{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:32:40Z","timestamp":1791361960414,"version":"4.3.1"},"reference-count":25,"publisher":"Journal of Neurosurgery Publishing Group (JNSPG)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,9]]},"abstract":"<jats:sec><jats:title>OBJECTIVE<\/jats:title><jats:p>Therapeutic neovascularization is a promising strategy for treating patients after an ischemic stroke; however, single-factor therapy has limitations. Stromal cell-derived factor 1 (SDF-1) and vascular endothelial growth factor (VEGF) proteins synergistically promote angiogenesis. In this study, the authors assessed the effect of combined gene therapy with <jats:italic>VEGF<jats:sub>165<\/jats:sub><\/jats:italic> and <jats:italic>SDF-1<\/jats:italic> in a rat model of cerebral infarction.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>An adenoviral vector expressing <jats:italic>VEGF<jats:sub>165<\/jats:sub><\/jats:italic> and <jats:italic>SDF-1<\/jats:italic> connected via an internal ribosome entry site was constructed (Ad-<jats:italic>VEGF<jats:sub>165<\/jats:sub>-SDF-1<\/jats:italic>). A rat model of middle cerebral artery occlusion (MCAO) was established; either Ad-<jats:italic>VEGF<jats:sub>165<\/jats:sub>-SDF-1<\/jats:italic> or control adenovirus Ad-<jats:italic>LacZ<\/jats:italic> was stereotactically microinjected into the lateral ventricle of 80 rats 24 hours after MCAO. Coexpression and distribution of <jats:italic>VEGF<jats:sub>165<\/jats:sub><\/jats:italic> and <jats:italic>SDF-1<\/jats:italic> were examined by reverse-transcription polymerase chain reaction, Western blotting, and immunofluorescence. The neurological severity score of each rat was measured on Days 3, 7, 14, 21, and 28 after MCAO. Angiogenesis and vascular remodeling were evaluated via bromodeoxyuridine and CD34 immunofluorescence labeling. Relative cerebral infarction volumes were determined by T2-weighted MRI and triphenyltetrazolium chloride staining. Cerebral blood flow, relative cerebral blood volume, and relative mean transmit time were assessed using perfusion-weighted MRI.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>The Ad-<jats:italic>VEGF<jats:sub>165<\/jats:sub>-SDF-1<\/jats:italic> vector mediated coexpression of <jats:italic>VEGF<jats:sub>165<\/jats:sub><\/jats:italic> and <jats:italic>SDF-1<\/jats:italic> in multiple sites around the ischemic core, including the cortex, corpus striatum, and hippocampal granular layer. Coexpression of <jats:italic>VEGF<jats:sub>165<\/jats:sub><\/jats:italic> and <jats:italic>SDF-1<\/jats:italic> improved neural function, reduced cerebral infarction volume, increased microvascular density and promoted angiogenesis in the ischemic penumbra, and improved cerebral blood flow and perfusion.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>Combined <jats:italic>VEGF<jats:sub>165<\/jats:sub><\/jats:italic> and <jats:italic>SDF-1<\/jats:italic> gene therapy represents a potential strategy for improving vascular remodeling and recovery of neural function after cerebral infarction.<\/jats:p><\/jats:sec>","DOI":"10.3171\/2016.9.jns161234","type":"journal-article","created":{"date-parts":[[2016,12,16]],"date-time":"2016-12-16T15:54:04Z","timestamp":1481903644000},"page":"670-678","source":"Crossref","is-referenced-by-count":15,"title":["Effect of combined VEGF165\/SDF-1 gene therapy on vascular remodeling and blood perfusion in cerebral ischemia"],"prefix":"10.3171","volume":"127","author":[{"given":"Guo-jie","family":"Hu","sequence":"first","affiliation":[{"name":"Departments of Traditional Chinese Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-gong","family":"Feng","sequence":"additional","affiliation":[{"name":"Neurosurgery, Affiliated Hospital of Qingdao University; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-peng","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, People's Hospital of Jining, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan-ting","family":"Li","sequence":"additional","affiliation":[{"name":"Neurosurgery, Affiliated Hospital of Qingdao University; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-wei","family":"Xie","sequence":"additional","affiliation":[{"name":"Neurosurgery, Affiliated Hospital of Qingdao University; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-fang","family":"Li","sequence":"additional","affiliation":[{"name":"Neurosurgery, Affiliated Hospital of Qingdao University; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1754","reference":[{"key":"b1-jns161234","series-title":"PLoS One","doi-asserted-by":"publisher","first-page":"e0131445","DOI":"10.1371\/journal.pone.0131445","article-title":"The role of vascular endothelial growth factor receptor-1 signaling in the recovery from ischemia","volume":"10","author":"Amano H,","year":"2015","unstructured":"Amano H, Kato S, Ito Y, Eshima K, Ogawa F, Takahashi R, : The role of vascular endothelial growth factor receptor-1 signaling in the recovery from ischemia. PLoS One 10:e0131445, 20152613398910.1371\/journal.pone.0131445"},{"key":"b2-jns161234","series-title":"Nat Med","doi-asserted-by":"publisher","first-page":"1609","DOI":"10.1038\/nm.2990","article-title":"Not just a rush of blood to the head","volume":"18","author":"Brumm AJ,","year":"2012","unstructured":"Brumm AJ, Carmichael ST: Not just a rush of blood to the head. Nat Med 18:1609\u20131610, 201210.1038\/nm.299023135507"},{"key":"b3-jns161234","series-title":"Stroke","doi-asserted-by":"publisher","first-page":"2244","DOI":"10.1161\/STROKEAHA.108.541128","article-title":"Update of the stroke therapy academic industry roundtable preclinical recommendations","volume":"40","author":"Fisher M,","year":"2009","unstructured":"Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SI, : Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke 40:2244\u20132250, 20091924669010.1161\/STROKEAHA.108.541128"},{"issue":"Suppl 8","key":"b4-jns161234","series-title":"Epilepsia","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1111\/j.1528-1167.2011.03227.x","article-title":"Blood-brain barrier dysfunction, status epilepticus, seizures, and epilepsy: a puzzle of a chicken and egg?","volume":"52","author":"Friedman A:","year":"2011","unstructured":"Friedman A: Blood-brain barrier dysfunction, status epilepticus, seizures, and epilepsy: a puzzle of a chicken and egg?. Epilepsia 52:Suppl 819\u201320, 201110.1111\/j.1528-1167.2011.03227.x21967353"},{"key":"b5-jns161234","series-title":"Cell","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.cell.2005.10.036","article-title":"VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells.","volume":"124","author":"Grunewald M,","year":"2006","unstructured":"Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Jung S, : VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells.. Cell 124:175\u2013189, 2006. (Erratum in Cell 126: 811, 2006)1641349010.1016\/j.cell.2005.10.036"},{"key":"b6-jns161234","series-title":"Circulation","doi-asserted-by":"publisher","first-page":"1772","DOI":"10.1161\/CIRCULATIONAHA.114.013003","article-title":"Vascular signal transducer and activator of transcription-3 promotes angiogenesis and neuroplasticity long-term after stroke","volume":"131","author":"Hoffmann CJ,","year":"2015","unstructured":"Hoffmann CJ, Harms U, Rex A, Szulzewsky F, Wolf SA, Grittner U, : Vascular signal transducer and activator of transcription-3 promotes angiogenesis and neuroplasticity long-term after stroke. Circulation 131:1772\u20131782, 201510.1161\/CIRCULATIONAHA.114.01300325794850"},{"key":"b7-jns161234","series-title":"Nat Med","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1038\/nm1400","article-title":"Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes","volume":"12","author":"Jin DK,","year":"2006","unstructured":"Jin DK, Shido K, Kopp HG, Petit I, Shmelkov SV, Young LM, : Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes. Nat Med 12:557\u2013567, 20061664885910.1038\/nm1400"},{"key":"b8-jns161234","series-title":"Epilepsia","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1111\/j.1528-1167.2008.01718.x","article-title":"Region-specific plasticity in the epileptic rat brain: a hippocampal and extrahippocampal analysis","volume":"50","author":"Jung KH,","year":"2009","unstructured":"Jung KH, Chu K, Lee ST, Kim JH, Kang KM, Song EC, : Region-specific plasticity in the epileptic rat brain: a hippocampal and extrahippocampal analysis. Epilepsia 50:537\u2013549, 200910.1111\/j.1528-1167.2008.01718.x"},{"key":"b9-jns161234","series-title":"Science","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1126\/science.1251141","article-title":"Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors","volume":"344","author":"Katsimpardi L,","year":"2014","unstructured":"Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, : Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344:630\u2013634, 20142479748210.1126\/science.1251141"},{"key":"b10-jns161234","series-title":"J Cereb Blood Flow Metab","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1097\/00004647-200405000-00009","article-title":"Characterization of BrdU-positive neurons induced by transient global ischemia in adult hippocampus","volume":"24","author":"Kawai T,","year":"2004","unstructured":"Kawai T, Takagi N, Miyake-Takagi K, Okuyama N, Mochizuki N, Takeo S: Characterization of BrdU-positive neurons induced by transient global ischemia in adult hippocampus. J Cereb Blood Flow Metab 24:548\u2013555, 20041512918710.1097\/00004647-200405000-00009"},{"key":"b11-jns161234","series-title":"Neurosurgery","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1227\/01.NEU.0000349931.61771.52","article-title":"Recombinant adeno-associated virus serotype 1-vascular endothelial growth factor promotes neurogenesis and neuromigration in the subventricular zone and rescues neuronal function in ischemic rats","volume":"65","author":"Li SF,","year":"2009","unstructured":"Li SF, Sun YB, Meng QH, Li SR, Yao WC, Hu GJ, : Recombinant adeno-associated virus serotype 1-vascular endothelial growth factor promotes neurogenesis and neuromigration in the subventricular zone and rescues neuronal function in ischemic rats. Neurosurgery 65:771\u2013779, 20091983438310.1227\/01.NEU.0000349931.61771.52"},{"key":"b12-jns161234","series-title":"Brain Res","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.brainres.2006.09.042","article-title":"Intraventricular infusion of rAAV1-EGFP resulted in transduction in multiple regions of adult rat brain: a comparative study with rAAV2 and rAAV5 vectors","volume":"1122","author":"Li SF,","year":"2006","unstructured":"Li SF, Wang RZ, Meng QH, Li GL, Hu GJ, Dou WC, : Intraventricular infusion of rAAV1-EGFP resulted in transduction in multiple regions of adult rat brain: a comparative study with rAAV2 and rAAV5 vectors. Brain Res 1122:1\u20139, 200610.1016\/j.brainres.2006.09.042"},{"key":"b13-jns161234","series-title":"Neurology","doi-asserted-by":"publisher","first-page":"1666","DOI":"10.1212\/WNL.56.12.1666","article-title":"Treatment of stroke in rat with intracarotid administration of marrow stromal cells","volume":"56","author":"Li Y,","year":"2001","unstructured":"Li Y, Chen J, Wang L, Lu M, Chopp M: Treatment of stroke in rat with intracarotid administration of marrow stromal cells. Neurology 56:1666\u20131672, 20011142593110.1212\/WNL.56.12.1666"},{"key":"b14-jns161234","series-title":"Neurol Res","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1179\/174313208X309720","article-title":"Intraventricular pre-treatment with rAAV-VEGF induces intracranial hypertension and aggravates ischemic injury at the early stage of transient focal cerebral ischemia in rats","volume":"30","author":"Li Z,","year":"2008","unstructured":"Li Z, Wang R, Li S, Wei J, Zhang Z, Li G, : Intraventricular pre-treatment with rAAV-VEGF induces intracranial hypertension and aggravates ischemic injury at the early stage of transient focal cerebral ischemia in rats. Neurol Res 30:868\u2013875, 200810.1179\/174313208X30972018534058"},{"key":"b15-jns161234","series-title":"J Biomed Biotechnol","doi-asserted-by":"publisher","first-page":"464701","DOI":"10.1155\/2011\/464701","article-title":"Middle cerebral artery occlusion model in rodents: methods and potential pitfalls","volume":"2011","author":"Liu F,","year":"2011","unstructured":"Liu F, McCullough LD: Middle cerebral artery occlusion model in rodents: methods and potential pitfalls. J Biomed Biotechnol 2011:464701, 20112133135710.1155\/2011\/464701"},{"key":"b16-jns161234","series-title":"Curr Gene Ther","doi-asserted-by":"publisher","first-page":"15","DOI":"10.2174\/1566523044578095","article-title":"Exploiting internal ribosome entry sites in gene therapy vector design","volume":"4","author":"Ngoi SM,","year":"2004","unstructured":"Ngoi SM, Chien AC, Lee CG: Exploiting internal ribosome entry sites in gene therapy vector design. Curr Gene Ther 4:15\u201331, 200410.2174\/156652304457809515032611"},{"key":"b17-jns161234","series-title":"J Neurosci","doi-asserted-by":"publisher","first-page":"13007","DOI":"10.1523\/JNEUROSCI.4323-06.2006","article-title":"A neurovascular niche for neurogenesis after stroke","volume":"26","author":"Ohab JJ,","year":"2006","unstructured":"Ohab JJ, Fleming S, Blesch A, Carmichael ST: A neurovascular niche for neurogenesis after stroke. J Neurosci 26:13007\u201313016, 200610.1523\/JNEUROSCI.4323-06.200617167090"},{"key":"b18-jns161234","series-title":"Zhonghua Yi Xue Za Zhi","first-page":"544","article-title":"[Construction of recombinant adenovirus vector co-expressing VEGF165 and SDF-1 genes and its expression in ischemic cerebral tissue of rats.]","volume":"94","author":"Si J,","year":"2014","unstructured":"Si J, Hu G, Zhu H, Li S, Meng Q, Yao W, : [Construction of recombinant adenovirus vector co-expressing VEGF165 and SDF-1 genes and its expression in ischemic cerebral tissue of rats.]. Zhonghua Yi Xue Za Zhi 94:544\u2013548, 2014. (Chinese)24767301"},{"key":"b19-jns161234","series-title":"Blood","doi-asserted-by":"publisher","first-page":"5102","DOI":"10.1182\/blood-2009-07-230284","article-title":"Microarray analysis of retinal endothelial tip cells identifies CXCR4 as a mediator of tip cell morphology and branching","volume":"115","author":"Strasser GA,","year":"2010","unstructured":"Strasser GA, Kaminker JS, Tessier-Lavigne M: Microarray analysis of retinal endothelial tip cells identifies CXCR4 as a mediator of tip cell morphology and branching. Blood 115:5102\u20135110, 201010.1182\/blood-2009-07-23028420154215"},{"key":"b20-jns161234","series-title":"J Cereb Blood Flow Metab","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1038\/jcbfm.1990.47","article-title":"A semiautomated method for measuring brain infarct volume","volume":"10","author":"Swanson RA,","year":"1990","unstructured":"Swanson RA, Morton MT, Tsao-Wu G, Savalos RA, Davidson C, Sharp FR: A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab 10:290\u2013293, 1990168932210.1038\/jcbfm.1990.47"},{"key":"b21-jns161234","series-title":"Mol Cell Biochem","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1007\/s11010-009-0374-0","article-title":"Combination of chemokine and angiogenic factor genes and mesenchymal stem cells could enhance angiogenesis and improve cardiac function after acute myocardial infarction in rats","volume":"339","author":"Tang J,","year":"2010","unstructured":"Tang J, Wang J, Zheng F, Kong X, Guo L, Yang J, : Combination of chemokine and angiogenic factor genes and mesenchymal stem cells could enhance angiogenesis and improve cardiac function after acute myocardial infarction in rats. Mol Cell Biochem 339:107\u2013118, 201010.1007\/s11010-009-0374-020058054"},{"key":"b22-jns161234","series-title":"Cardiovasc Res","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1093\/cvr\/cvr053","article-title":"VEGF\/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart","volume":"91","author":"Tang JM,","year":"2011","unstructured":"Tang JM, Wang JN, Zhang L, Zheng F, Yang JY, Kong X, : VEGF\/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart. Cardiovasc Res 91:402\u2013411, 201110.1093\/cvr\/cvr05321345805"},{"key":"b23-jns161234","series-title":"Invest Ophthalmol Vis Sci","doi-asserted-by":"publisher","first-page":"3362","DOI":"10.1167\/iovs.09-4978","article-title":"SDF-1\/CXCR4 contributes to the activation of tip cells and microglia in retinal angiogenesis","volume":"51","author":"Unoki N,","year":"2010","unstructured":"Unoki N, Murakami T, Nishijima K, Ogino K, van Rooijen N, Yoshimura N: SDF-1\/CXCR4 contributes to the activation of tip cells and microglia in retinal angiogenesis. Invest Ophthalmol Vis Sci 51:3362\u20133371, 201010.1167\/iovs.09-497820181837"},{"key":"b24-jns161234","series-title":"Circulation","doi-asserted-by":"publisher","first-page":"1322","DOI":"10.1161\/01.CIR.0000055313.77510.22","article-title":"Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization","volume":"107","author":"Yamaguchi J,","year":"2003","unstructured":"Yamaguchi J, Kusano KF, Masuo O, Kawamoto A, Silver M, Murasawa S, : Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation 107:1322\u20131328, 200310.1161\/01.CIR.0000055313.77510.2212628955"},{"key":"b25-jns161234","series-title":"Blood","doi-asserted-by":"publisher","first-page":"3546","DOI":"10.1182\/blood-2005-08-3215","article-title":"Bone marrow mononuclear cells are recruited to the sites of VEGF-induced neovascularization but are not incorporated into the newly formed vessels","volume":"107","author":"Zentilin L,","year":"2006","unstructured":"Zentilin L, Tafuro S, Zacchigna S, Arsic N, Pattarini L, Sinigaglia M, : Bone marrow mononuclear cells are recruited to the sites of VEGF-induced neovascularization but are not incorporated into the newly formed vessels. Blood 107:3546\u20133554, 20061639101610.1182\/blood-2005-08-3215"}],"container-title":["Journal of Neurosurgery"],"original-title":[],"link":[{"URL":"https:\/\/thejns.org\/view\/journals\/j-neurosurg\/127\/3\/article-p670.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/thejns.org\/downloadpdf\/journals\/j-neurosurg\/127\/3\/article-p670.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/thejns.org\/downloadpdf\/journals\/j-neurosurg\/127\/3\/article-p670.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,23]],"date-time":"2025-03-23T02:45:13Z","timestamp":1742697913000},"score":1,"resource":{"primary":{"URL":"https:\/\/thejns.org\/view\/journals\/j-neurosurg\/127\/3\/article-p670.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9]]},"references-count":25,"journal-issue":{"issue":"3"},"URL":"https:\/\/doi.org\/10.3171\/2016.9.jns161234","relation":{},"ISSN":["0022-3085","1933-0693"],"issn-type":[{"value":"0022-3085","type":"print"},{"value":"1933-0693","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9]]}}}