title: Inhibition of vascular endothelial growth factor receptor 2 activity in experimental brain contusions aggravates injury outcome and leads to early increased neuronal and glial degeneration.
abstract: Angiogenesis following traumatic brain injuries (TBIs) may be of importance for post-traumatic reparative processes and the development of secondary injuries. We have previously shown expression of vascular endothelial growth factor (VEGF), a major regulator of endothelial cell proliferation, angiogenesis and vascular permeability, and VEGF receptors (VEGFR1 and 2) after TBI in rat. In the present work we tried to further elucidate the role of VEGF after TBI by performing specific VEGFR2 activity inhibition. In rats subjected to VEGFR2 blockage we report an increased haemorrhagic area (P < 0.05), early increase in serum levels of neural injury marker neuron-specific enolase (P < 0.05) and glial injury marker S100beta (P < 0.05), and increased numbers of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labelling- (TUNEL-) and FluoroJade B- (P < 0.05) positive cells, all increases preceding the known VEGF/VEGFR vascular response in brain trauma. An increase in lesion area, as measured by decreased microtubuli-associated protein 2 expression (P < 0.05) and increased glial fibrillary acidic protein reactivity (P < 0.05), could also be demonstrated. In addition, vascular density, as measured by von Willebrandt factor-positive cells, was decreased (P < 0.05). No differences in post-traumatic inflammatory response, as measured by stainings for macrophages, granulocytes and intracellular adhesion molecules, were shown between the groups. Taken together, our findings point towards VEGF/VEGFR2 up-regulation after TBI as being an important endogenous cytoprotective mechanism in TBI. The possible importance of VEGF on the vascular, neuronal and glial compartments of the neurovascular unit after TBI is discussed.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, S-17177 Stockholm, Sweden. Mattias.Skold@neuro.ki.se
authors.forename: Mattias K
authors.initials: MK
authors.lastname: Sköld
authors.forename: Mårten
authors.initials: M
authors.lastname: Risling
authors.forename: Staffan
authors.initials: S
authors.lastname: Holmin
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000097:blood; D000818:Animals; D001930:Brain Injuries / Q000150:complications / Q000473:pathology*; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005452:Fluoresceins; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007163:Immunosorbent Techniques; D017403:In Situ Hybridization / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D007211:Indoles / Q000008:administration & dosage / Q000097:blood; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D018992:Myelin-Associated Glycoprotein / Q000235:genetics / Q000378:metabolism; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D009414:Nerve Growth Factors / Q000097:blood; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009930:Organic Chemicals / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000097:blood; D013997:Time Factors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D005452:Fluoresceins; D005904:Glial Fibrillary Acidic Protein; D007211:Indoles; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D018992:Myelin-Associated Glycoprotein; D009414:Nerve Growth Factors; D009930:Organic Chemicals; D011758:Pyrroles; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C435731:fluoro jade; C116890:Semaxinib; D040301:Vascular Endothelial Growth Factor Receptor-2