title: Src regulates angiogenic factors and vascular permeability after focal cerebral ischemia-reperfusion.
abstract: Developing new strategies to treat cerebral ischemic-reperfusion injury will require a better understanding of the mechanisms that underlie vascular permeability. In this study we examined the temporal expression of Src and angiogenic factors in rat brain after focal cerebral ischemia and reperfusion and analyzed the relationships among those factors. We also investigated the effect of Src inhibitor PP1 (4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) in ischemic reperfusion. Rats were subjected to middle cerebral artery occlusion for 90 min followed by reperfusion with or without PP1 treatment. Src mRNA increased at 3h after reperfusion and then gradually declined. Phosphorylation of Src at Y418 displayed a biphasic increase. Phosphorylation increased as early as 3h and peaked at 6h; after decreasing, it peaked again at 3-7 days. Increases in Src mRNA and phosphorylation correlated positively with levels of vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2), and negatively with levels of angiopoietin-1 (Ang-1) and zonula occludens-1 (ZO-1). Changes in the expression of these factors correlated with the progress of vascular permeability, especially early after reperfusion. Hence, dynamic temporal changes in Src Y418 phosphorylation may modulate vascular permeability after cerebral ischemia and reperfusion. PP1 effectively decreased Src Y418 phosphorylation and the expression of VEGF and Ang-2 and increased the expression of Ang-1 and ZO-1. It also reduced cerebral infarct size and neurologic dysfunction. Therefore, Src may represent a new therapeutic target for reducing tissue damage caused by increased vascular permeability.
authors.affiliation: Department of Pathology, Shanxi Cancer Hospital, Taiyuan, 3 Zhigong New Street, Xinghualing District, Shanxi 030013, PR China.
authors.forename: L
authors.initials: L
authors.lastname: Zan
authors.affiliation: Department of Colorectal Surgery, Shanxi Cancer Hospital, Taiyuan 030013, PR China.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Shanxi Cancer Hospital, Taiyuan, 3 Zhigong New Street, Xinghualing District, Shanxi 030013, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Xi
authors.affiliation: Department of Pathology, First Affiliated of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin 150001, PR China.
authors.forename: H
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Digestive System, First Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Pathology, Jinan Lixia People's Hospital, Jinan 250014, PR China.
authors.forename: G
authors.initials: G
authors.lastname: Teng
authors.affiliation: Department of Pathology, First Affiliated of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin 150001, PR China.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pathology, First Affiliated of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin 150001, PR China. Electronic address: qijiping2003@163.com.
authors.forename: J
authors.initials: J
authors.lastname: Qi
authors.affiliation: Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA. Electronic address: jwang79@jhmi.edu.
authors.forename: J
authors.initials: J
authors.lastname: Wang
mesh_terms: D042683:Angiopoietin-1 / Q000378:metabolism; D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D001929:Brain Edema / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D042683:Angiopoietin-1; D042702:Angiopoietin-2; C467629:Angpt1 protein, rat; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; C569044:Tjp1 protein, rat; D042461:Vascular Endothelial Growth Factor A; D062826:Zonula Occludens-1 Protein; C467498:vascular endothelial growth factor A, rat; D019061:src-Family Kinases
keywords: PP1; Src; angiogenic factors; cerebral ischemia; vascular permeability; zonula occludens-1