title: Pericytes contribute to the disruption of the cerebral endothelial barrier via increasing VEGF expression: implications for stroke.
abstract: Disruption of the blood-brain barrier (BBB) integrity occurring during the early onset of stroke is not only a consequence of, but also contributes to the further progression of stroke. Although it has been well documented that brain microvascular endothelial cells and astrocytes play a critical role in the maintenance of BBB integrity, pericytes, sandwiched between endothelial cells and astrocytes, remain poorly studied in the pathogenesis of stroke. Our findings demonstrated that treatment of human brain microvascular pericytes with sodium cyanide (NaCN) and glucose deprivation resulted in increased expression of vascular endothelial growth factor (VEGF) via the activation of tyrosine kinase Src, with downstream activation of mitogen activated protein kinase and PI3K/Akt pathways and subsequent translocation of NF-κB into the nucleus. Conditioned medium from NaCN-treated pericytes led to increased permeability of endothelial cells, and this effect was significantly inhibited by VEGF-neutralizing antibody. The in vivo relevance of these findings was further corroborated in the stroke model of mice wherein the mice, demonstrated disruption of the BBB integrity and concomitant increase in the expression of VEGF in the brain tissue as well as in the isolated microvessel. These findings thus suggest the role of pericyte-derived VEGF in modulating increased permeability of BBB during stroke. Understanding the regulation of VEGF expression could open new avenues for the development of potential therapeutic targets for stroke and other neurological disease.
authors.affiliation: Department of Pharmacology, Medical School of Southeast University, Nanjing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Pharmacology, Medical School of Southeast University, Nanjing, China.
authors.forename: Xinjian
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Physiology, Medical School of Southeast University, Nanjing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chao
authors.affiliation: Department of Pharmacology, Medical School of Southeast University, Nanjing, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Radiology, Medical School of Southeast University, Nanjing, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Qian
authors.affiliation: Department of Radiology, Medical School of Southeast University, Nanjing, China.
authors.forename: Peicheng
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Radiology, Medical School of Southeast University, Nanjing, China.
authors.forename: Dongfang
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Medical School of Southeast University, Nanjing, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.affiliation: Department of Pharmacology, Medical School of Southeast University, Nanjing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Immunology, Medical School of Southeast University, Nanjing, China.
authors.forename: Jianqiong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Buch
authors.affiliation: Department of Radiology, Medical School of Southeast University, Nanjing, China.
authors.forename: Gaojun
authors.initials: G
authors.lastname: Teng
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Medical School of Southeast University, Nanjing, China.
authors.forename: Honghong
authors.initials: H
authors.lastname: Yao
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D016391:Genes, src; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020286:Pericytes / Q000166:cytology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012966:Sodium Cyanide / Q000494:pharmacology; D020521:Stroke / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012966:Sodium Cyanide