title: Functions for the cAMP/Epac/Rap1 Signaling Pathway in Low-Dose Endothelial Monocyte-Activating Polypeptide-II-Induced Opening of Blood-Tumor Barrier.
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 cAMP/PKA-dependent and cAMP/PKA-independent signaling pathways are both involved in EMAP-II-induced BTB hyperpermeability. The present study further investigated the exact mechanisms through which the cAMP/PKA-independent 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 Rap1 activity in RBMECs. Pretreatment with forskolin to elevate intracellular cAMP concentration completely blocked EMAP-II-induced Rap1 inactivation. Epac/Rap1 activation by 8-pCPT-2'-O-Me-cAMP significantly prevented EMAP-II-induced activation of RhoA/ROCK. Furthermore, 8-pCPT-2'-O-Me-cAMP pretreatment significantly inhibited EMAP-II-induced decreases in TEER and increases in HRP flux. Pretreatment also significantly prevented EMAP-II-induced changes in MLC phosphorylation, actin cytoskeleton arrangement, and expression and distribution of ZO-1 in RBMECs. This study demonstrates that the cAMP/Epac/Rap1 signaling cascade is a crucial pathway in EMAP-II-induced BTB hyperpermeability.
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.forename: Xiao-Bai
authors.initials: XB
authors.lastname: Liu
authors.forename: Yun-Hui
authors.initials: YH
authors.lastname: Liu
authors.forename: Yi-Xue
authors.initials: YX
authors.lastname: Xue
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Li-Bo
authors.initials: LB
authors.lastname: Liu
authors.forename: Yi-Long
authors.initials: YL
authors.lastname: Yao
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D005910:Glioma / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015290:Second Messenger Systems; D062826:Zonula Occludens-1 Protein / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: C485473:Eml2 protein, rat; D020662:Guanine Nucleotide Exchange Factors; D008869:Microtubule-Associated Proteins; C526973:Rapgef3 protein, rat; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; D000242:Cyclic AMP; D054460:rho-Associated Kinases; D020827:rap1 GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein