Rhiannon R Baggott1, Arantzazu Alfranca1, Dolores López-Maderuelo1, Tamer M A Mohamed1, Amelia Escolano1, Jorge Oller1, Beatriz C Ornes1, Sathishkumar Kurusamy1, Farjana B Rowther1, James E Brown1, Delvac Oceandy1, Elizabeth J Cartwright1, Weiguang Wang1, Pablo Gómez-del Arco1, Sara Martínez-Martínez1, Ludwig Neyses1, Juan Miguel Redondo2, Angel Luis Armesilla2. 1. From 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.). 2. From 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.). jmredondo@cnic.es A.Armesilla@wlv.ac.uk.
Abstract
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.
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.
Authors: Lan Huang; Colette Bichsel; Alexis L Norris; Jeremy Thorpe; Jonathan Pevsner; Sanda Alexandrescu; Anna Pinto; David Zurakowski; Robin J Kleiman; Mustafa Sahin; Arin K Greene; Joyce Bischoff Journal: Arterioscler Thromb Vasc Biol Date: 2021-10-21 Impact factor: 8.311
Authors: Ulrike Peters; Eleni Solominidou; Yüksel Korkmaz; Stefan Rüttermann; Astrid Klocke; Thomas Frank Flemmig; Thomas Beikler Journal: Mediators Inflamm Date: 2016-06-15 Impact factor: 4.711
Authors: Robert Little; Min Zi; Sally K Hammad; Loan Nguyen; Alexandra Njegic; Sathishkumar Kurusamy; Sukhpal Prehar; Angel L Armesilla; Ludwig Neyses; Clare Austin; Elizabeth J Cartwright Journal: Aging Cell Date: 2017-08-09 Impact factor: 9.304