title: Vascular Endothelial Growth Factor Isoform-B Stimulates Neurovascular Repair After Ischemic Stroke by Promoting the Function of Pericytes via Vascular Endothelial Growth Factor Receptor-1.
abstract: Ischemic stroke triggers endogenous angiogenic mechanisms, which correlates with longer survival in patients. As such, promoting angiogenesis appears to be a promising approach. Experimental studies investigated mostly the potent angiogenic factor vascular endothelial growth factor isoform-A (VEGF-A). However, VEGF-A increases the risk of destabilizing the brain microvasculature, thus hindering the translation of its usage in clinics. An attractive alternative VEGF isoform-B (VEGF-B) was recently reported to act as a survival factor rather than a potent angiogenic factor. In this study, we investigated the therapeutic potential of VEGF-B in ischemic stroke using different in vivo and in vitro approaches. We showed that the delayed intranasal administration of VEGF-B reduced neuronal damage and inflammation. Unexpectedly, VEGF-B stimulated the formation of stable brain microvasculature within the injured region by promoting the interaction between endothelial cells and pericytes. Our data indicate that the effects of VEGF-B were mediated via its specific receptor VEGF receptor-1 (VEGFR-1) that is predominately expressed in brain pericytes. Importantly, VEGF-B promoted the survival of pericytes, and not brain endothelial cells, by inducing expression of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) and the main protein involved in energy homeostasis AMP-activated protein kinase α (AMPKα). Moreover, we showed that VEGF-B stimulated the pericytic release of factors stimulating a "reparative angiogenesis" that does not compromise microvasculature stability. Our study unraveled hitherto unknown role of VEGF-B/VEGFR-1 signaling in regulating the function of pericytes. Furthermore, our findings suggest that brain microvasculature stabilization via VEGF-B constitutes a safe therapeutic approach for ischemic stroke.
authors.affiliation: Neuroscience Axis, CHU de Québec Research Center (CHUL) and Department of Psychiatry and Neuroscience, Faculty of Medicine, Laval University, 2705 Laurier Boulevard, Quebec City, QC, G1V 4G2, Canada.
authors.forename: Noëmie
authors.initials: N
authors.lastname: Jean LeBlanc
authors.affiliation: Neuroscience Axis, CHU de Québec Research Center (CHUL) and Department of Psychiatry and Neuroscience, Faculty of Medicine, Laval University, 2705 Laurier Boulevard, Quebec City, QC, G1V 4G2, Canada.
authors.forename: Revathy
authors.initials: R
authors.lastname: Guruswamy
authors.affiliation: Neuroscience Axis, CHU de Québec Research Center (CHUL) and Department of Psychiatry and Neuroscience, Faculty of Medicine, Laval University, 2705 Laurier Boulevard, Quebec City, QC, G1V 4G2, Canada. ayman.el-ali@crchudequebec.ulaval.ca.
authors.forename: Ayman
authors.initials: A
authors.lastname: ElAli
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism; D020286:Pericytes / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism; D042561:Vascular Endothelial Growth Factor B / Q000494:pharmacology / Q000627:therapeutic use*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
chemical_list: D042561:Vascular Endothelial Growth Factor B; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: Angiogenesis; Endothelial cells; Pericytes; Repair; Stroke; VEGF-B; VEGFR-1