title: Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia.
abstract: We investigated the hypothesis that hypoxia induces angiogenesis and thereby may counteract the detrimental neurological effects associated with stroke. Forty-eight to seventy-two hours after permanent middle cerebral artery occlusion we found a strong increase in the number of newly formed vessels at the border of the infarction. Using the hypoxia marker nitroimidazole EF5, we detected hypoxic cells in the ischemic border of the neocortex. Expression of vascular endothelial growth factor (VEGF), which is the main regulator of angiogenesis and is inducible by hypoxia, was strongly up-regulated in the ischemic border, at times between 6 and 24 hours after occlusion. In addition, both VEGF receptors (VEGFRs) were up-regulated at the border after 48 hours and later in the ischemic core. Finally, the two transcription factors, hypoxia-inducible factor-1 (HIF-1) and HIF-2, known to be involved in the regulation of VEGF and VEGFR gene expression, were increased in the ischemic border after 72 hours, suggesting a regulatory function for these factors. These results strongly suggest that the VEGF/VEGFR system, induced by hypoxia, leads to the growth of new vessels after cerebral ischemia. Exogenous support of this natural protective mechanism might lead to enhanced survival after stroke.
authors.affiliation: Department of Molecular Cell Biology, the Max Planck Institute for Physiological and Clinical Research, Bad Nauheim, Germany. hugo.marti@kerckhoff.mpg.de
authors.forename: H J
authors.initials: HJ
authors.lastname: Marti
authors.forename: M
authors.initials: M
authors.lastname: Bernaudin
authors.forename: A
authors.initials: A
authors.lastname: Bellail
authors.forename: H
authors.initials: H
authors.lastname: Schoch
authors.forename: M
authors.initials: M
authors.lastname: Euler
authors.forename: E
authors.initials: E
authors.lastname: Petit
authors.forename: W
authors.initials: W
authors.lastname: Risau
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D004247:DNA / Q000032:analysis; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*; D000860:Hypoxia / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D019394:Ki-67 Antigen / Q000378:metabolism; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D010448:Peptide Initiation Factors / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; C485502:HIF-2 protein, mouse; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019394:Ki-67 Antigen; D008222:Lymphokines; D009687:Nuclear Proteins; D010448:Peptide Initiation Factors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004247:DNA; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1