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

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.

• Authors: 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 Luis Armesilla
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 34 Issue 10 Pg. 2310-20 (Oct 2014) ISSN: 1524-4636 [Electronic] United States
• PMID: 25147342 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 American Heart Association, Inc.

Chemical References

• Angiogenesis Inducing Agents
• Calcium-Binding Proteins
• DNA-Binding Proteins
• DSCR1 protein, mouse
• Intracellular Signaling Peptides and Proteins
• Muscle Proteins
• NFATC Transcription Factors
• PMCA4 protein, mouse
• RCAN1 protein, human
• Vascular Endothelial Growth Factor A
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• PTGS2 protein, human
• Calcineurin
• ATP2B4 protein, human
• Plasma Membrane Calcium-Transporting ATPases
• Calcium-Transporting ATPases

Topics

• Angiogenesis Inducing Agents (pharmacology)
• Animals
• Calcineurin (metabolism)
• Calcium-Binding Proteins
• Calcium-Transporting ATPases (deficiency, genetics, metabolism)
• Cell Movement
• Cell Proliferation
• Cyclooxygenase 2 (metabolism)
• DNA-Binding Proteins
• Disease Models, Animal
• Endothelial Cells (drug effects, enzymology)
• HEK293 Cells
• Hindlimb
• Human Umbilical Vein Endothelial Cells (drug effects, enzymology)
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• Ischemia (enzymology, physiopathology)
• Mice
• Mice, Knockout
• Muscle Proteins (metabolism)
• Muscle, Skeletal (blood supply)
• NFATC Transcription Factors (genetics, metabolism)
• Neovascularization, Physiologic (drug effects)
• Plasma Membrane Calcium-Transporting ATPases (genetics, metabolism)
• RNA Interference
• Signal Transduction
• Time Factors
• Transfection
• Vascular Endothelial Growth Factor A (pharmacology)