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Vascular Endothelial Growth Factors A and C are Induced in the SVZ Following Neonatal Hypoxia–Ischemia and Exert Different Effects on Neonatal Glial Progenitors

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Abstract

Episodes of neonatal hypoxia–ischemia (H-I) are strongly associated with cerebral palsy and a wide spectrum of other neurological deficits in children. Two key processes required to repair damaged organs are to amplify the number of precursors capable of regenerating damaged cells and to direct their differentiation towards the cell types that need to be replaced. Since hypoxia induces vascular endothelial growth factor (VEGF) production, it is logical to predict that VEGFs are key mediators of tissue repair after H-I injury. The goal of this study was to test the hypothesis that certain VEGF isoforms increase during recovery from neonatal H-I and that they would differentially affect the proliferation and differentiation of subventricular zone (SVZ) progenitors. During the acute recovery period from H-I, both VEGF-A and VEGF-C were transiently induced in the SVZ, which correlated with an increase in SVZ blood vessel diameter. These growth factors were produced by glial progenitors, astrocytes, and to a lesser extent, microglia. VEGF-A promoted the production of astrocytes from SVZ glial progenitors, while VEGF-C stimulated the proliferation of both early and late oligodendrocyte progenitor cells (OPCs), which was abolished by blocking VEGFR-3. Altogether, these results provide new insights into the signals that coordinate the reactive responses of the progenitors in the SVZ to neonatal H-I. Our studies further suggest that therapeutics that can extend VEGF-C production and/or agonists that stimulate VEGFR-3 will promote OPC development to enhance myelination after perinatal brain injury.

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Acknowledgments

The authors thank ImClone Systems/Eli Lilly for providing the neutralizing antibody to VEGFR-3 (IMC-3C5) and for advice on our studies. We are also grateful to Qasim Husain for the assistance with the initial sphere studies and to Kedar Mahajan and Jungsoo Min in Dr. Terri Wood’s laboratory for occasionally providing OPCs from mixed glial cell cultures.

Conflicts of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Neurology and Neurosciences, UMDNJ—New Jersey Medical School, Newark, NJ, 07103, USA

    Jennifer M. Bain, Lisamarie Moore, Zhihua Ren, Sophia Simonishvili & Steven W. Levison

  2. UMDNJ—Graduate School Biomedical Sciences, Newark, NJ, 07103, USA

    Jennifer M. Bain, Lisamarie Moore, Zhihua Ren, Sophia Simonishvili & Steven W. Levison

  3. New Jersey Medical School University Hospital Cancer Center, Newark, NJ, 07103, USA

    Jennifer M. Bain, Lisamarie Moore, Zhihua Ren, Sophia Simonishvili & Steven W. Levison

  4. Department of Neurology and Neurosciences, NJMS-UH Cancer Center, Office H-1226, 205 South Orange Avenue, Newark, NJ, 07103, USA

    Steven W. Levison

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  1. Jennifer M. Bain
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  2. Lisamarie Moore
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Correspondence to Steven W. Levison.

Additional information

This study was supported by grants from the National Institute of Neurological Disorders and Stroke and National Institute of Child Health and Development (grant numbers F31NS062629 awarded to JMB and F31NS076269 awarded to LM) and from the Leducq Foundation (grant number R01HD052064 awarded to SWL).

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Bain, J.M., Moore, L., Ren, Z. et al. Vascular Endothelial Growth Factors A and C are Induced in the SVZ Following Neonatal Hypoxia–Ischemia and Exert Different Effects on Neonatal Glial Progenitors. Transl. Stroke Res. 4, 158–170 (2013). https://doi.org/10.1007/s12975-012-0213-6

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  • DOI: https://doi.org/10.1007/s12975-012-0213-6

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