THE CYCLOSPORINE A-SENSITIVE NUCLEAR FACTOR OF ACTIVATED T-CELLS (NFAT) PROTEINS ARE EXPRESSED IN VASCULAR SMOOTH-MUSCLE CELLS - DIFFERENTIAL LOCALIZATION OF NFAT ISOFORMS AND INDUCTION OF NFAT-MEDIATED TRANSCRIPTION BY PHOSPHOLIPASE C-COUPLED CELL-SURFACE RECEPTORS

Expression of the antigen-regulated, cyclosporin A-sensitive nuclear f actor of activated T cells (NFAT) is not restricted to lymphoid cells, as thought initially, but the physiological inducers of NFAT-mediated transcription in non-lymphoid cells are unknown. Here, cultured vascu lar smooth muscle cells (VSMC) are shown to express two isoforms of th e NFAT family endogenously, which are localized differentially in cell s under resting conditions. Using a retroviral NFAT-specific luciferas e reporter, we show that VSMC support previously unrecognized complexi ties in NEAT-mediated transcription, including evidence for negative r egulation by Ca2+ signaling and positive regulation through co-activat ion of adenylyl cyclase and Ca2+ mobilization, The VSMC mitogen platel et derived growth factor-BE (PDGF-EB) induces NFAT-mediated transcript ion in VSMC, Thrombin and angiotensin II, which activate G alpha(q)-co upled receptors, are significantly weaker inducers of NFAT-mediated lu ciferase expression than is PDGF-BB, However, co-stimulation studies s how that G alpha(q) receptor agonists augment the NEAT-mediated transc riptional response to PDGF-BB, This synergy can be explained in part b y augmented intracellular Ca2+ transients elicited by multiple agonist challenges. These data indicate that agonists for phospholipase C-cou pled receptors stimulate NFAT-mediated transcription in VSMC different ially, and that NEAT can function to integrate co-activating signals i n the extracellular environment.