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

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)897-905
Number of pages9
JournalCirculation research
Volume105
Issue number9
DOIs
StatePublished - Oct 23 2009

Keywords

  • Hematopoietic stem cells
  • Insulin-like growth factor binding protein-3
  • Nitric oxide
  • Vascular repair

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Kielczewski, J. L., Jarajapu, Y. P. R., McFarland, E. L., Cai, J., Afzal, A., Calzi, S. L., Chang, K. H., Lydic, T., Shaw, L. C., Busik, J., Hughes, J., Cardounel, A. J., Wilson, K., Lyons, T. J., Boulton, M. E., Mames, R. N., Chan-Ling, T., & Grant, M. B. (2009). Insulin-like growth factor binding protein-3 mediates vascular repair by enhancing nitric oxide generation. Circulation research, 105(9), 897-905. https://doi.org/10.1161/CIRCRESAHA.109.199059