title: Human Urinary Kallidinogenase Promotes Angiogenesis and Cerebral Perfusion in Experimental Stroke.
abstract: Angiogenesisis a key restorative mechanism in response to ischemia, and pro-angiogenic therapy could be beneficial in stroke. Accumulating experimental and clinical evidence suggest that human urinary kallidinogenase (HUK) improves stroke outcome, but the underlying mechanisms are not clear. The aim of current study was to verify roles of HUK in post-ischemic angiogenesis and identify relevant mediators. In rat middle cerebral artery occlusion (MCAO) model, we confirmed that HUK treatment could improve stroke outcome, indicated by reduced infarct size and improved neurological function. Notably, the 18F-FDG micro-PET scan indicated that HUK enhanced cerebral perfusion in rats after MCAO treatment. In addition, HUK promotespost-ischemic angiogenesis, with increased vessel density as well as up-regulated VEGF andapelin/APJ expression in HUK-treated MCAO mice. In endothelial cell cultures, induction of VEGF and apelin/APJ expression, and ERK1/2 phosphorylation by HUK was further confirmed. These changes were abrogated by U0126, a selective ERK1/2 inhibitor. Moreover, F13A, a competitive antagonist of APJ receptor, significantly suppressed HUK-induced VEGF expression. Furthermore, angiogenic functions of HUK were inhibited in the presence of selective bradykinin B1 or B2 receptor antagonist both in vitro and in vivo. Our findings indicate that HUK treatment promotes post-ischemic angiogenesis and cerebral perfusion via activation of bradykinin B1 and B2 receptors, which is potentially due to enhancement expression of VEGF and apelin/APJ in ERK1/2 dependent way.
authors.affiliation: Departments of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China; The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Han
authors.affiliation: Departments of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China; Department of Neurology, Affiliated Yixing People's Hospital of Jiangsu University, Yixing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Departments of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China; The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
authors.forename: Yanting
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Departments of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China; The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Departments of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China; The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
authors.forename: Lai
authors.initials: L
authors.lastname: Qian
authors.affiliation: Departments of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China; The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Departments of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China; The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
authors.forename: Zhengzheng
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Departments of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China; The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing, China; Nanjing Neuropsychiatry Clinic Medical Center, Nanjing, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Departments of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China; The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing, China; Nanjing Neuropsychiatry Clinic Medical Center, Nanjing, China.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000503:physiopathology; D007610:Kallikreins / Q000494:pharmacology* / Q000652:urine*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043783:Receptor, Bradykinin B1 / Q000819:agonists; D043782:Receptor, Bradykinin B2 / Q000819:agonists; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
chemical_list: D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D007610:Kallikreins