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dc.contributor.authorKurusamy, Sathishkumar
dc.contributor.authorLopez-Maderuelo, Dolores 
dc.contributor.authorLittle, Robert
dc.contributor.authorCadagan, David
dc.contributor.authorSavage, Aaron M
dc.contributor.authorIhugba, Jude C
dc.contributor.authorBaggott, Rhiannon R
dc.contributor.authorRowther, Farjana B
dc.contributor.authorMartinez-Martinez, Sara 
dc.contributor.authorGomez-del Arco, Pablo 
dc.contributor.authorMurcott, Clare
dc.contributor.authorWang, Weiguang
dc.contributor.authorFrancisco Nistal, J
dc.contributor.authorOceandy, Delvac
dc.contributor.authorNeyses, Ludwig
dc.contributor.authorWilkinson, Robert N
dc.contributor.authorCartwright, Elizabeth J
dc.contributor.authorRedondo, Juan Miguel 
dc.contributor.authorArmesilla, Angel Luis
dc.identifier.citationJ Mol Cell Cardiol. 2017; 109:38-47es_ES
dc.description.abstractAIMS: Ischaemic cardiovascular disease is a major cause of morbidity and mortality worldwide. Despite promising results from pre-clinical animal models, VEGF-based strategies for therapeutic angiogenesis have yet to achieve successful reperfusion of ischaemic tissues in patients. Failure to restore efficient VEGF activity in the ischaemic organ remains a major problem in current pro-angiogenic therapeutic approaches. Plasma membrane calcium ATPase 4 (PMCA4) negatively regulates VEGF-activated angiogenesis via inhibition of the calcineurin/NFAT signalling pathway. PMCA4 activity is inhibited by the small molecule aurintricarboxylic acid (ATA). We hypothesize that inhibition of PMCA4 with ATA might enhance VEGF-induced angiogenesis. METHODS AND RESULTS: We show that inhibition of PMCA4 with ATA in endothelial cells triggers a marked increase in VEGF-activated calcineurin/NFAT signalling that translates into a strong increase in endothelial cell motility and blood vessel formation. ATA enhances VEGF-induced calcineurin signalling by disrupting the interaction between PMCA4 and calcineurin at the endothelial-cell membrane. ATA concentrations at the nanomolar range, that efficiently inhibit PMCA4, had no deleterious effect on endothelial-cell viability or zebrafish embryonic development. However, high ATA concentrations at the micromolar level impaired endothelial cell viability and tubular morphogenesis, and were associated with toxicity in zebrafish embryos. In mice undergoing experimentally-induced hindlimb ischaemia, ATA treatment significantly increased the reperfusion of post-ischaemic limbs. CONCLUSIONS: Our study provides evidence for the therapeutic potential of targeting PMCA4 to improve VEGF-based pro-angiogenic interventions. This goal will require the development of refined, highly selective versions of ATA, or the identification of novel PMCA4 inhibitors.es_ES
dc.description.sponsorshipThis work was supported by the Research Institute in Healthcare Sciences, Faculty of Science and Engineering, University of Wolverhampton (to A.L.A.), and by an MRC programme grant (grant G1002082 to L.N. and E.J.C.). J.M.R. is supported by the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) (grant SAF2015-636333 to J.M.R.) and CIBERCV of Ministerio de Sanidad (grant CB16/11/00264 to J.M.R.), all projects cofounded by FEDER. J.M.R. and J.F.N. are supported by Red de Investigacion Cardiovascular (RD12/0042/0018 and 0022) cofounded by FEDER. S.K. and A.L.A. are supported by the Rosetrees Trust (grant M531 to A.L.A). S.M-M. and J.M.R. are supported by grants from the Fundacion La Marato TV3 (grant 20122532 to S.M-M. and grant 20151331 to J.M.R.). The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (Award SEV-2015-0505).es_ES
dc.subject.meshAnimals es_ES
dc.subject.meshAurintricarboxylic Acid es_ES
dc.subject.meshCalcium-Transporting ATPases es_ES
dc.subject.meshCell Membrane es_ES
dc.subject.meshCell Movement es_ES
dc.subject.meshHuman Umbilical Vein Endothelial Cells es_ES
dc.subject.meshHumans es_ES
dc.subject.meshMice es_ES
dc.subject.meshMice, Knockout es_ES
dc.subject.meshNeovascularization, Physiologices_ES
dc.subject.meshZebrafish es_ES
dc.subject.meshZebrafish Proteins es_ES
dc.titleSelective inhibition of plasma membrane calcium ATPase 4 improves angiogenesis and vascular reperfusiones_ES
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.contributor.funderMinisterio de Economía, Industria y Competitividad (España)es_ES
dc.contributor.funderMinisterio de Sanidad y Política Social (España)es_ES
dc.contributor.funderCentro de Investigación Biomedica en Red - CIBERes_ES
dc.contributor.funderEuropean Regional Development Fund (ERDF/FEDER)es_ES
dc.contributor.funderFundació La Maratóes_ES
dc.contributor.funderFundación ProCNICes_ES
dc.identifier.journalJournal of molecular and cellular cardiologyes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Regulación Génica en Remodelado Vascular e Inflamaciónes_ES

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Attribution-NonCommercial-NoDerivatives 4.0 Internacional
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