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(Circulation Research. 2009;105:897.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Insulin-Like Growth Factor Binding Protein-3 Mediates Vascular Repair by Enhancing Nitric Oxide Generation

Jennifer L. Kielczewski^*, Yagna P.R. Jarajapu^*, Evan L. McFarland^*, Jun Cai, Aqeela Afzal, Sergio Li Calzi, Kyung Hee Chang, Todd Lydic, Lynn C. Shaw, Julia Busik, Jeffrey Hughes, Arturo J. Cardounel, Kenneth Wilson, Timothy J. Lyons, Michael E. Boulton, Robert N. Mames, Tailoi Chan-Ling, Maria B. Grant

From the Program in Stem Cell Biology and Regenerative Medicine (J.L.K., Y.J., A.A., S.L.C., K.H.C., L.C.S., M.B.G.); and Departments of Pharmacology and Therapeutics (J.L.K., Y.J., A.A., S.L.C., K.H.C., L.C.S., M.B.G.), Anatomy and Cell Biology (J.C., M.E.B.), Pharmaceutics (J.H.), and Physiology and Functional Genomics (A.J.C.), University of Florida, Gainesville; Department of Anatomy (E.L.M., T.C.-L.), Bosch Institute, University of Sydney, Australia; Department of Physiology (T.L., J.B.), Michigan State University, East Lansing; Harold Hamm Oklahoma Diabetes Center (K.W., T.J.L.), Section of Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, Oklahoma City; and The Retina Center (R.N.M.), Gainesville, Fla.

Correspondence to M.B. Grant, MD, University of Florida, Department of Pharmacology and Therapeutics, 1600 SW Archer Rd, Box 100267, Gainesville, FL 32610. E-mail grantma{at}ufl.edu

Rationale: Insulin-like growth factor binding protein (IGFBP)-3 modulates vascular development by regulating endothelial progenitor cell (EPC) behavior, specifically stimulating EPC cell migration. This study was undertaken to investigate the mechanism of IGFBP-3 effects on EPC function and how IGFBP-3 mediates cytoprotection following vascular injury.

Objective: To examine the mechanism of IGFBP-3–mediated repair following vascular injury.

Methods and Results: We used 2 complementary vascular injury models: laser occlusion of retinal vessels in adult green fluorescent protein (GFP) chimeric mice and oxygen-induced retinopathy in mouse pups. Intravitreal injection of IGFBP-3–expressing plasmid into lasered GFP chimeric mice stimulated homing of EPCs, whereas reversing ischemia induced increases in macrophage infiltration. IGFBP-3 also reduced the retinal ceramide/sphingomyelin ratio that was increased following laser injury. In the OIR model, IGFBP-3 prevented cell death of resident vascular endothelial cells and EPCs, while simultaneously increasing astrocytic ensheathment of vessels. For EPCs to orchestrate repair, these cells must migrate into ischemic tissue. This migratory ability is mediated, in part, by endogenous NO generation. Thus, we asked whether the migratory effects of IGFBP-3 were attributable to stimulation of NO generation. IGFBP-3 increased endothelial NO synthase expression in human EPCs leading to NO generation. IGFBP-3 exposure also led to the redistribution of vasodilator-stimulated phosphoprotein, an NO regulated protein critical for cell migration. IGFBP-3–mediated NO generation required high-density lipoprotein receptor activation and stimulation of phosphatidylinositol 3-kinase/Akt pathway.

Conclusion: These studies support consideration of IGFBP-3 as a novel agent to restore the function of injured vasculature and restore NO generation.

Key Words: hematopoietic stem cells • nitric oxide • insulin-like growth factor binding protein-3 • vascular repair