IGFBP3 suppresses retinopathy through suppression of oxygen-induced vessel loss and promotion of vascular regrowth

doi:10.1073/pnas.0702031104

IGFBP3 suppresses retinopathy through suppression of oxygen-induced vessel loss and promotion of vascular regrowth

*Department of Ophthalmology, Children's Hospital, Harvard Medical School, Boston, MA 02115;
^†Departments of Pediatrics and
^¶Clinical Neurosciences, Sahlgrenska Academy, Göteborg University, SE-416 85 Göteborg, Sweden;
^‡Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854; and
^§Institute for Cancer Genetics, Department of Pathology, Columbia University, New York, NY 10032

Edited by Judah Folkman, Harvard Medical School, Boston, MA, and approved May 9, 2007 (received for review March 7, 2007)

Abstract

Vessel loss precipitates many diseases. In particular, vessel loss resulting in hypoxia induces retinal neovascularization in diabetic retinopathy and in retinopathy of prematurity (ROP), major causes of blindness. Here we define insulin-like growth factor binding protein-3 (IGFBP3) as a new modulator of vascular survival and regrowth in oxygen-induced retinopathy. In IGFBP3-deficient mice, there was a dose-dependent increase in oxygen-induced retinal vessel loss. Subsequent to oxygen-induced retinal vessel loss, Igfbp3 ^−/− mice had a 31% decrease in retinal vessel regrowth versus controls after returning to room air. No difference in serum insulin-like growth factor 1 (IGF1) levels was observed among groups. Wild-type mice treated with exogenous IGFBP3 had a significant increase in vessel regrowth. This correlated with a 30% increase in endothelial progenitor cells in the retina at postnatal day 15, indicating that IGFBP3 could be serving as a progenitor cell chemoattractant. In a prospective clinical study, we measured IGFBP3 (and IGF1) plasma levels weekly and examined retinas in all premature infants born at gestational ages <32 weeks at high risk for ROP. The mean level of IGFBP3 at 30–35 weeks postmenstrual age (PMA) for infants with proliferative ROP (ROP stages 3>, n = 13) was 802 μg/liter, and for infants with no ROP (ROP stage 0, n = 38) the mean level was 974 μg/liter (P < 0.03). These results suggest that IGFBP3, acting independently of IGF1, helps to prevent oxygen-induced vessel loss and to promote vascular regrowth after vascular destruction in vivo in a dose-dependent manner, resulting in less retinal neovascularization.

Footnotes

^‖To whom correspondence should be addressed. E-mail: lois.smith{at}childrens.harvard.edu
Author contributions: C.L., K.M.C., A.C.H.S., A.H., and L.E.H.S. designed research; J.C., K.M.C., A.C.H.S., C.M.A., N.L., and A.H. performed research; J.E.P. and T.L. contributed new reagents/analytic tools; C.L., J.C., K.M.C., A.C.H.S., C.M.A., N.L., A.H., and L.E.H.S. analyzed data; and C.L., J.C., K.M.C., and L.E.H.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Abbreviations:

CV,

coefficient of variation;

EPC,

endothelial progenitor cell;

NV,

neovascularization;

OIR,

oxygen-induced retinopathy;

Pn,

postnatal day;

PMA,

postmenstrual age;

ROP,

retinopathy of prematurity.