{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T13:07:59Z","timestamp":1771938479547,"version":"3.50.1"},"reference-count":52,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2014,2,12]],"date-time":"2014-02-12T00:00:00Z","timestamp":1392163200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"crossref","award":["30901781"],"award-info":[{"award-number":["30901781"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81171131"],"award-info":[{"award-number":["81171131"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81172197"],"award-info":[{"award-number":["81172197"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81272564"],"award-info":[{"award-number":["81272564"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"crossref","award":["30973079"],"award-info":[{"award-number":["30973079"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81072056"],"award-info":[{"award-number":["81072056"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Special fund for Scientific Research of Doctor-Degree Subjects in Colleges and Universities","award":["20102104110009"],"award-info":[{"award-number":["20102104110009"]}]},{"name":"Special fund for Scientific Research of Doctor-Degree Subjects in Colleges and Universities","award":["20102104120023"],"award-info":[{"award-number":["20102104120023"]}]},{"name":"Natural Science Foundation of Liaoning Province in China","award":["201102300"],"award-info":[{"award-number":["201102300"]}]},{"name":"Liaoning Science and Technology Plan Projects in China","award":["2011225020"],"award-info":[{"award-number":["2011225020"]}]},{"name":"Liaoning Science and Technology Plan Projects in China","award":["2012225016"],"award-info":[{"award-number":["2012225016"]}]},{"name":"Shenyang Science and Technology Plan Projects in China","award":["F11-264-1-15"],"award-info":[{"award-number":["F11-264-1-15"]}]},{"name":"Shenyang Science and Technology Plan Projects in China","award":["F12-277-1-05."],"award-info":[{"award-number":["F12-277-1-05."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Neuroscience Research"],"published-print":{"date-parts":[[2014,6]]},"abstract":"<jats:p>This study aims to determine the effects of vascular endothelial growth factor (VEGF), papaverine (PA), and the combination of VEGF and PA on the permeability of the blood\u2013tumor barrier (BTB) and to determine possible molecular mechanisms contributing to the effects. In the rat C<jats:sub>6<\/jats:sub> glioma model, the extravasation of Evans blue (EB) through the BTB was increased significantly by VEGF and PA. VEGF\u2010induced and PA\u2010induced increase of EB extravasation was further increased after combining VEGF with PA infusion. Transmission electron microscopy (TEM) showed that the combination of VEGF and PA not only opened tight junctions (TJ) dramatically but increased the presence of pinocytotic vesicles of brain microvascular endothelial cells (BMECs) significantly. Meanwhile, the downregulation of the TJ\u2010associated proteins occludin and claudin\u20105 and the upregulation of the caveolae structure proteins caveolin\u20101 and caveolin\u20102 caused by the combination of VEGF and PA were observed by Western blot and immunohistochemistry, which were more remarkable than those by the two strategies separately. In addition, after VEGF and PA infusion, the results of radioimmunoassay, Western blot, and enzyme\u2010linked immunosorbent assay (ELISA) revealed a significant increase in expression levels of cGMP and protein kinase G\u20101 (PKG\u20101) and the activation of nuclear factor\u2010\u03baB (NF\u2010\u03baB) p65. This study demonstrates that combination of VEGF and PA can increase the permeability of the BTB by a paracellular pathway (downregulation of occludin and claudin\u20105) and a transcellular pathway (upregulation of caveolin\u20101 and caveolin\u20102) and that the cGMP\/PKG\/NF\u2010\u03baB signal pathway might be involved in the modulation process. \u00a9 2014 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/jnr.23348","type":"journal-article","created":{"date-parts":[[2014,2,12]],"date-time":"2014-02-12T13:36:40Z","timestamp":1392212200000},"page":"703-713","source":"Crossref","is-referenced-by-count":17,"title":["Permeability of the blood\u2013tumor barrier is enhanced by combining vascular endothelial growth factor with papaverine"],"prefix":"10.1002","volume":"92","author":[{"given":"Zhi\u2010hang","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Neurobiology College of Basic Medicine China Medical University Shenyang People's Republic of China"},{"name":"Institute of Pathology and Pathophysiology China Medical University Shenyang People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li\u2010bo","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurobiology College of Basic Medicine China Medical University Shenyang People's Republic of China"},{"name":"Institute of Pathology and Pathophysiology China Medical University Shenyang People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li\u2010ni","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neurobiology College of Basic Medicine China Medical University Shenyang People's Republic of China"},{"name":"Institute of Pathology and Pathophysiology China Medical University Shenyang People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yun\u2010hui","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Shengjing Hospital of China Medical University Shenyang People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi\u2010xue","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Neurobiology College of Basic Medicine China Medical University Shenyang People's Republic of China"},{"name":"Institute of Pathology and Pathophysiology China Medical University Shenyang People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,2,12]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0008727"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.33.23463"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2011.10.016"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0145-2126(03)00256-X"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1677\/jme.0.0320325"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1469-7580.2002.00065.x"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1006907608230"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1062688"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1177\/002215540104900401"},{"key":"e_1_2_5_11_1","first-page":"1926","article-title":"Vascular permeability factor\/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis","volume":"146","author":"Dvorak HF","year":"1995","journal-title":"Am J Pathol"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1006\/mvre.2001.2333"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.01-0938fje"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1006\/mvre.2001.2367"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199512283332608"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01248.2007"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.123.6.1777"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.127.6.1617"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-0173(01)00102-3"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.110.14.1603"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.186056"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-4827(03)00354-9"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.24.15099"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-021909-135833"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/bem.20138"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2007.00083.x"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425240903167942"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0902687"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pathol.1.110304.100043"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-005-9068-y"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1999.276.5.C1148"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1186\/1476-511X-8-8"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1139\/y93-034"},{"key":"e_1_2_5_34_1","first-page":"8899","article-title":"Adenosine 5\u2010triphosphate\u2010sensitive potassium channel\u2010mediated blood\u2013brain tumor barrier permeability increase in a rat brain tumor model","volume":"63","author":"Ningaraj NS","year":"2003","journal-title":"Cancer Res"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(71)90086-5"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(78)90312-X"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.260166"},{"key":"e_1_2_5_38_1","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1242\/jcs.114.4.739","article-title":"Internalization of the M2 muscarinic acetylcholine receptor proceeds through an atypical pathway in HEK293 cells that is independent of clathrin and caveolae","volume":"114","author":"Roseberry AG","year":"2001","journal-title":"J Cell Sci"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00665960"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2011.02.015"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.3171\/jns.1987.67.5.0697"},{"key":"e_1_2_5_42_1","first-page":"914","article-title":"Cyclic GMP\u2010specific phosphodiesterase inhibition and intracarotid bradykinin infusion enhances permeability into brain tumors","volume":"58","author":"Sugita M","year":"1998","journal-title":"Cancer Res"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2007.060693"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M703153200"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2990.2006.00815.x"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-010-0321-7"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6600075"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1537-1891(02)00200-8"},{"key":"e_1_2_5_49_1","first-page":"751","article-title":"Opening blood\u2013brain barrier by intracarotid infusion of papaverine in treatment of malignant cerebral glioma","volume":"111","author":"Xue H","year":"1998","journal-title":"Chin Med J (Engl)"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1537-1891(03)00010-7"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI9369"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12031-010-9487-x"},{"key":"e_1_2_5_53_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.172360799"}],"container-title":["Journal of Neuroscience Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjnr.23348","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jnr.23348","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T02:49:43Z","timestamp":1696387783000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jnr.23348"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,2,12]]},"references-count":52,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2014,6]]}},"alternative-id":["10.1002\/jnr.23348"],"URL":"https:\/\/doi.org\/10.1002\/jnr.23348","archive":["Portico"],"relation":{},"ISSN":["0360-4012","1097-4547"],"issn-type":[{"value":"0360-4012","type":"print"},{"value":"1097-4547","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,2,12]]}}}