{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T14:33:10Z","timestamp":1792679590658,"version":"4.5.0"},"reference-count":39,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2018,7,2]],"date-time":"2018-07-02T00:00:00Z","timestamp":1530489600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["RE\/13\/1\/30181"],"award-info":[{"award-number":["RE\/13\/1\/30181"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2018,8]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\"><jats:list-item><jats:p>Prolonged exposure to vascular endothelial growth factor A (VEGF\u2010A) inhibits agonist\u2010mediated endothelial cell Ca<jats:sup>2+<\/jats:sup>release and subsequent activation of intermediate conductance Ca<jats:sup>2+<\/jats:sup>\u2010activated K<jats:sup>+<\/jats:sup>(IK<jats:sub>Ca<\/jats:sub>) channels, which underpins vasodilatation as a result of endothelium\u2010dependent hyperpolarization (EDH) in mouse resistance arteries.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>Signalling via mitogen\u2010activated protein\/extracellular signal\u2010regulated kinase kinase (MEK) downstream of VEGF\u2010A was required to attenuate endothelial cell Ca<jats:sup>2+<\/jats:sup>responses and the EDH\u2010vasodilatation mediated by IK<jats:sub>Ca<\/jats:sub>activation.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>VEGF\u2010A exposure did not modify vasodilatation as a result of the direct activation of IK<jats:sub>Ca<\/jats:sub>channels, nor the pattern of expression of inositol 1,4,5\u2010trisphosphate receptor 1 within endothelial cells of resistance arteries.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>These results indicate a novel role for VEGF\u2010A in resistance arteries and suggest a new avenue for investigation into the role of VEGF\u2010A in cardiovascular diseases.<\/jats:p><\/jats:list-item><\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Vascular endothelial growth factor A (VEGF\u2010A) is a potent permeability and angiogenic factor that is also associated with the remodelling of the microvasculature. Elevated VEGF\u2010A levels are linked to a significant increase in the risk of cardiovascular dysfunction, although it is unclear how VEGF\u2010A has a detrimental, disease\u2010related effect. Small resistance arteries are central determinants of peripheral resistance and endothelium\u2010dependent hyperpolarization (EDH) is the predominant mechanism by which these arteries vasodilate. Using isolated, pressurized resistance arteries, we demonstrate that VEGF\u2010A acts via VEGF receptor\u20102 (R2) to inhibit both endothelial cell (EC) Ca<jats:sup>2+<\/jats:sup>release and the associated EDH vasodilatation mediated by intermediate conductance Ca<jats:sup>2+<\/jats:sup>\u2010activated K<jats:sup>+<\/jats:sup>(IK<jats:sub>Ca<\/jats:sub>) channels. Importantly, VEGF\u2010A had no direct effect against IK<jats:sub>Ca<\/jats:sub>channels. Instead, the inhibition was crucially reliant on the downstream activation of the mitogen\u2010activated protein\/extracellular signal\u2010regulated kinase kinase 1\/2 (MEK1\/2). The distribution of EC inositol 1,4,5\u2010trisphosphate (IP<jats:sub>3<\/jats:sub>) receptor\u20101 (R1) was not affected by exposure to VEGF\u2010A and we propose an inhibition of IP<jats:sub>3<\/jats:sub>R1 through the MEK pathway, probably via ERK1\/2. Inhibition of EC Ca<jats:sup>2+<\/jats:sup>via VEGFR2 has profound implications for EDH\u2010mediated dilatation of resistance arteries and could provide a mechanism by which elevated VEGF\u2010A contributes towards cardiovascular dysfunction.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp275793","type":"journal-article","created":{"date-parts":[[2018,6,4]],"date-time":"2018-06-04T05:30:02Z","timestamp":1528090202000},"page":"3553-3566","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["VEGF\u2010A inhibits agonist\u2010mediated Ca<sup>2+<\/sup>responses and activation of IK<sub>Ca<\/sub>channels in mouse resistance artery endothelial cells"],"prefix":"10.1113","volume":"596","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1694-2786","authenticated-orcid":false,"given":"Xi","family":"Ye","sequence":"first","affiliation":[{"name":"Department of Pharmacology University of Oxford Mansfield Road Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor","family":"Beckett","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Oxford Mansfield Road Oxford UK"},{"name":"School of Biomedical Sciences University of Queensland Brisbane Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pooneh","family":"Bagher","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Oxford Mansfield Road Oxford UK"},{"name":"Department of Medical Physiology, College of Medicine Texas A&amp;M University Health Science Center Bryan TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Garland","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Oxford Mansfield Road Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8014-2775","authenticated-orcid":false,"given":"Kim A.","family":"Dora","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Oxford Mansfield Road Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,7,2]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00425.2011"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.07.208"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0029-7844(95)00259-T"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr181"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00924.2015"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2011.07.040"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000231518.86795.0f"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.172379"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1159\/000074549"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/24388"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00316.2016"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1406029111"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/376066a0"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aal3806"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/apha.12649"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3627"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP270818"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1080\/10739680802220323"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-200204000-00014"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201606840"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2015-309155"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-6577"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1993.265.2.H586"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1021588227705"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.27.12.2918"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000015982.70785.B7"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0704469"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2016.87"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00214.2011"},{"key":"e_1_2_5_31_1","first-page":"e50759","article-title":"Isolation of microvascular endothelial tubes from mouse resistance arteries","volume":"25","author":"Socha M. 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