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

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. Brown, Delvac Oceandy, Elizabeth J. Cartwright, Weiguang Wang, Pablo Gómez-del Arco, Sara Martínez-Martínez, Ludwig Neyses, Juan Miguel Redondo, Angel L. Armesilla

Research output: Contribution to journalArticle

Abstract

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.

LanguageEnglish
Pages2310-2320
Number of pages11
JournalArteriosclerosis, Thrombosis, and Vascular biology
Volume34
Issue number10
Early online date21 Aug 2014
DOIs
Publication statusPublished - 31 Oct 2014

Fingerprint

Plasma Membrane Calcium-Transporting ATPases
Calcineurin
NFATC Transcription Factors
Vascular Endothelial Growth Factor A
Protein Isoforms
Pathologic Neovascularization
Endothelial Cells
Physiologic Neovascularization
Cardiac Myocytes
Cell Movement
Blood Vessels
Down-Regulation
Breast Neoplasms

Bibliographical note

© 2014 American Heart Association, Inc.

Keywords

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

Cite this

Baggott, Rhiannon R. ; Alfranca, Arantzazu ; López-Maderuelo, Dolores ; Mohamed, Tamer M.A. ; Escolano, Amelia ; Oller, Jorge ; Ornes, Beatriz C. ; Kurusamy, Sathishkumar ; Rowther, Farjana B. ; Brown, James E. ; Oceandy, Delvac ; Cartwright, Elizabeth J. ; Wang, Weiguang ; Gómez-del Arco, Pablo ; Martínez-Martínez, Sara ; Neyses, Ludwig ; Redondo, Juan Miguel ; Armesilla, Angel L. / Plasma membrane calcium ATPase isoform 4 inhibits vascular endothelial growth factor-mediated angiogenesis through interaction with calcineurin. In: Arteriosclerosis, Thrombosis, and Vascular biology. 2014 ; Vol. 34, No. 10. pp. 2310-2320.
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abstract = "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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Baggott, RR, Alfranca, A, López-Maderuelo, D, Mohamed, TMA, Escolano, A, Oller, J, Ornes, BC, Kurusamy, S, Rowther, FB, Brown, JE, Oceandy, D, Cartwright, EJ, Wang, W, Gómez-del Arco, P, Martínez-Martínez, S, Neyses, L, Redondo, JM & Armesilla, AL 2014, 'Plasma membrane calcium ATPase isoform 4 inhibits vascular endothelial growth factor-mediated angiogenesis through interaction with calcineurin' Arteriosclerosis, Thrombosis, and Vascular biology, vol. 34, no. 10, pp. 2310-2320. https://doi.org/10.1161/ATVBAHA.114.304363

Plasma membrane calcium ATPase isoform 4 inhibits vascular endothelial growth factor-mediated angiogenesis through interaction with calcineurin. / Baggott, Rhiannon R.; Alfranca, Arantzazu; López-Maderuelo, Dolores; Mohamed, Tamer M.A.; Escolano, Amelia; Oller, Jorge; Ornes, Beatriz C.; Kurusamy, Sathishkumar; Rowther, Farjana B.; Brown, James E.; Oceandy, Delvac; Cartwright, Elizabeth J.; Wang, Weiguang; Gómez-del Arco, Pablo; Martínez-Martínez, Sara; Neyses, Ludwig; Redondo, Juan Miguel; Armesilla, Angel L.

In: Arteriosclerosis, Thrombosis, and Vascular biology, Vol. 34, No. 10, 31.10.2014, p. 2310-2320.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Plasma membrane calcium ATPase isoform 4 inhibits vascular endothelial growth factor-mediated angiogenesis through interaction with calcineurin

AU - Baggott, Rhiannon R.

AU - Alfranca, Arantzazu

AU - López-Maderuelo, Dolores

AU - Mohamed, Tamer M.A.

AU - Escolano, Amelia

AU - Oller, Jorge

AU - Ornes, Beatriz C.

AU - Kurusamy, Sathishkumar

AU - Rowther, Farjana B.

AU - Brown, James E.

AU - Oceandy, Delvac

AU - Cartwright, Elizabeth J.

AU - Wang, Weiguang

AU - Gómez-del Arco, Pablo

AU - Martínez-Martínez, Sara

AU - Neyses, Ludwig

AU - Redondo, Juan Miguel

AU - Armesilla, Angel L.

N1 - © 2014 American Heart Association, Inc.

PY - 2014/10/31

Y1 - 2014/10/31

N2 - 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.

AB - 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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KW - calcineurin

KW - calcium

KW - nuclear factors of activated T cells

KW - plasma membrane calcium-transporting ATPase

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DO - 10.1161/ATVBAHA.114.304363

M3 - Article

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JF - Arteriosclerosis, Thrombosis, and Vascular biology

SN - 1079-5642

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