title: Low-Dose Endothelial Monocyte-Activating Polypeptide-II Induces Blood-Tumor Barrier Opening Via the cAMP/PKA/Rac1 Pathway.
abstract: Previous studies have demonstrated that low-dose endothelial monocyte-activating polypeptide-II (EMAP-II) induces blood-tumor barrier (BTB) hyperpermeability via both paracellular and transcellular pathways. In a recent study, we revealed that cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)-dependent signaling pathway is involved in EMAP-II-induced BTB hyperpermeability. This study further investigated the exact mechanisms through which the cAMP/PKA-dependent signaling pathway affects EMAP-II-induced BTB hyperpermeability. In an in vitro BTB model, low-dose EMAP-II (0.05 nM) induced a significant decrease in Rac1 activity in rat brain microvascular endothelial cells (RBMECs). Pretreatment with forskolin to elevate intracellular cAMP concentration completely blocked EMAP-II-induced inactivation of Rac1. Besides, pretreatment with 6Bnz-cAMP to activate PKA partially attenuated EMAP-II-induced Rac1 inactivation. Moreover, 6Bnz-cAMP pretreatment significantly diminished EMAP-II-induced changes in BTB permeability, myosin light chain (MLC) phosphorylation, expression and distribution of ZO-1, and actin cytoskeleton arrangement in RBMECs. These effects of 6Bnz-cAMP were completely blocked in the presence of NSC-23766 (the specific inhibitor of Rac1). In conclusion, this study demonstrates that low-dose EMAP-II induces BTB hyperpermeability via the cAMP/PKA/Rac1 signaling pathway.
authors.affiliation: Department of Neurosurgery, Shengjing Hospital, China Medical University, Shenyang, Liaoning Province, 110004, People's Republic of China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: The 96th Class, 7-Year Program, China Medical University, Shenyang, Liaoning Province, 110001, People's Republic of China.
authors.forename: Xiao-bai
authors.initials: XB
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Shengjing Hospital, China Medical University, Shenyang, Liaoning Province, 110004, People's Republic of China. liuyh@sj-hospital.org.
authors.forename: Yun-hui
authors.initials: YH
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, Liaoning Province, 110001, People's Republic of China.|Institute of Pathology and Pathophysiology, China Medical University, Shenyang, Liaoning Province, 110001, People's Republic of China.
authors.forename: Yi-xue
authors.initials: YX
authors.lastname: Xue
authors.affiliation: Department of Neurosurgery, Shengjing Hospital, China Medical University, Shenyang, Liaoning Province, 110004, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Shengjing Hospital, China Medical University, Shenyang, Liaoning Province, 110004, People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Teng
authors.affiliation: Department of Neurosurgery, Shengjing Hospital, China Medical University, Shenyang, Liaoning Province, 110004, People's Republic of China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Xi
authors.affiliation: Department of Neurosurgery, Shengjing Hospital, China Medical University, Shenyang, Liaoning Province, 110004, People's Republic of China.
authors.forename: Yi-long
authors.initials: YL
authors.lastname: Yao
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism*; D002199:Capillary Permeability; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D005910:Glioma / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015290:Second Messenger Systems; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D016207:Cytokines; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; C077219:small inducible cytokine subfamily E, member 1; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein
keywords: Blood−tumor barrier; Endothelial monocyte-activating polypeptide-II; PKA; Permeability; Rac1; cAMP