title: Induction of HIF1alpha but not HIF2alpha in motoneurons after ventral funiculus axotomy-implication in neuronal survival strategies.
abstract: Spinal cord injury is frequently associated with local tissue hypoxia. As neuronal cells are susceptible to damage caused by low oxygen levels, hypoxia-induced activation of tissue-protective factors could represent an endogenous mechanism for neuron survival following injury. We studied in vivo, in a rat model of intraspinal axotomy of motoneurons, the cell- and time-dependent regulation of the hypoxia-inducible transcription factors (HIFs), HIF1alpha and HIF2alpha, as well as one of their target genes, vascular endothelial growth factor (VEGF). VEGF is a potent hypoxia-regulated angiogenic growth factor with recently discovered neuroprotective and neurotrophic activities. While neither HIF1alpha, HIF2alpha, nor VEGF mRNA were detected in noninjured motoneurons, we found a strong induction of HIF1alpha, but not HIF2alpha mRNA in axotomized motoneurons. HIF1alpha expression peaked at about 7 days after injury. Moreover, we found increased VEGF mRNA and protein expression around and within the scar but also within motoneurons, peaking around 3 days after axotomy. In addition, increased survival of cultured motoneurons after treatment with VEGF could also be shown. We conclude that axotomized motoneurons in this model respond to injury by specific induction of HIF1alpha and VEGF expression that may provide an endogenous mechanism with the potential to promote motoneuron survival after injury.
authors.affiliation: Department of Neuroscience, Retzius Laboratory, Karolinska Institutet, S-171 77, Stockholm, Sweden. Mattias.Skold@neuro.ki.se
authors.forename: Mattias K
authors.initials: MK
authors.lastname: Sköld
authors.forename: Hugo H
authors.initials: HH
authors.lastname: Marti
authors.forename: Tomas
authors.initials: T
authors.lastname: Lindholm
authors.forename: Hans
authors.initials: H
authors.lastname: Lindå
authors.forename: Henrik
authors.initials: H
authors.lastname: Hammarberg
authors.forename: Mårten
authors.initials: M
authors.lastname: Risling
authors.forename: Staffan
authors.initials: S
authors.lastname: Cullheim
mesh_terms: D000818:Animals; D000870:Anterior Horn Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019771:Axotomy; D051792:Basic Helix-Loop-Helix Proteins; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009434:Neural Pathways / Q000293:injuries / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1