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.
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.
KW - angiogenesis effect
KW - calcineurin
KW - calcium
KW - nuclear factors of activated T cells
KW - plasma membrane calcium-transporting ATPase
UR - http://www.scopus.com/inward/record.url?scp=84913590141&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.114.304363
DO - 10.1161/ATVBAHA.114.304363
M3 - Article
C2 - 25147342
VL - 34
SP - 2310
EP - 2320
JO - Arteriosclerosis, Thrombosis, and Vascular biology
JF - Arteriosclerosis, Thrombosis, and Vascular biology
SN - 1079-5642
IS - 10
ER -