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

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.

journal_name

J Mol Cell Cardiol

journal_title

Journal of molecular and cellular cardiology

authors

Kurusamy S,López-Maderuelo D,Little R,Cadagan D,Savage AM,Ihugba JC,Baggott RR,Rowther FB,Martínez-Martínez S,Arco PG,Murcott C,Wang W,Francisco Nistal J,Oceandy D,Neyses L,Wilkinson RN,Cartwright EJ,Redondo JM,Armesi

doi

10.1016/j.yjmcc.2017.07.001

subject

Has Abstract

pub_date

2017-08-01 00:00:00

pages

38-47

eissn

0022-2828

issn

1095-8584

pii

S0022-2828(17)30128-1

journal_volume

109

pub_type

杂志文章

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