title: Angiotensin II type-2 receptor stimulation induces neuronal VEGF synthesis after cerebral ischemia.
abstract: Intense efforts are being undertaken to understand the pathobiology of ischemia and to develop novel and effective treatments. Angiotensin II type 2 receptor (AT2R) is related with a beneficial role in neurodegenerative disorders, including ischemia. However, the underlying molecular mechanism remains elusive. In this study, we have established that AT2R stimulation by C21 compound, a specific AT2R agonist, caused a VEGF upregulation. Using mouse primary cortical neurons exposed to oxygen-glucose deprivation (OGD), we established that this effect was mediated by a mechanism dependent of mTORC1 signaling since mTOR inhibition abolished the C21-induced VEGF upregulation. Also, we have temporally characterized the changes on VEGF levels after ischemia induction in rats using two different approaches: transient and permanent middle cerebral artery occlusion (tMCAO and pMCAO). VEGF levels were permanently augmented after reperfusion (tMCAO) whereas lower levels of VEGF were found after pMCAO, remarkably at 21days. Therefore, C21 compound accelerated the recovery of the neurological status of pMCAO rats, reduced the ischemic damage area and abolished pMCAO-induced VEGF downregulation at 21days. This effect of C21 compound was mainly observed in neurons of the peri-infarct area. Our results suggest that a C21-induced VEGF upregulation may be crucial after an ischemic neuronal insult in both of our experimental approaches. This upregulation was mediated by a mechanism dependent of Akt/mTOR signaling pathway, since mTOR inhibition abolished the VEGF upregulation induced by C21. Considering that VEGF is involved in regenerative processes, we propose that AT2R activation could be used as a potential pharmacological strategy after ischemic stroke.
authors.affiliation: Spanish National Biotechnology Centre (CSIC). C/Darwin 3, 28049 Madrid, Spain; Centro de Biología Molecular "Severo Ochoa", CSIC-UAM, C/ Nicolas Cabrera 1, 28049 Madrid, Spain. Electronic address: laura.mateos-montejo@ki.se.
authors.forename: Laura
authors.initials: L
authors.lastname: Mateos
authors.affiliation: Centro de Biología Molecular "Severo Ochoa", CSIC-UAM, C/ Nicolas Cabrera 1, 28049 Madrid, Spain; Facultad de Ciencias, Dpto Biología (Fisiología Animal), Universidad Autónoma de Madrid, C/Darwin 2, 28049 Madrid, Spain.
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Perez-Alvarez
authors.affiliation: Centro de Biología Molecular "Severo Ochoa", CSIC-UAM, C/ Nicolas Cabrera 1, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain. Electronic address: fwandosell@cbm.csic.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Wandosell
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D017208:Rats, Wistar; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D018696:Neuroprotective Agents; D044139:Receptor, Angiotensin, Type 2; D042461:Vascular Endothelial Growth Factor A; D058570:TOR Serine-Threonine Kinases
keywords: AT2 receptor; Ischemic stroke; MCAO; Oxygen–glucose deprivation and VEGF