Selective inhibition of plasma membrane calcium ATPase 4 improves angiogenesis and vascular reperfusion

2.50
Hdl Handle:
http://hdl.handle.net/2436/620553
Title:
Selective inhibition of plasma membrane calcium ATPase 4 improves angiogenesis and vascular reperfusion
Authors:
Kurusamy, Sathishkumar; López-Maderuelo, Dolores; Little, Robert; Cadagan, David; Savage, Aaron M; Ihugba, Jude C; Baggott, Rhiannon Rebecca; Rowther, Farjana B; Martínez-Martínez, Sara; Gómez-del Arco, Pablo; Murcott, Clare; Wang, Weiguang; Nistal, J Francisco; Oceandy, Delvac; Neyses, Ludwig; Wilkinson, Robert N; Cartwright, Elizabeth J.; Miguel Redondo, Juan; Armesilla, Angel Luis
Abstract:
Aims 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.
Publisher:
Elsevier
Journal:
Journal of Molecular and Cellular Cardiology
Issue Date:
Jul-2017
URI:
http://hdl.handle.net/2436/620553
Additional Links:
http://www.sciencedirect.com/science/article/pii/S0022282817301281
Type:
Article
Language:
en
ISSN:
0022-2828
Appears in Collections:
FSE

Full metadata record

DC FieldValue Language
dc.contributor.authorKurusamy, Sathishkumaren
dc.contributor.authorLópez-Maderuelo, Doloresen
dc.contributor.authorLittle, Roberten
dc.contributor.authorCadagan, Daviden
dc.contributor.authorSavage, Aaron Men
dc.contributor.authorIhugba, Jude Cen
dc.contributor.authorBaggott, Rhiannon Rebeccaen
dc.contributor.authorRowther, Farjana Ben
dc.contributor.authorMartínez-Martínez, Saraen
dc.contributor.authorGómez-del Arco, Pabloen
dc.contributor.authorMurcott, Clareen
dc.contributor.authorWang, Weiguangen
dc.contributor.authorNistal, J Franciscoen
dc.contributor.authorOceandy, Delvacen
dc.contributor.authorNeyses, Ludwigen
dc.contributor.authorWilkinson, Robert Nen
dc.contributor.authorCartwright, Elizabeth J.en
dc.contributor.authorMiguel Redondo, Juanen
dc.contributor.authorArmesilla, Angel Luisen
dc.date.accessioned2017-07-04T13:45:59Z-
dc.date.available2017-07-04T13:45:59Z-
dc.date.issued2017-07-
dc.identifier.issn0022-2828en
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.en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urlhttp://www.sciencedirect.com/science/article/pii/S0022282817301281en
dc.subjectPMCA4en
dc.subjectangiogenesisen
dc.subjectATAen
dc.subjectCalcineurin/NFATen
dc.subjectVEGFen
dc.titleSelective inhibition of plasma membrane calcium ATPase 4 improves angiogenesis and vascular reperfusionen
dc.typeArticleen
dc.identifier.journalJournal of Molecular and Cellular Cardiologyen
dc.date.accepted2017-07-
rioxxterms.funderInternalen
rioxxterms.identifier.projectUoW040717AAen
rioxxterms.versionAMen
rioxxterms.licenseref.urihttps://creativecommons.org/CC BY-NC-ND 4.0en
rioxxterms.licenseref.startdate2018-07-01en
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