{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:32:39Z","timestamp":1791361959772,"version":"4.3.1"},"reference-count":44,"publisher":"Portland Press Ltd.","issue":"10","license":[{"start":{"date-parts":[[2019,10,15]],"date-time":"2019-10-15T00:00:00Z","timestamp":1571097600000},"content-version":"vor","delay-in-days":14,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,10,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Rationale: Houshiheisan (HSHS), a classic prescription in traditional Chinese medicine (TCM), has remarkable efficacy in the treatment of ischemic stroke.<\/jats:p>\n               <jats:p>Objective: To investigate the pro-angiogenic effect and molecular mechanism of HSHS for stroke recovery.<\/jats:p>\n               <jats:p>Methods and results: The rat permanent middle cerebral artery occlusion (pMCAO) model was constructed by suture method, HSHS (5.25 or 10.5 g\/kg) and Ginaton (28 mg\/kg) treatment was intragastrically administrated at 6 h after modeling which remained for 7 consecutive days. Pathological evaluation conducted by Hematoxylin\u2013Eosin (HE) staining and the results showed that HSHS alleviated blood vessel edema, reduced the damage to blood vessels and neurons in the ischemic areas. Immunostaining, quantitative real-time fluorescence PCR results showed that HSHS up-regulated pro-angiogenic factors including platelet endothelial cell adhesion molecule-1 (cluster of differentiation 31 (CD31)), vascular endothelial growth factor (VEGF), vascular endothelial growth factor A (VEGFA), VEGF receptor 2 (VEGFR2), angiopoietin-1 (Ang-1), while down-regulated angiopoietin-2 (Ang-2), stromal cell derived factor-1 (SDF-1), and cxc chemokine receptor 4 (CXCR4) expression in infarct rat cortex, and similar results were obtained in subsequent Western blot experiment. Furthermore, CCK8 assay and transwell migration assay were performed to assess cell proliferation, migration, and tube formation. The medicated serum (MS) of HSHS appeared to have beneficial effects for immortalized human umbilical vein cells (Im-HUVECs) on proliferation and migration after persistence hypoxia. Western blot analysis revealed that the expression of hypoxia inducible factor-1\u03b1 (HIF-1\u03b1), VEGFA, Ang-1, Ang-2, and CXCR4 were significantly up-regulated while Ang-2 was down-regulated by HSHS MS treatment compared with vehicle group in vitro.<\/jats:p>\n               <jats:p>Conclusion: The present study suggests a novel application of HSHS as an effective angiogenic formula for stroke recovery.<\/jats:p>","DOI":"10.1042\/bsr20191006","type":"journal-article","created":{"date-parts":[[2019,10,15]],"date-time":"2019-10-15T10:52:19Z","timestamp":1571136739000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Houshiheisan promotes angiogenesis via HIF-1\u03b1\/VEGF and SDF-1\/CXCR4 pathways: <i>in vivo<\/i> and <i>in vitro<\/i>"],"prefix":"10.1042","volume":"39","author":[{"given":"Yangyang","family":"Xiang","sequence":"first","affiliation":[{"name":"School of Traditional Chinese Medicine, Capital Medical University, Beijing, China"},{"name":"Beijing Key Lab of TCM Collateral Disease Theory Research, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoquan","family":"Yao","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Capital Medical University, Beijing, China"},{"name":"Beijing Key Lab of TCM Collateral Disease Theory Research, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Capital Medical University, Beijing, China"},{"name":"Beijing Key Lab of TCM Collateral Disease Theory Research, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Capital Medical University, Beijing, China"},{"name":"Beijing Key Lab of TCM Collateral Disease Theory Research, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Zou","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Capital Medical University, Beijing, China"},{"name":"Beijing Key Lab of TCM Collateral Disease Theory Research, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Capital Medical University, Beijing, China"},{"name":"Beijing Key Lab of TCM Collateral Disease Theory Research, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6751-5699","authenticated-orcid":false,"given":"Qiu-Xia","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Capital Medical University, Beijing, China"},{"name":"Beijing Key Lab of TCM Collateral Disease Theory Research, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2019,10,15]]},"reference":[{"key":"2021111619522815800_B1","first-page":"8079578","article-title":"Treatment outcomes and associated factors among hospitalized stroke patients at Shashemene Referral Hospital, Ethiopia","volume":"2018","author":"Temesgen","year":"2018","journal-title":"Stroke Res. Treat."},{"key":"2021111619522815800_B2","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1186\/1748-5908-9-38","article-title":"Thrombolysis ImPlementation in Stroke (TIPS): evaluating the effectiveness of a strategy to increase the adoption of best evidence practice\u2013protocol for a cluster randomised controlled trial in acute stroke care","volume":"9","author":"Paul","year":"2014","journal-title":"Implement. Sci."},{"key":"2021111619522815800_B3","doi-asserted-by":"publisher","first-page":"S54","DOI":"10.1161\/STROKEAHA.110.596106","article-title":"Annexin A2: a tissue plasminogen activator amplifier for thrombolytic stroke therapy","volume":"41","author":"Fan","year":"2010","journal-title":"Stroke"},{"key":"2021111619522815800_B4","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.pneurobio.2013.11.004","article-title":"Vascular remodeling after ischemic stroke: mechanisms and therapeutic potentials","volume":"115","author":"Liu","year":"2013","journal-title":"Prog. Neurobiol."},{"key":"2021111619522815800_B5","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1038\/jcbfm.2013.162","article-title":"Augmenting collateral blood flow during ischemic stroke via transient aortic occlusion","volume":"34","author":"Winship","year":"2013","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"2021111619522815800_B6","doi-asserted-by":"publisher","first-page":"e2706","DOI":"10.1038\/cddis.2017.123","article-title":"MiRNA199a-3p suppresses tumor growth, migration, invasion and angiogenesis in hepatocellular carcinoma by targeting VEGFA, VEGFR1, VEGFR2, HGF and MMP2","volume":"8","author":"Ghosh","year":"2017","journal-title":"Cell Death Dis."},{"key":"2021111619522815800_B7","doi-asserted-by":"publisher","first-page":"H687","DOI":"10.1152\/ajpheart.00744.2012","article-title":"The myosin motor Myo1c is required for VEGFR2 delivery to the cell surface and for angiogenic signaling","volume":"304","author":"Tiwari","year":"2012","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"2021111619522815800_B8","doi-asserted-by":"publisher","first-page":"3352","DOI":"10.1074\/jbc.M113.507194","article-title":"Endoplasmic reticulum (ER) stress and hypoxia response pathways interact to potentiate hypoxia-inducible factor 1 (HIF-1) transcriptional activity on targets like vascular endothelial growth factor (VEGF)","volume":"289","author":"Pereira","year":"2013","journal-title":"J. Biol. Chem."},{"key":"2021111619522815800_B9","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1016\/j.tins.2012.06.003","article-title":"Chemokine CXCL12 in neurodegenerative diseases: an SOS signal for stem cell-based repair","volume":"35","author":"Li","year":"2012","journal-title":"Trends Neurosci."},{"key":"2021111619522815800_B10","doi-asserted-by":"publisher","first-page":"1293","DOI":"10.1161\/CIRCRESAHA.109.197533","article-title":"Inhibition of the SDF-1\/CXCR4 axis attenuates neonatal hypoxia-induced pulmonary hypertension","volume":"104","author":"Young","year":"2009","journal-title":"Circ. Res."},{"key":"2021111619522815800_B11","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1186\/s12906-018-2364-9","article-title":"Baicalin promotes apoptosis and inhibits proliferation and migration of hypoxia-induced pulmonary artery smooth muscle cells by up-regulating A2a receptor via the SDF-1\/CXCR4 signaling pathway","volume":"18","author":"Huang","year":"2018","journal-title":"BMC Complement. Alternat. Med."},{"key":"2021111619522815800_B12","first-page":"21","article-title":"Clinical observation of 20 cases of cerebral ischemic stroke sequela treated with HSHS","volume":"15","author":"Deng","year":"2017","journal-title":"Guiding J. Trad. Chinese Med. Pharm."},{"key":"2021111619522815800_B13","first-page":"140","article-title":"45 cases of acute ischemic stroke treat with Houshiheisan and modern medicine","volume":"13","author":"Cai","year":"2015","journal-title":"Chin. Med. Modern Distance Edu. China"},{"key":"2021111619522815800_B14","first-page":"42","article-title":"Therapeutic effect of Houshiheisan on sciatica caused by lumbar disc herniation","volume":"33","author":"Zhao","year":"2017","journal-title":"Shanxi J. Trad. Chinese Med."},{"key":"2021111619522815800_B15","first-page":"26","article-title":"53 cases of cervical hypertension treat with Houshiheisan","volume":"5","author":"Pi","year":"2008","journal-title":"J. Pract. Trad. Chinese Int. Med."},{"key":"2021111619522815800_B16","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.4103\/1673-5374.235031","article-title":"Houshiheisan and its components promote axon regeneration after ischemic brain injury","volume":"13","author":"Lu","year":"2018","journal-title":"Neural Regen. Res."},{"key":"2021111619522815800_B17","doi-asserted-by":"publisher","first-page":"1032","DOI":"10.1016\/j.jep.2016.11.005","article-title":"BDNF\/PI3K\/Akt and Nogo-A\/RhoA\/ROCK signaling pathways contribute to neurorestorative effect of Houshiheisan against cerebral ischemia injury in rats","volume":"194","author":"Chang","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"2021111619522815800_B18","doi-asserted-by":"publisher","first-page":"11495","DOI":"10.1523\/JNEUROSCI.1741-11.2011","article-title":"Mild sensory stimulation reestablishes cortical function during the acute phase of ischemia","volume":"31","author":"Lay","year":"2011","journal-title":"J. Neurosci."},{"key":"2021111619522815800_B19","first-page":"9050754","article-title":"Evaluation of decalcification techniques for rat femurs using HE and immunohistochemical staining","volume":"2017","author":"Liu","year":"2017","journal-title":"Biomed Res. Int."},{"key":"2021111619522815800_B20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/15548627.2018.1476811","article-title":"RAB26-dependent autophagy protects adherens junctional integrity in acute lung injury","author":"Dong","year":"2018","journal-title":"Autophagy"},{"key":"2021111619522815800_B21","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/s13287-018-0777-5","article-title":"Therapeutic effect of human umbilical cord-derived mesenchymal stem cells on injured rat endometrium during its chronic phase","volume":"9","author":"Zhang","year":"2018","journal-title":"Stem Cell Res. Ther."},{"key":"2021111619522815800_B22","doi-asserted-by":"publisher","first-page":"6857398","DOI":"10.1155\/2018\/6857398","article-title":"Long-Zhi decoction medicated serum promotes angiogenesis in human umbilical vein endothelial cells based on autophagy","volume":"2018","author":"He","year":"2018","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"2021111619522815800_B23","doi-asserted-by":"publisher","first-page":"e0149537","DOI":"10.1371\/journal.pone.0149537","article-title":"The angiogenic effect of microRNA-21 targeting TIMP3 through the regulation of MMP2 and MMP9","volume":"11","author":"Hu","year":"2016","journal-title":"PLoS ONE"},{"key":"2021111619522815800_B24","doi-asserted-by":"publisher","first-page":"21565","DOI":"10.1038\/srep21565","article-title":"A microRNA-mediated decrease in eukaryotic initiation factor 2\u03b1 promotes cell survival during PS-341 treatment","volume":"6","author":"Jiang","year":"2016","journal-title":"Sci. Rep."},{"key":"2021111619522815800_B25","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1161\/CIRCRESAHA.118.312945","article-title":"Binding of Dickkopf-3 to CXCR7 enhances vascular progenitor cell migration and degradable graft regeneration","volume":"123","author":"Issa Bhaloo","year":"2018","journal-title":"Circ. Res."},{"key":"2021111619522815800_B26","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/1471-2377-13-32","article-title":"Clinical significance of plasma VEGF value in ischemic stroke - research for biomarkers in ischemic stroke (REBIOS) study","volume":"13","author":"Matsuo","year":"2013","journal-title":"BMC Neurol."},{"key":"2021111619522815800_B27","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.pneurobio.2013.11.004","article-title":"Vascular remodeling after ischemic stroke: mechanisms and therapeutic potentials","volume":"115","author":"Liu","year":"2013","journal-title":"Prog. Neurobiol."},{"key":"2021111619522815800_B28","first-page":"1639","article-title":"Angiogenic effects of apigenin on endothelial cells after hypoxia-reoxygenation via the caveolin-1 pathway","volume":"40","author":"Tu","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"2021111619522815800_B29","doi-asserted-by":"publisher","first-page":"741","DOI":"10.4103\/1673-5374.131580","article-title":"Houshiheisan compound prescription protects neurovascular units after cerebral ischemia","volume":"9","author":"Wang","year":"2014","journal-title":"Neural Regen. Res."},{"key":"2021111619522815800_B30","doi-asserted-by":"publisher","first-page":"2187","DOI":"10.15252\/embj.201696150","article-title":"Endothelial cell metabolism in health and disease: impact of hypoxia","volume":"36","author":"Wong","year":"2017","journal-title":"EMBO J."},{"key":"2021111619522815800_B31","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1016\/0006-291X(89)92678-8","article-title":"Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells","volume":"161","author":"Ferrara","year":"1989","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021111619522815800_B32","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1038\/380439a0","article-title":"Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene","volume":"380","author":"Ferrara","year":"1996","journal-title":"Nature"},{"key":"2021111619522815800_B33","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1007\/s10456-017-9552-y","article-title":"Anti-angiogenesis for cancer revisited: is there a role for combinations with immunotherapy?","volume":"20","author":"Ramjiawan","year":"2017","journal-title":"Angiogenesis"},{"key":"2021111619522815800_B34","doi-asserted-by":"publisher","first-page":"1891","DOI":"10.1111\/j.1476-5381.2011.01677.x","article-title":"A novel angiopoietin-derived peptide displays anti-angiogenic activity and inhibits tumour-induced and retinal neovascularization","volume":"165","author":"Palmer","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"2021111619522815800_B35","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1186\/scrt324","article-title":"Mesenchymal stem cells modified with angiopoietin-1 gene promote wound healing","volume":"4","author":"Li","year":"2013","journal-title":"Stem Cell Res. Ther."},{"key":"2021111619522815800_B36","doi-asserted-by":"publisher","first-page":"1991","DOI":"10.1172\/JCI58832","article-title":"Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling","volume":"122","author":"Felcht","year":"2012","journal-title":"J. Clin. Invest."},{"key":"2021111619522815800_B37","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1007\/s10456-013-9349-6","article-title":"Inhibition of apelin expression switches endothelial cells from proliferative to mature state in pathological retinal angiogenesis","volume":"16","author":"Kasai","year":"2013","journal-title":"Angiogenesis"},{"key":"2021111619522815800_B38","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.biomaterials.2015.08.052","article-title":"Applications of stripe assay in the study of CXCL12-mediated neural progenitor cell migration and polarization","volume":"72","author":"Zhang","year":"2015","journal-title":"Biomaterials"},{"key":"2021111619522815800_B39","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1161\/CIRCRESAHA.109.197723","article-title":"Hypoxic preconditioning enhances the benefit of cardiac progenitor cell therapy for treatment of myocardial infarction by inducing CXCR4 expression","volume":"104","author":"Tang","year":"2009","journal-title":"Circ. Res."},{"key":"2021111619522815800_B40","doi-asserted-by":"publisher","first-page":"e90400","DOI":"10.1371\/journal.pone.0090400","article-title":"CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis","volume":"9","author":"Roy","year":"2014","journal-title":"PLoS ONE"},{"key":"2021111619522815800_B41","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1186\/1471-2202-6-63","article-title":"The neuroblast and angioblast chemotaxic factor SDF-1 (CXCL12) expression is briefly up regulated by reactive astrocytes in brain following neonatal hypoxic-ischemic injury","volume":"6","author":"Miller","year":"2005","journal-title":"BMC Neurosci."},{"key":"2021111619522815800_B42","doi-asserted-by":"publisher","first-page":"13061","DOI":"10.1038\/s41598-017-13436-7","article-title":"Ginsenoside Rb1 prevents homocysteine-induced EPC dysfunction via VEGF\/p38MAPK and SDF-1\/CXCR4 activation","volume":"7","author":"Lan","year":"2017","journal-title":"Sci. Rep."},{"key":"2021111619522815800_B43","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1146\/annurev-physiol-021113-170322","article-title":"Hypoxia-inducible factor 1 and cardiovascular disease","volume":"76","author":"Semenza","year":"2013","journal-title":"Annu. Rev. Physiol."},{"key":"2021111619522815800_B44","doi-asserted-by":"publisher","first-page":"4158","DOI":"10.1096\/fj.14-255711","article-title":"RLIP76 regulates HIF-1 activity, VEGF expression and secretion in tumor cells, and secretome transactivation of endothelial cells","volume":"28","author":"Lee","year":"2014","journal-title":"FASEB J."}],"container-title":["Bioscience Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/bioscirep\/article-pdf\/doi\/10.1042\/BSR20191006\/858901\/bsr-2019-1006.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/bioscirep\/article-pdf\/doi\/10.1042\/BSR20191006\/858901\/bsr-2019-1006.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T20:35:25Z","timestamp":1637094925000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/bioscirep\/article\/39\/10\/BSR20191006\/220749\/Houshiheisan-promotes-angiogenesis-via-HIF-1-VEGF"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10]]},"references-count":44,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2019,10,30]]}},"URL":"https:\/\/doi.org\/10.1042\/bsr20191006","relation":{},"ISSN":["0144-8463","1573-4935"],"issn-type":[{"value":"0144-8463","type":"print"},{"value":"1573-4935","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,10]]},"published":{"date-parts":[[2019,10]]},"article-number":"BSR20191006"}}