescence. Model control: Right, or treated, eyes from 4 representative C57BL/6.gfp animals in which retinal ischemia was induced according to our standard model. GFP+ progeny suggestive of astrocytes or glia are also seen incorporated outside of the vasculature. Negative control: Left, or untreated, eyes of the same 4 C57BL/6.gfp mice in which retinal ischemia was induced according to our standard model in their right eyes. Note the lack of recruitment and incorporation of transplanted gfp+ HSC progeny. Mock injections: Right, or treated, eyes from 4 representative C57BL/6.gfp mice in which retinal ischemia was induced according to our standard model with the added step of intravitreal injection with PBS containing an isotype control antibody to a final concentration of 1 μg/μl. Note the similar recruitment and incorporation of transplanted GFP+ HSC, as in model control. Anti–SDF-1, 1×, 4 injections: Right, or treated, eyes from 4 representative C57BL/6.gfp mice in which retinal ischemia was induced according to our standard model with the added step of intravitreal injection with PBS containing an anti–SDF-1 antibody to a final concentration of 1 μg/μl. Note the absence of newly formed GFP+ HSC in the vascular tufts.