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THE PLASMA MEMBRANE CALCIUM ATPASE 4 SPECIFIC INHIBITOR AURINTRICARBOXYLIC ACID ENHANCES VEGF-INDUCED ANGIOGENESIS
  1. S Kurusamy1,
  2. RR Baggott1,
  3. MD López-Maderuelo2,
  4. V Kannappan1,
  5. A Escolano2,
  6. J Oller2,
  7. R Little3,
  8. SJ Dunmore1,
  9. D Oceandy3,
  10. EJ Cartwright3,
  11. W Wang1,
  12. L Neyses3,
  13. JM Redondo2,
  14. AL Armesilla1
  1. 1Research Institute in Healthcare Science, University of Wolverhampton, Wolverhampton, UK
  2. 2Dept of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares CNIC, Madrid, Spain
  3. 3Cardiovascular Research Group, University of Manchester, Manchester, UK

Abstract

Angiogenesis, the formation of new capillaries from pre-existing ones, is a biological process essential for successful embryonic development, organ growth and tissue repair. Excessive or insufficient growth of blood vessels, due to de-regulation of this process, plays a major role in the pathophysiology of several human diseases. The pro-angiogenic factor Vascular Endothelial Growth Factor (VEGF) has been identified as a crucial regulator of both physiological and pathological angiogenesis. VEGF activates the calcineurin/Nuclear Factor of Activated T-cells (NFAT) signalling pathway which is a critical mediator of angiogenesis. Our group has recently identified a novel role for the plasma membrane calcium ATPase 4 (PMCA4) as a negative regulator of VEGF-dependent angiogenesis. The small molecule Aurintricarboxylic acid (ATA) has been characterised as a selective inhibitor of PMCA4. We hypothesise that ATA-mediated inhibition of PMCA4 in endothelial cells will enhance VEGF-driven angiogenesis. Consistent with this hypothesis, we demonstrate in this work that inhibition of PMCA4 by treatment with ATA increases calcineurin/NFAT activity and the expression of the NFAT-dependent, pro-angiogenic protein RCAN1.4 in VEGF-stimulated HUVEC. Moreover, ATA treatment significantly enhanced endothelial cell migration and tubular morphogenesis in response to VEGF-stimulation. Interestingly, incubation of HUVEC with ATA had no effect on the cell viability or Erk1/2 phosphorylation (activation) status of VEGF-stimulated cells. Our results show a novel role for the PMCA4 specific inhibitor ATA as a stimulator of VEGF-induced angiogenesis. Thus, ATA might lead to the design of new therapeutic strategies to improve blood vessel formation in diseases associated with insufficient angiogenesis.

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