PUBLICATION
Selective inhibition of plasma membrane calcium ATPase 4 improves angiogenesis and vascular reperfusion
- Authors
- Kurusamy, S., López-Maderuelo, D., Little, R., Cadagan, D., Savage, A.M., Ihugba, J.C., Baggott, R.R., Rowther, F.B., Martínez-Martínez, S., Arco, P.G., Murcott, C., Wang, W., Francisco Nistal, J., Oceandy, D., Neyses, L., Wilkinson, R.N., Cartwright, E.J., Redondo, J.M., Armesilla, A.L.
- ID
- ZDB-PUB-170708-9
- Date
- 2017
- Source
- Journal of Molecular and Cellular Cardiology 109: 38-47 (Journal)
- Registered Authors
- Wilkinson, Robert
- Keywords
- ATA, Angiogenesis, Calcineurin/NFAT, PMCA4, VEGF
- MeSH Terms
-
- Animals
- Aurintricarboxylic Acid/pharmacology
- Calcium-Transporting ATPases/genetics
- Calcium-Transporting ATPases/metabolism*
- Cell Membrane/genetics
- Cell Membrane/metabolism*
- Cell Movement/drug effects
- Cell Movement/physiology
- Human Umbilical Vein Endothelial Cells/cytology
- Human Umbilical Vein Endothelial Cells/metabolism*
- Humans
- Mice
- Mice, Knockout
- Neovascularization, Physiologic/drug effects
- Neovascularization, Physiologic/physiology*
- Zebrafish/genetics
- Zebrafish/metabolism*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 28684310 Full text @ J. Mol. Cell. Cardiol.
Citation
Kurusamy, S., López-Maderuelo, D., Little, R., Cadagan, D., Savage, A.M., Ihugba, J.C., Baggott, R.R., Rowther, F.B., Martínez-Martínez, S., Arco, P.G., Murcott, C., Wang, W., Francisco Nistal, J., Oceandy, D., Neyses, L., Wilkinson, R.N., Cartwright, E.J., Redondo, J.M., Armesilla, A.L. (2017) Selective inhibition of plasma membrane calcium ATPase 4 improves angiogenesis and vascular reperfusion. Journal of Molecular and Cellular Cardiology. 109:38-47.
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.
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