title: Low-Dose Endothelial Monocyte-Activating Polypeptide-II Increases Blood-Tumor Barrier Permeability by Activating the RhoA/ROCK/PI3K Signaling Pathway.
abstract: Previous studies have demonstrated that low-dose endothelial monocyte-activating polypeptide-II (EMAP-II) can increase blood-tumor barrier (BTB) permeability via both paracellular and transcellular pathways. In addition, we revealed that the RhoA/Rho kinase (ROCK) signaling pathway is involved in EMAP-II-induced BTB opening. This study further investigated the exact mechanisms by which the RhoA/ROCK signaling pathway affects EMAP-II-induced BTB hyperpermeability. In an in vitro BTB model, low-dose EMAP-II significantly activated phosphatidylinositol-3-kinase (PI3K) in rat brain microvascular endothelial cells (RBMECs) at 0.75 h. Pretreatment with RhoA inhibitor C3 exoenzyme or ROCK inhibitor Y-27632 completely blocked EMAP-II-induced activation of PI3K. PKC-α/β inhibitor GÖ6976 pretreatment caused no change in EMAP-II-induced activation of PI3K. Besides, pretreatment with LY294002, a specific inhibitor of PI3K, did not affect EMAP-II-induced activation of PKC-α/β. Furthermore, LY294002 pretreatment significantly diminished EMAP-II-induced changes in BTB permeability, phosphorylation of myosin light chain and cofilin, expression and distribution of tight junction-associated protein ZO-1, and actin cytoskeleton arrangement in RBMECs. In summary, this study demonstrates that low-dose EMAP-II can increase BTB permeability by activating the RhoA/ROCK/PI3K 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. cmuliuyunhui1962@163.com.
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: D008841:Actin Cytoskeleton / Q000378:metabolism; D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism; D009363:Neoplasm Proteins / Q000494:pharmacology*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D062826:Zonula Occludens-1 Protein / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; D016207:Cytokines; D018994:Myosin Light Chains; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D016601:RNA-Binding Proteins; D062826:Zonula Occludens-1 Protein; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; C077219:small inducible cytokine subfamily E, member 1
keywords: Blood–tumor barrier; Endothelial monocyte-activating polypeptide-II; PI3K; Permeability; ROCK; RhoA