title: SERCA2a controls the mode of agonist-induced intracellular Ca2+ signal, transcription factor NFAT and proliferation in human vascular smooth muscle cells.
abstract: In blood vessels, tone is maintained by agonist-induced cytosolic Ca(2+) oscillations of quiescent/contractile vascular smooth muscle cells (VSMCs). However, in synthetic/proliferative VSMCs, Gq/phosphoinositide receptor-coupled agonists trigger a steady-state increase in cytosolic Ca(2+) followed by a Store Operated Calcium Entry (SOCE) which translates into activation of the proliferation-associated transcription factor NFAT. Here, we report that in human coronary artery smooth muscle cells (hCASMCs), the sarco/endoplasmic reticulum calcium ATPase type 2a (SERCA2a) expressed in the contractile form of the hCASMCs, controls the nature of the agonist-induced Ca(2+) transient and the resulting down-stream signaling pathway. Indeed, restoring SERCA2a expression by gene transfer in synthetic hCASMCs 1) increased Ca(2+) storage capacity; 2) modified agonist-induced IP(3)R Ca(2+) release from steady-state to oscillatory mode (the frequency of agonist-induced IP(3)R Ca(2+) signal was 11.66 ± 1.40/100 s in SERCA2a-expressing cells (n=39) vs 1.37 ± 0.20/100 s in control cells (n=45), p<0.01); 3) suppressed SOCE by preventing interactions between SR calcium sensor STIM1 and pore forming unit ORAI1; 4) inhibited calcium regulated transcription factor NFAT and its down-stream physiological function such as proliferation and migration. This study provides evidence for the first time that oscillatory and steady-state patterns of Ca(2+) transients have different effects on calcium-dependent physiological functions in smooth muscle cells.
authors.affiliation: INSERM U770; Univ Paris Sud, Le Kremlin-Bicêtre, 94276, France.
authors.forename: Regis
authors.initials: R
authors.lastname: Bobe
authors.forename: Lahouaria
authors.initials: L
authors.lastname: Hadri
authors.forename: Jose J
authors.initials: JJ
authors.lastname: Lopez
authors.forename: Yassine
authors.initials: Y
authors.lastname: Sassi
authors.forename: Fabrice
authors.initials: F
authors.lastname: Atassi
authors.forename: Ioannis
authors.initials: I
authors.lastname: Karakikes
authors.forename: Lifan
authors.initials: L
authors.lastname: Liang
authors.forename: Isabelle
authors.initials: I
authors.lastname: Limon
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lompré
authors.forename: Stephane N
authors.initials: SN
authors.lastname: Hatem
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Larissa
authors.initials: L
authors.lastname: Lipskaia
mesh_terms: D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D018613:Microscopy, Confocal; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D050778:NFATC Transcription Factors; D019938:Cyclin D1; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium