{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:02:15Z","timestamp":1780963335343,"version":"3.54.1"},"reference-count":52,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2014,4,11]],"date-time":"2014-04-11T00:00:00Z","timestamp":1397174400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2014,5]]},"abstract":"Background and Purpose<\/jats:title>Fostamatinib is an inhibitor of spleen tyrosine kinase (TK)<\/jats:styled-content>. In patients, fostamatinib treatment was associated with increased BP<\/jats:styled-content>. Some TK<\/jats:styled-content> inhibitors cause BP elevation, by inhibiting the VEGF<\/jats:styled-content> receptor 2 (VEGFR<\/jats:styled-content>2). Here, we have assessed the mechanistic link between fostamatinib\u2010induced BP<\/jats:styled-content> elevation and inhibition of VEGF<\/jats:styled-content> signalling.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>We used conscious rats with automated blood sampling and radio telemetry and anaesthetized rats to measure cardiovascular changes. Rat isolated aorta and isolated hearts, and human resistance vessels in vitro<\/jats:italic> were also used. NO production by human microvascular endothelial cells was measured with the NO\u2010dependent probe, DAF\u2010FM and VEGFR2 phosphorylation was determined in mouse lung, ex vivo.<\/jats:italic><\/jats:p><\/jats:sec>Key Results<\/jats:title>In conscious rats, fostamatinib dose\u2010dependently increased BP<\/jats:styled-content>. The time course of the BP<\/jats:styled-content> effect correlated closely with the plasma concentrations of R<\/jats:styled-content>406 (the active metabolite of fostamatinib). In anaesthetized rats, infusion of R<\/jats:styled-content>406 increased BP<\/jats:styled-content> and decreased femoral arterial conductance. Endothelial function was unaffected, as infusion of R<\/jats:styled-content>406 did not inhibit hyperaemia\u2010 or ACh<\/jats:styled-content>\u2010induced vasodilatation in rats. R<\/jats:styled-content>406 did not affect contraction of isolated blood vessels. R<\/jats:styled-content>406 inhibited VEGF<\/jats:styled-content>\u2010stimulated NO<\/jats:styled-content> production from human endothelial cells in vitro<\/jats:italic>, and treatment with R<\/jats:styled-content>406 inhibited VEGFR<\/jats:styled-content>2 phosphorylation in vivo<\/jats:italic>. R<\/jats:styled-content>406 inhibited VEGF<\/jats:styled-content>\u2010induced hypotension in anaesthetized rats.<\/jats:p><\/jats:sec>Conclusions and Implications<\/jats:title>Increased vascular resistance, secondary to reduced VEGF<\/jats:styled-content>\u2010induced NO<\/jats:styled-content> release from endothelium, may contribute to BP<\/jats:styled-content> increases observed with fostamatanib. This is consistent with the elevated BP<\/jats:styled-content> induced by other drugs inhibiting VEGF<\/jats:styled-content> signalling, although the contribution of other mechanisms cannot be excluded.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12559","type":"journal-article","created":{"date-parts":[[2013,12,16]],"date-time":"2013-12-16T11:36:14Z","timestamp":1387193774000},"page":"2308-2320","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["The contribution of VEGF<\/scp> signalling to fostamatinib\u2010induced blood pressure elevation"],"prefix":"10.1111","volume":"171","author":[{"given":"M","family":"Skinner","sequence":"first","affiliation":[{"name":"AstraZeneca R&D Macclesfield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Philp","sequence":"additional","affiliation":[{"name":"AstraZeneca R&D Macclesfield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Lengel","sequence":"additional","affiliation":[{"name":"AstraZeneca R&D Waltham MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"Coverley","sequence":"additional","affiliation":[{"name":"AstraZeneca R&D Macclesfield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Lamm Bergstr\u00f6m","sequence":"additional","affiliation":[{"name":"AstraZeneca R&D M\u00f6lndal Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Glaves","sequence":"additional","affiliation":[{"name":"AstraZeneca R&D Macclesfield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H","family":"Musgrove","sequence":"additional","affiliation":[{"name":"AstraZeneca R&D Macclesfield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H","family":"Prior","sequence":"additional","affiliation":[{"name":"AstraZeneca R&D Macclesfield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Braddock","sequence":"additional","affiliation":[{"name":"AstraZeneca R&D Macclesfield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Huby","sequence":"additional","affiliation":[{"name":"AstraZeneca R&D Macclesfield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J O","family":"Curwen","sequence":"additional","affiliation":[{"name":"AstraZeneca R&D Macclesfield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Duffy","sequence":"additional","affiliation":[{"name":"AstraZeneca R&D Macclesfield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A R","family":"Harmer","sequence":"additional","affiliation":[{"name":"AstraZeneca R&D Macclesfield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,4,11]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12449"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2011.10.024"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2012.02.053"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.90502.2008"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1755-5922.2011.00278.x"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.106.109058"},{"key":"e_1_2_9_8_1","first-page":"271","article-title":"Vandetanib inhibits both VEGFR\u20102 and EGFR signalling at clinically relevant drug levels in preclinical models of human cancer","volume":"39","author":"Brave SR","year":"2011","journal-title":"Int J Oncol"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2009.94"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-4783"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1990"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2012.136"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.109.129973"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.108.144816"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/288373a0"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1990.tb14131.x"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.30114"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-012-2030-8"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.103.10.1378"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.17.11.2793"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1472-8206.2006.00406.x"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2010.04.014"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.109.149690"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.182220"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2010-0271"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.00872.x"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1097\/HJH.0b013e32835c1d1b"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1513\/pats.201102-021MW"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1097\/FJC.0b013e31827afd29"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2094"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.00873.x"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1207759109"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.110.168120"},{"key":"e_1_2_9_34_1","first-page":"H1435","article-title":"Postischemic vasodilation in human forearm is dependent on endothelium\u2010derived nitric oxide","volume":"270","author":"Meredith IT","year":"1996","journal-title":"Am J Physiol"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.530"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1681.2012.05699.x"},{"key":"e_1_2_9_37_1","first-page":"R1213","article-title":"Role of endothelium\u2010derived relaxing factor in hindlimb reactive and active hyperemia in conscious dogs","volume":"266","author":"O'Leary DS","year":"1994","journal-title":"Am J Physiol"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1990.tb14151.x"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2010.05.001"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semnephrol.2010.09.007"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-07-0142"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-5050"},{"key":"e_1_2_9_43_1","first-page":"H1224","article-title":"Coronary response to large decreases of hemoglobin\u2010O2 affinity in isolated rat heart","volume":"249","author":"Stucker O","year":"1985","journal-title":"Am J Physiol"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.2174\/157016111795495503"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-199002000-00006"},{"key":"e_1_2_9_46_1","volume-title":"Pharmacological Experiments on Isolated Preparations","author":"University of Edinburgh, Department of Pharmacology","year":"1970"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(89)91013-1"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.02.0503"},{"key":"e_1_2_9_49_1","first-page":"4645","article-title":"ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration","volume":"62","author":"Wedge SR","year":"2002","journal-title":"Cancer Res"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1000500"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1517\/13543784.13.7.743"},{"key":"e_1_2_9_52_1","first-page":"H8","article-title":"Role of endothelium\u2010derived nitric oxide in myocardial reactive hyperemia","volume":"263","author":"Yamabe H","year":"1992","journal-title":"Am J Physiol"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-199606000-00011"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fbph.12559","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.12559","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T02:11:18Z","timestamp":1696299078000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bph.12559"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,4,11]]},"references-count":52,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2014,5]]}},"alternative-id":["10.1111\/bph.12559"],"URL":"https:\/\/doi.org\/10.1111\/bph.12559","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,4,11]]},"assertion":[{"value":"2013-07-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-12-11","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-04-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}