Vascular endothelial growth factor enhances migration of astroglial cells in subventricular zone neurosphere cultures

Abstract

Vascular endothelial growth factor (VEGF) is an endothelial and neuronal survival factor and a mitogen for endothelial cells and astrocytes in both explant and in vivo injury models. In the CNS, interplay between the vasculature and neural stem progenitor (NSP) cells is required for the maintenance of angiogenic/neurogenic coordination in the germinal niche in the subventricular zone (SVZ) of the lateral ventricle. Using an in vitro SVZ neurosphere (NS) model, this study aimed to understand the direct effects of VEGF and its receptor signaling on neonatal NSP cell growth and migration. Our data indicate that VEGF administration, compared with untreated or brain-derived neurotrophic factor-treated NS, significantly increased growth and migratory capacity of glial fibrillary acidic protein (GFAP)(+) and nestin(+) NSP cells and in secondary cultures induced a stellate astrocyte morphology. Blockade of both VEGF, which is normally expressed in some NS cells, and its flt-1 receptor signaling by neutralizing antibodies caused morphological changes specifically in GFAP(+) cells and disrupted sphere formation and outward migration. These cells did not appear as conventional polygonal astrocytes; their process growth was severely restricted, and overall migration was reduced by up to 76% of control cultures. Blockade of VEGF's flk-1 receptor reduced VEGF expression and caused a lesser, though significant, decrease (29%) in NSP (GFAP(+)) cell migration. The results show that both VEGF and, in particular, flt-1 receptor signaling are critical to the proper configuration of the NS and its subsequent development. VEGF is also an important growth and migratory factor particularly for GFAP(+) cells developing in SVZ-derived NS in culture.

Involvement of placental growth factor in Wallerian degeneration

“…Interestingly, mice lacking the neuropilin-2 receptor for PlGF-2 do also show a delayed regeneration after sciatic crush injury, due to a delayed reestablishment of contact between axons and SCs (Bannerman et al, 2008). Moreover, it is known that VEGF has migratory effects on SCs mainly through its tyrosine kinase receptors flk-1 and flt-1 (Mani et al, 2010; . Model of PlGF function in the injured peripheral nerve.…”

Lake-Front Property: A Unique Germinal Niche by the Lateral Ventricles of the Adult Brain

“…Vascular endothelial growth factor (VEGF) signaling has been implicated in NSC and progenitor survival, proliferation within the VZ-SVZ, and neuroblast migration and maturation, highlighting a pathway that may be able to act on both VZ-SVZ progenitors and the vasculature in this region (Zhang et al, 2003; Schanzer et al, 2004; Gotts and Chesselet, 2005c; Meng et al, 2006; Wada et al, 2006; Mani et al, 2009; Wittko et al, 2009; Licht et al, 2010). Angiogenesis elsewhere in the brain, after tumor growth or injury, has also been reported to induce proliferation and migration of neural progenitors (Schmidt et al, 2009; Harms et al, 2010).…”

Hypoxic Conditioned Medium from Rat Cerebral Cortical Cells Enhances the Proliferation and Differentiation of Neural Stem Cells Mainly through PI3-K/Akt Pathways

“…Previous reports have suggested that infusion of VEGF into the lateral ventricle increases neurogenesis by promoting survival of newborn neurons and NSCs [23], [24]. Consistently, blockade of VEGF disrupts sphere formation and neuroblasts migration [25]. VEGF exerts its biological functions through several receptors, among them VEGFR-2 (Flk-1) is believed to mediate most of the neuron-specific effects of VEGF, including neurogenesis [26], although there is recent evidence that VEGFR-1 (Flt-1) and VEGFR-3 (Flt-4) also regulate neurogenesis in the subventricular zone and dentate SGZ [27].…”