Plasma membrane calcium ATPase isoform 4 inhibits vascular endothelial growth factor-mediated angiogenesis through interaction with calcineurin

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  • Rhiannon R. Baggott
  • Arantzazu Alfranca
  • Dolores López-Maderuelo
  • Tamer M.A. Mohamed
  • Amelia Escolano
  • Jorge Oller
  • Beatriz C. Ornes
  • Sathishkumar Kurusamy
  • Farjana B. Rowther
  • James E. BrownORCiD:
  • Delvac Oceandy
  • Elizabeth J. Cartwright
  • Weiguang Wang
  • Pablo Gómez-del Arco
  • Sara Martínez-Martínez
  • Ludwig Neyses
  • Juan Miguel Redondo
  • Angel L. Armesilla

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Approach and Results - Using in vitro and in vivo assays, we here demonstrate that the interaction between PMCA4 and calcineurin in VEGF-stimulated endothelial cells leads to downregulation of the calcineurin/NFAT pathway and to a significant reduction in the subsequent expression of the NFAT-dependent, VEGF-activated, proangiogenic genes RCAN1.4 and Cox-2. PMCA4-dependent inhibition of calcineurin signaling translates into a reduction in endothelial cell motility and blood vessel formation that ultimately impairs in vivo angiogenesis by VEGF.

Objective - Vascular endothelial growth factor (VEGF) has been identified as a crucial regulator of physiological and pathological angiogenesis. Among the intracellular signaling pathways triggered by VEGF, activation of the calcineurin/ nuclear factor of activated T cells (NFAT) signaling axis has emerged as a critical mediator of angiogenic processes. We and others previously reported a novel role for the plasma membrane calcium ATPase (PMCA) as an endogenous inhibitor of the calcineurin/NFAT pathway, via interaction with calcineurin, in cardiomyocytes and breast cancer cells. However, the functional significance of the PMCA/calcineurin interaction in endothelial pathophysiology has not been addressed thus far.

Conclusions - Given the importance of the calcineurin/NFAT pathway in the regulation of pathological angiogenesis, targeted modulation of PMCA4 functionality might open novel therapeutic avenues to promote or attenuate new vessel formation in diseases that occur with angiogenesis.

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Original languageEnglish
Pages (from-to)2310-2320
Number of pages11
JournalArteriosclerosis, Thrombosis, and Vascular biology
Issue number10
Early online date21 Aug 2014
Publication statusPublished - 31 Oct 2014

Bibliographic note

© 2014 American Heart Association, Inc.


  • angiogenesis effect, calcineurin, calcium, nuclear factors of activated T cells, plasma membrane calcium-transporting ATPase

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