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Updated: Apr 25, 2026
In Vitro Model of Coronary Angiogenesis
Published on: March 10, 2020
Plasma membrane calcium ATPase isoform 4 inhibits vascular endothelial growth factor-mediated angiogenesis through
Rhiannon R Baggott1, Arantzazu Alfranca1, Dolores López-Maderuelo1
1From the Molecular Pharmacology Group, School of Pharmacy (R.R.B., S.K., A.L.A.), Brain Tumor UK Neuro-oncology Research Centre (F.B.R.), and Oncology Group (W.W.), Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, United Kingdom; Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (A.A., D.L.-M., A.E., J.O., B.C.O., P.G.-d.A., S.M.-M., J.M.R.); Human Genetics Department, Institute for Rare Diseases Research, Carlos III Health Institute, Madrid, Spain (A.A.); Institute of Cardiovascular Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom (T.M.A.M., D.O., E.J.C., L.N.); Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt (T.M.A.M.); Aston Research Centre for Healthy Ageing, School of Life and Health Sciences, Aston University, Birmingham, United Kingdom (J.E.B.); Department of Molecular Biology, Universidad Autónoma de Madrid, Madrid, Spain (P.G.-d.A.); and University of Luxembourg, Walferdange, Luxembourg (L.N.).
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.
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.
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.
Insights
Plasma membrane calcium ATPase 4 (PMCA4) inhibits vascular endothelial growth factor (VEGF)-induced angiogenesis by downregulating the calcineurin/NFAT pathway. This finding offers potential therapeutic targets for diseases involving abnormal blood vessel formation.
Area of Science:
- Endothelial cell biology
- Molecular signaling pathways
- Angiogenesis research
Background:
- Vascular endothelial growth factor (VEGF) drives angiogenesis, a process crucial in both normal physiology and disease.
- The calcineurin/nuclear factor of activated T cells (NFAT) pathway is a key mediator of VEGF-induced angiogenic processes.
- Plasma membrane calcium ATPase (PMCA) has been identified as an inhibitor of calcineurin/NFAT signaling in other cell types.
Purpose of the Study:
- To investigate the functional role of the PMCA/calcineurin interaction in endothelial cells.
- To determine the significance of PMCA in VEGF-mediated angiogenesis.
Main Methods:
- In vitro and in vivo assays were employed.
- The interaction between PMCA4 and calcineurin in VEGF-stimulated endothelial cells was analyzed.
- Expression of NFAT-dependent genes (RCAN1.4, Cox-2) was measured.
- Endothelial cell motility and blood vessel formation were assessed.
Main Results:
- PMCA4 interaction with calcineurin downregulated the calcineurin/NFAT pathway in endothelial cells.
- This inhibition led to reduced expression of proangiogenic genes RCAN1.4 and Cox-2.
- PMCA4-dependent signaling inhibition decreased endothelial cell motility and blood vessel formation.
- In vivo angiogenesis induced by VEGF was impaired.
Conclusions:
- The calcineurin/NFAT pathway is critical for regulating pathological angiogenesis.
- Targeting PMCA4 functionality presents a novel therapeutic strategy.
- Modulating PMCA4 could control new vessel formation in angiogenesis-related diseases.
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