Effects of VEGF Administration or Neutralization on the BBB of Developing Rat Brain
We investigated the effects of exogenous Vascular Endothelial Growth Factor VEGF combined with an enriched environment on BBB integrity after a minimal trauma induced during the first days of the critical visual period in rats, when peak levels of endogen
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Abstract We investigated the effects of exogenous Vascular Endothelial Growth Factor VEGF combined with an enriched environment on BBB integrity after a minimal trauma induced during the first days of the critical visual period in rats, when peak levels of endogenous VEGF secretion are reached. VEGF was administered using osmotic minipumps placed in middle cortical layers of P18 Long-Evans rats. Tissue changes were evaluated using conventional histology. BBB integrity was shown by immunohistochemistry techniques for EBA and GluT-1. Mini-pump implantation produced a wider cavity in anti-VEGF infused rats. In VEGF-infused rats there was a damaged region around the cannula that was smaller in rats raised in an enriched environment (EE). The administration of VEGF induced a high concentration of plasma proteins in the neuropil around the point of cannula placement and a high inflammatory reaction. VEGF-infused rats raised in an EE showed a lower degree of extravasation and better tissue preservation. AntiVEGF administration produced a lower protein expression profile and more widespread deterioration of tissue. Double immunofluorescence for EBA and GluT-1 showed that the administration of VEGF preserves the tissue, which remains present but not fully functional. In contrast, a combination of VEGF administration and an EE partially protects the functionally damaged tissue with a higher preservation of BBB integrity. Keywords Blood–brain barrier • endothelial barrier antigen • glucose transporter • vascular endothelial growth factor • visual cortex • enriched environment
J.V. Lafuente () Clinical and Experimental Neuroscience Laboratory, Department of Neuroscience, University of Basque Country, Leioa, Spain e-mail: [email protected] N. Ortuzar, E.G. Argandoña, H. Bengoetxea, O. Leis, and S. Bulnes Department of Neuroscience, LaNCE; Clinical and Experimental Neuroscience Laboratory, University of Basque Country, Leioa, Spain
Introduction Postnatal development of the visual cortex is modulated by experience. Experience-mediated changes produce an increase in neuronal activity, which in turn leads to adaptive changes in the vascular network (4). Most of these occur during the critical period. In the rat visual system, this period is between the third and fifth postnatal weeks (7). Previous research has reported the effects of visual experience on the cortex vasculature (1,2) and the increase of several factors such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), or neurotrophin-3 (NT-3) related to an enriched environment (EE) (8,17). Vascular Endothelial Growth Factor (VEGF) plays a major role in angiogenesis and vascular permeability, inducing leakage in the blood–brain barrier (BBB) (12,20). In pathological situations, VEGF has also shown strong neuroprotective and neurotrophic properties (19). The main human isoform is VEGF165; the rodent isoform of VEGF is one amino acid shorter. Among BBB markers, Endothelial Barrier Antigen (EBA) is a rat-specific protein that is only expressed in
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