Neonatal hypoxic preconditioning involves vascular endothelial growth factor.
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.
Laudenbach
Vincent
V
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
Fontaine
Romain H
RH
Medja
Fadia
F
Carmeliet
Peter
P
Hicklin
Daniel J
DJ
Gallego
Jorge
J
Leroux
Philippe
P
Marret
Stéphane
S
Gressens
Pierre
P
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
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