title: A recombinant inhibitory isoform of vascular endothelial growth factor164/165 aggravates ischemic brain damage in a mouse model of focal cerebral ischemia.
abstract: Vascular endothelial growth factors (VEGF) are a Janus-faced family of growth factors exerting both neuroprotective and maladaptive effects on the blood-brain barrier. For example, VEGFs are beneficial in promoting postischemic brain angiogenesis, but the newly formed vessels are leaky. We investigated the role of the naturally occurring murine inhibitory VEGF isoform VEGF165b in a mouse model of focal cerebral ischemia by middle cerebral artery occlusion and reperfusion (I/R) in male C57BL/6 mice. We investigated the roles of VEGF164/165 and VEGF165b in both brain and nonbrain endothelial barrier, angiogenesis, and neutrophil migration using oxygen glucose deprivation and reoxygenation as in vitro model. We investigated the role of VEGF165b in brain edema, neutrophil infiltration, ischemic brain damage, and neuronal death in vivo using an adenovirus encoding a recombinant VEGF164b isoform. Neither VEGF164/165 nor VEGF165b significantly altered brain endothelial barrier or angiogenesis in vitro. However, treatment of brain endothelial cells with VEGF165b increased neutrophil migration in vitro and exacerbated stroke injury by aggravating neutrophil infiltration and neurodegeneration in vivo. Our results indicate that alterations in the delicate balance in the relative levels of pro- and antiangiogenic VEGF isoforms can result in either adaptive or detrimental effects, depending on the VEGF isoform levels and on the duration and extent of injury.
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana 71130, USA.
authors.forename: Ganta V
authors.initials: GV
authors.lastname: Chaitanya
authors.forename: Walter E
authors.initials: WE
authors.lastname: Cromer
authors.forename: Courtney P
authors.initials: CP
authors.lastname: Parker
authors.forename: Pierre O
authors.initials: PO
authors.lastname: Couraud
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Romero
authors.forename: Babette
authors.initials: B
authors.lastname: Weksler
authors.forename: J Michael
authors.initials: JM
authors.lastname: Mathis
authors.forename: Alireza
authors.initials: A
authors.lastname: Minagar
authors.forename: J Steven
authors.initials: JS
authors.lastname: Alexander
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D001929:Brain Edema / Q000150:complications / Q000473:pathology; D002545:Brain Ischemia / Q000097:blood / Q000150:complications / Q000473:pathology*; D002460:Cell Line; D002463:Cell Membrane Permeability; D002633:Chemotaxis; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects; D020033:Protein Isoforms / Q000009:adverse effects; D011994:Recombinant Proteins / Q000009:adverse effects*; D020521:Stroke / Q000097:blood / Q000150:complications / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000009:adverse effects*
chemical_list: D020033:Protein Isoforms; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A