{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T16:32:32Z","timestamp":1786984352866,"version":"build-2736575974"},"reference-count":50,"publisher":"Elsevier BV","issue":"10","license":[{"start":{"date-parts":[[2017,10,1]],"date-time":"2017-10-01T00:00:00Z","timestamp":1506816000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2019,12,13]],"date-time":"2019-12-13T00:00:00Z","timestamp":1576195200000},"content-version":"vor","delay-in-days":803,"URL":"http:\/\/www.elsevier.com\/open-access\/userlicense\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["P01 CA-92644"],"award-info":[{"award-number":["P01 CA-92644"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["5 R01 CA196996-02"],"award-info":[{"award-number":["5 R01 CA196996-02"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["clinicalkey.jp","clinicalkey.com","ajp.amjpathol.org","clinicalkey.es","clinicalkey.com.au","clinicalkey.fr","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["The American Journal of Pathology"],"published-print":{"date-parts":[[2017,10]]},"DOI":"10.1016\/j.ajpath.2017.06.010","type":"journal-article","created":{"date-parts":[[2017,7,20]],"date-time":"2017-07-20T22:15:33Z","timestamp":1500588933000},"page":"2337-2347","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":32,"title":["Early Actions of Anti\u2013Vascular Endothelial Growth Factor\/Vascular Endothelial Growth Factor Receptor Drugs on Angiogenic Blood Vessels"],"prefix":"10.1016","volume":"187","author":[{"given":"Basel","family":"Sitohy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunghee","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracey E.","family":"Sciuto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Masse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter M.","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shou-Ching","family":"Jaminet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E.","family":"Benjamin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rupal S.","family":"Bhatt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann M.","family":"Dvorak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice A.","family":"Nagy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harold F.","family":"Dvorak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.ajpath.2017.06.010_bib1","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/labinvest.3700436","article-title":"Permeability properties of tumor surrogate blood vessels induced by VEGF-A","volume":"86","author":"Nagy","year":"2006","journal-title":"Lab Invest"},{"key":"10.1016\/j.ajpath.2017.06.010_bib2","series-title":"Cancer Drug Discovery and Function Antiangiogenic Agents in Cancer Therapy","first-page":"205","article-title":"Tumor blood vessels: structure, function, and classification","author":"Fu","year":"2007"},{"key":"10.1016\/j.ajpath.2017.06.010_bib3","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1146\/annurev.pathol.2.010506.134925","article-title":"VEGF-A and the induction of pathological angiogenesis","volume":"2","author":"Nagy","year":"2007","journal-title":"Annu Rev Pathol"},{"key":"10.1016\/j.ajpath.2017.06.010_bib4","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1016\/S0002-9440(10)64309-X","article-title":"Rous-Whipple Award Lecture. How tumors make bad blood vessels and stroma","volume":"162","author":"Dvorak","year":"2003","journal-title":"Am J Pathol"},{"key":"10.1016\/j.ajpath.2017.06.010_bib5","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.yexcr.2005.11.012","article-title":"Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis","volume":"312","author":"Shibuya","year":"2006","journal-title":"Exp Cell Res"},{"key":"10.1016\/j.ajpath.2017.06.010_bib6","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/labinvest.3780013","article-title":"Heterogeneity of the angiogenic response induced in different normal adult tissues by vascular permeability factor\/vascular endothelial growth factor","volume":"80","author":"Pettersson","year":"2000","journal-title":"Lab Invest"},{"key":"10.1016\/j.ajpath.2017.06.010_bib7","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0076-6879(08)02803-6","article-title":"Chapter 3. The adenoviral vector angiogenesis\/lymphangiogenesis assay","volume":"444","author":"Nagy","year":"2008","journal-title":"Methods Enzymol"},{"key":"10.1016\/j.ajpath.2017.06.010_bib8","first-page":"334","article-title":"First steps of tumor-related angiogenesis","volume":"65","author":"Paku","year":"1991","journal-title":"Lab Invest"},{"key":"10.1016\/j.ajpath.2017.06.010_bib9","series-title":"Tumor Blood Circulation: Angiogenesis, Vascular Morphology and Blood Flow of Experimental and Human Tumors","first-page":"1","article-title":"The vascular morphology of tumors","author":"Warren","year":"1979"},{"key":"10.1016\/j.ajpath.2017.06.010_bib10","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1084\/jem.20051523","article-title":"Orphan nuclear receptor TR3\/Nur77 regulates VEGF-A-induced angiogenesis through its transcriptional activity","volume":"203","author":"Zeng","year":"2006","journal-title":"J Exp Med"},{"key":"10.1016\/j.ajpath.2017.06.010_bib11","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/S0002-9440(10)64062-X","article-title":"Glomeruloid microvascular proliferation follows adenoviral vascular permeability factor\/vascular endothelial growth factor-164 gene delivery","volume":"158","author":"Sundberg","year":"2001","journal-title":"Am J Pathol"},{"key":"10.1016\/j.ajpath.2017.06.010_bib12","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/nrc2346","article-title":"Lessons from multidisciplinary translational trials on anti-angiogenic therapy of cancer","volume":"8","author":"Jain","year":"2008","journal-title":"Nat Rev Cancer"},{"key":"10.1016\/j.ajpath.2017.06.010_bib13","doi-asserted-by":"crossref","first-page":"41857","DOI":"10.18632\/oncotarget.9621","article-title":"Inhibition of ALK1 signaling with dalantercept combined with VEGFR TKI leads to tumor stasis in renal cell carcinoma","volume":"7","author":"Wang","year":"2016","journal-title":"Oncotarget"},{"key":"10.1016\/j.ajpath.2017.06.010_bib14","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/nrc2403","article-title":"VEGF-targeted therapy: mechanisms of anti-tumour activity","volume":"8","author":"Ellis","year":"2008","journal-title":"Nat Rev Cancer"},{"key":"10.1016\/j.ajpath.2017.06.010_bib15","first-page":"209","article-title":"Vascular endothelial growth factor: basic biology and clinical implications","volume":"79","author":"Ferrara","year":"1997","journal-title":"EXS"},{"key":"10.1016\/j.ajpath.2017.06.010_bib16","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1172\/JCI200317929","article-title":"Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors","volume":"111","author":"Bergers","year":"2003","journal-title":"J Clin Invest"},{"key":"10.1016\/j.ajpath.2017.06.010_bib17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1158\/2326-6066.CIR-14-0209","article-title":"Tumors: wounds that do not heal-redux","volume":"3","author":"Dvorak","year":"2015","journal-title":"Cancer Immunol Res"},{"key":"10.1016\/j.ajpath.2017.06.010_bib18","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.ccell.2014.10.006","article-title":"Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia","volume":"26","author":"Jain","year":"2014","journal-title":"Cancer Cell"},{"key":"10.1016\/j.ajpath.2017.06.010_bib19","doi-asserted-by":"crossref","first-page":"7021","DOI":"10.1158\/0008-5472.CAN-11-1693","article-title":"Tumor-surrogate blood vessel subtypes exhibit differential susceptibility to anti-VEGF therapy","volume":"71","author":"Sitohy","year":"2011","journal-title":"Cancer Res"},{"key":"10.1016\/j.ajpath.2017.06.010_bib20","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1158\/0008-5472.CAN-11-3406","article-title":"Anti-VEGF\/VEGFR therapy for cancer: reassessing the target","volume":"72","author":"Sitohy","year":"2012","journal-title":"Cancer Res"},{"key":"10.1016\/j.ajpath.2017.06.010_bib21","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.vph.2009.08.004","article-title":"Pharmacological inhibition of the hypertensive response to combretastatin A-4 phosphate in rats","volume":"51","author":"Ke","year":"2009","journal-title":"Vascul Pharmacol"},{"key":"10.1016\/j.ajpath.2017.06.010_bib22","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1074\/jbc.M508199200","article-title":"Cross-species vascular endothelial growth factor (VEGF)-blocking antibodies completely inhibit the growth of human tumor xenografts and measure the contribution of stromal VEGF","volume":"281","author":"Liang","year":"2006","journal-title":"J Biol Chem"},{"key":"10.1016\/j.ajpath.2017.06.010_bib23","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1158\/1078-0432.CCR-05-2257","article-title":"Roles of nitric oxide synthase inhibition and vascular endothelial growth factor receptor-2 inhibition on vascular morphology and function in an in\u00a0vivo model of pancreatic cancer","volume":"12","author":"Camp","year":"2006","journal-title":"Clin Cancer Res"},{"key":"10.1016\/j.ajpath.2017.06.010_bib24","doi-asserted-by":"crossref","first-page":"6573","DOI":"10.1158\/1078-0432.CCR-06-0831","article-title":"Anti-vascular endothelial growth factor receptor-1 antagonist antibody as a therapeutic agent for cancer","volume":"12","author":"Wu","year":"2006","journal-title":"Clin Cancer Res"},{"key":"10.1016\/j.ajpath.2017.06.010_bib25","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s10616-010-9315-8","article-title":"A multi-gene transcriptional profiling approach to the discovery of cell signature markers","volume":"63","author":"Wada","year":"2011","journal-title":"Cytotechnology"},{"key":"10.1016\/j.ajpath.2017.06.010_bib26","doi-asserted-by":"crossref","first-page":"4537","DOI":"10.1158\/0008-5472.CAN-08-4539","article-title":"VEGF-A induces angiogenesis by perturbing the cathepsin-cysteine protease inhibitor balance in venules, causing basement membrane degradation and mother vessel formation","volume":"69","author":"Chang","year":"2009","journal-title":"Cancer Res"},{"key":"10.1016\/j.ajpath.2017.06.010_bib27","doi-asserted-by":"crossref","first-page":"11393","DOI":"10.1073\/pnas.172398299","article-title":"VEGF-Trap: a VEGF blocker with potent antitumor effects","volume":"99","author":"Holash","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1016\/j.ajpath.2017.06.010_bib28","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/nrc1628","article-title":"Disrupting tumour blood vessels","volume":"5","author":"Tozer","year":"2005","journal-title":"Nat Rev Cancer"},{"key":"10.1016\/j.ajpath.2017.06.010_bib29","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1161\/HYPERTENSIONAHA.109.129973","article-title":"Vascular endothelial growth factor receptor 2 controls blood pressure by regulating nitric oxide synthase expression","volume":"54","author":"Facemire","year":"2009","journal-title":"Hypertension"},{"key":"10.1016\/j.ajpath.2017.06.010_bib30","first-page":"H1054","article-title":"VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells","volume":"274","author":"Hood","year":"1998","journal-title":"Am J Physiol"},{"key":"10.1016\/j.ajpath.2017.06.010_bib31","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1038\/nrc1910","article-title":"The role of nitric oxide in tumour progression","volume":"6","author":"Fukumura","year":"2006","journal-title":"Nat Rev Cancer"},{"key":"10.1016\/j.ajpath.2017.06.010_bib32","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1038\/nature06778","article-title":"Tumour maintenance is mediated by eNOS","volume":"452","author":"Lim","year":"2008","journal-title":"Nature"},{"key":"10.1016\/j.ajpath.2017.06.010_bib33","first-page":"948","article-title":"Inhibition of nitric oxide synthase induces a selective reduction in tumor blood flow that is reversible with L-arginine","volume":"57","author":"Tozer","year":"1997","journal-title":"Cancer Res"},{"key":"10.1016\/j.ajpath.2017.06.010_bib34","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1161\/01.CIR.97.1.99","article-title":"Vascular endothelial growth factor\/vascular permeability factor enhances vascular permeability via nitric oxide and prostacyclin","volume":"97","author":"Murohara","year":"1998","journal-title":"Circulation"},{"key":"10.1016\/j.ajpath.2017.06.010_bib35","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1016\/j.ejca.2014.05.013","article-title":"Cardiovascular events among 1090 cancer patients treated with sunitinib, interferon, or placebo: a comprehensive adjudicated database analysis demonstrating clinically meaningful reversibility of cardiac events","volume":"50","author":"Ewer","year":"2014","journal-title":"Eur J Cancer"},{"key":"10.1016\/j.ajpath.2017.06.010_bib36","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1161\/CIRCULATIONAHA.115.018347","article-title":"Vascular toxicities of cancer therapies: the old and the new\u2013an evolving avenue","volume":"133","author":"Herrmann","year":"2016","journal-title":"Circulation"},{"key":"10.1016\/j.ajpath.2017.06.010_bib37","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1093\/jnci\/djq091","article-title":"Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors","volume":"102","author":"Maitland","year":"2010","journal-title":"J\u00a0Natl Cancer Inst"},{"key":"10.1016\/j.ajpath.2017.06.010_bib38","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1093\/jnci\/djr128","article-title":"Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib","volume":"103","author":"Rini","year":"2011","journal-title":"J Natl Cancer Inst"},{"key":"10.1016\/j.ajpath.2017.06.010_bib39","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1007\/s11906-011-0206-y","article-title":"Mechanisms of antiangiogenic-induced arterial hypertension","volume":"13","author":"Mourad","year":"2011","journal-title":"Curr Hypertens Rep"},{"key":"10.1016\/j.ajpath.2017.06.010_bib40","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1097\/CAD.0b013e3283359c79","article-title":"Reduction in skin microvascular density and changes in vessel morphology in patients treated with sunitinib","volume":"21","author":"van der Veldt","year":"2010","journal-title":"Anticancer Drugs"},{"key":"10.1016\/j.ajpath.2017.06.010_bib41","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S0002-9440(10)63273-7","article-title":"Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts","volume":"165","author":"Inai","year":"2004","journal-title":"Am J Pathol"},{"key":"10.1016\/j.ajpath.2017.06.010_bib42","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.ejphar.2012.08.023","article-title":"The vascular-disrupting agent, combretastatin-A4-phosphate, enhances neurogenic vasoconstriction in rat small arteries","volume":"695","author":"Su","year":"2012","journal-title":"Eur J Pharmacol"},{"key":"10.1016\/j.ajpath.2017.06.010_bib43","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1038\/sj.bjc.6601195","article-title":"Glomeruloid microvascular proliferation is associated with p53 expression, germline BRCA1 mutations and an adverse outcome following breast cancer","volume":"89","author":"Goffin","year":"2003","journal-title":"Br J Cancer"},{"key":"10.1016\/j.ajpath.2017.06.010_bib44","first-page":"6808","article-title":"Prognostic importance of glomeruloid microvascular proliferation indicates an aggressive angiogenic phenotype in human cancers","volume":"62","author":"Straume","year":"2002","journal-title":"Cancer Res"},{"key":"10.1016\/j.ajpath.2017.06.010_bib45","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/S0002-9440(10)64025-4","article-title":"Glomeruloid microvascular proliferation orchestrated by VPF\/VEGF: a new world of angiogenesis research","volume":"158","author":"Brat","year":"2001","journal-title":"Am J Pathol"},{"key":"10.1016\/j.ajpath.2017.06.010_bib46","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1093\/jnen\/62.6.655","article-title":"A novel concept of glomeruloid body formation in experimental cerebral metastases","volume":"62","author":"Dome","year":"2003","journal-title":"J Neuropathol Exp Neurol"},{"key":"10.1016\/j.ajpath.2017.06.010_bib47","first-page":"167","article-title":"Tumoral vascularity as a prognostic factor in cancer","author":"Weidner","year":"1996","journal-title":"Important Adv Oncol"},{"key":"10.1016\/j.ajpath.2017.06.010_bib48","doi-asserted-by":"crossref","first-page":"4041","DOI":"10.1242\/dev.096255","article-title":"Dynamic responses of endothelial cells to changes in blood flow during vascular remodeling of the mouse yolk sac","volume":"140","author":"Udan","year":"2013","journal-title":"Development"},{"key":"10.1016\/j.ajpath.2017.06.010_bib49","doi-asserted-by":"crossref","first-page":"2943","DOI":"10.1158\/0008-5472.CAN-12-4354","article-title":"Vascular normalization as an emerging strategy to enhance cancer immunotherapy","volume":"73","author":"Huang","year":"2013","journal-title":"Cancer Res"},{"key":"10.1016\/j.ajpath.2017.06.010_bib50","doi-asserted-by":"crossref","first-page":"21247","DOI":"10.18632\/oncotarget.6918","article-title":"VEGF pathway targeting agents, vessel normalization and tumor drug uptake: from bench to bedside","volume":"7","author":"Arjaans","year":"2016","journal-title":"Oncotarget"}],"container-title":["The American Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0002944017304704?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0002944017304704?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T19:54:50Z","timestamp":1617220490000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0002944017304704"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,10]]},"references-count":50,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2017,10]]}},"alternative-id":["S0002944017304704"],"URL":"https:\/\/doi.org\/10.1016\/j.ajpath.2017.06.010","relation":{},"ISSN":["0002-9440"],"issn-type":[{"value":"0002-9440","type":"print"}],"subject":[],"published":{"date-parts":[[2017,10]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Early Actions of Anti\u2013Vascular Endothelial Growth Factor\/Vascular Endothelial Growth Factor Receptor Drugs on Angiogenic Blood Vessels","name":"articletitle","label":"Article Title"},{"value":"The American Journal of Pathology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ajpath.2017.06.010","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2017 American Society for Investigative Pathology. Published by Elsevier Inc.","name":"copyright","label":"Copyright"}]}}