Roles of the endogenous VEGF receptors flt-1 and flk-1 in astroglial and vascular remodeling after brain injury.
Following trauma to the brain significant changes occur in both the astroglial and vascular components of the neuropil. Angiogenesis is required to re-establish metabolic support and astrocyte activation encompasses several functions including scar formation and the production of growth factors. VEGF has seminal involvement in the process of brain repair and is upregulated during many pathological events. VEGF signaling is regulated mainly through its two primary receptors: flk-1 (KDR/VEGF-R2) is expressed on vascular endothelium and some neurons and flt-1 (VEGF-R1) in the CNS, is expressed predominantly by activated astrocytes. Using an injury model of chronic minipump infusion of neutralizing antibodies (NA) to block VEGF receptor signaling, this study takes advantage of these differences in VEGF receptor distribution in order to understand the role the cytokine plays after brain injury. Infusion of NA to flk-1 caused a significant decrease in vascular proliferation and increased endothelial cell degeneration compared to control IgG infusions but had no effect on astrogliosis. By contrast infusion of NA to flt-1 significantly decreased astroglial mitogenicity and scar formation and caused some increase in endothelial degeneration. Neutralization of the flt-1 receptor function, but not flk-1, caused significant reduction in the astroglial expression of the growth factors, CNTF and FGF by 7days. These data suggest that after CNS injury, endogenous VEGF upregulation (by astrocytes) induces angiogenesis and, by autocrine signaling, increases both astrocyte proliferation and facilitates expression of growth factors. It is likely that VEGF plays an important role in aspects of astroglial scar formation.
Krum
Janette M
JM
Department of Anatomy and Regenerative Biology, The George Washington University Medical Center, 2300 I Street NW, Washington, DC 20037, USA. anajmk@gwumc.edu
Mani
Nina
N
Rosenstein
Jeffrey M
JM
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count; D002536:Cerebral Arteries / Q000378:metabolism*; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005911:Gliosis / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic; D051381:Rats; D017208:Rats, Wistar; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D020127:Recovery of Function; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism
D000906:Antibodies; D020934:Ciliary Neurotrophic Factor; D042461:Vascular Endothelial Growth Factor A; D005346:Fibroblast Growth Factors; C501164:Flt1 protein, rat; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2