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

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 progenitors, which was abolished by blocking the 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 extend VEGF-C production and/or agonists that stimulate the VEGFR-3 will promote oligodendrocyte progenitor cell development to enhance myelination after perinatal brain injury.