title: Neonatal hypoxic preconditioning involves vascular endothelial growth factor.
abstract: We studied hypoxic preconditioning (HxP) in the murine developing brain, focusing on the role for vascular endothelial growth factor (VEGF). Newborn mice were used as follows: (1) HxP (or normoxia) then intracerebral (i.c.) NMDA or AMPA-kainate agonist; (2) HxP then intraperitoneal (i.p.) anti-VEGFR2/Flk1 or anti-VEGFR1/Flt1 monoclonal blocking antibody (mAb) then i.c. NMDA/AMPA-kainate agonist; (3) i.p. VEGF then i.c. NMDA/AMPA-kainate agonist; and (4) in mutants lacking the hypoxia-responsive element (HRE) of the VEGF-A gene (VEGF( partial differential/ partial differential)) and their wild-type littermates (VEGF(+/+)), HxP followed by i.c. NMDA agonist. HxP reduced the size of NMDA-related cortical and AMPA-kainate-related cortical and white matter excitotoxic lesions. Anti-VEGFR2/Flk1 mAb prevented HxP-induced neuroprotection. VEGF produced dose-dependent reduction in cortical lesions. HxP did not prevent, but instead exacerbated, brain lesions in VEGF( partial differential/ partial differential) mutants. Thus, exogenous as well as endogenous VEGF reduces excitotoxic brain lesions in the developing mouse. The VEGF/VEGFR2/Flk1 pathway is involved in the neuroprotective response to HxP.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, AVENIR Research Group, IFRMP23, University of Rouen, Department of Neonatal Pediatrics and Intensive Care, Rouen University Hospital, France. Vincent.laudenbach@chu-rouen.fr
authors.forename: Vincent
authors.initials: V
authors.lastname: Laudenbach
authors.forename: Romain H
authors.initials: RH
authors.lastname: Fontaine
authors.forename: Fadia
authors.initials: F
authors.lastname: Medja
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: Jorge
authors.initials: J
authors.lastname: Gallego
authors.forename: Philippe
authors.initials: P
authors.lastname: Leroux
authors.forename: Stéphane
authors.initials: S
authors.lastname: Marret
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
mesh_terms: D000375:Aging / Q000502:physiology; D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D019138:Antibodies, Blocking / Q000494:pharmacology; D001921:Brain / Q000254:growth & development / Q000473:pathology; D018690:Excitatory Amino Acid Agonists; D002534:Hypoxia, Brain / Q000473:pathology / Q000503:physiopathology*; D007051:Ibotenic Acid; D007274:Injections, Intraperitoneal; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011744:Pyrimidinones / Q000494:pharmacology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D014498:Uracil / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D015431:Weight Loss / Q000187:drug effects
chemical_list: D019138:Antibodies, Blocking; D018690:Excitatory Amino Acid Agonists; D011744:Pyrimidinones; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C002872:willardiine; D007051:Ibotenic Acid; D014498:Uracil; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000409:Alanine