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dc.contributor.authorKurusamy, Sathishkumar
dc.contributor.authorLópez-Maderuelo, Dolores
dc.contributor.authorLittle, Robert
dc.contributor.authorCadagan, David
dc.contributor.authorSavage, Aaron M
dc.contributor.authorIhugba, Jude C
dc.contributor.authorBaggott, Rhiannon Rebecca
dc.contributor.authorRowther, Farjana B
dc.contributor.authorMartínez-Martínez, Sara
dc.contributor.authorGómez-del Arco, Pablo
dc.contributor.authorMurcott, Clare
dc.contributor.authorWang, Weiguang
dc.contributor.authorNistal, J Francisco
dc.contributor.authorOceandy, Delvac
dc.contributor.authorNeyses, Ludwig
dc.contributor.authorWilkinson, Robert N
dc.contributor.authorCartwright, Elizabeth J.
dc.contributor.authorMiguel Redondo, Juan
dc.contributor.authorArmesilla, Angel Luis
dc.date.accessioned2017-07-04T13:45:59Z
dc.date.available2017-07-04T13:45:59Z
dc.date.issued2017-07-03
dc.identifier.citationKurusamy, S., López-Maderuelo, D., Little, R., Cadagan, D., Savage, AM., Ihugba, JC., Baggott, RR., Rowther, FB., Martínez-Martínez, S., Arco, PGD., Murcott, C., Wang, W., Francisco Nistal, J., Oceandy, D., Neyses, L., Wilkinson, RN., Cartwright, EJ., Redondo, JM., & Armesilla, AL. (2017) 'Selective inhibition of plasma membrane calcium ATPase 4 improves angiogenesis and vascular reperfusion', Journal of molecular and cellular cardiology, 109, pp. 38-47 doi: 10.1016/j.yjmcc.2017.07.001
dc.identifier.issn0022-2828
dc.identifier.doi10.1016/j.yjmcc.2017.07.001
dc.identifier.urihttp://hdl.handle.net/2436/620553
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.
dc.language.isoen
dc.publisherElsevier
dc.relation.urlhttp://www.sciencedirect.com/science/article/pii/S0022282817301281
dc.subjectPMCA4
dc.subjectangiogenesis
dc.subjectATA
dc.subjectCalcineurin/NFAT
dc.subjectVEGF
dc.titleSelective inhibition of plasma membrane calcium ATPase 4 improves angiogenesis and vascular reperfusion
dc.typeJournal article
dc.identifier.journalJournal of Molecular and Cellular Cardiology
dc.date.accepted2017-07-03
rioxxterms.funderUniversity of Wolverhampton
rioxxterms.identifier.projectUoW040717AA
rioxxterms.versionAM
rioxxterms.licenseref.urihttps://creativecommons.org/CC BY-NC-ND 4.0
rioxxterms.licenseref.startdate2018-07-03
dc.source.volume109
dc.source.beginpage38
dc.source.endpage47
refterms.dateFCD2018-10-19T09:26:31Z
refterms.versionFCDAM
refterms.dateFOA2018-07-03T00:00:00Z
html.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.


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