Genetic ablation of NFAT5/TonEBP in smooth muscle cells impairs flow- and pressure-induced arterial remodeling in mice

• Verfasst von: Arnold, Caroline [VerfasserIn]
• Verfasst von: Feldner, Anja [VerfasserIn]
• Verfasst von: Zappe, Maren [VerfasserIn]
• Verfasst von: Komljenovic, Dorde [VerfasserIn]
• Verfasst von: Torre, Carolina de la [VerfasserIn]
• Verfasst von: Hecker, Markus [VerfasserIn]
• Verfasst von: Neuhofer, Wolfgang [VerfasserIn]
• Verfasst von: Korff, Thomas [VerfasserIn]
• Titel: Genetic ablation of NFAT5/TonEBP in smooth muscle cells impairs flow- and pressure-induced arterial remodeling in mice
• Verf.angabe: Caroline Arnold, Anja Feldner, Maren Zappe, Dorde Komljenovic, Carolina De La Torre, Philipp Ruzicka, Markus Hecker, Wolfgang Neuhofer, Thomas Korff
• E-Jahr: 2019
• Jahr: 27 Feb 2019
• Umfang: 14 S.
• Fussnoten: Gesehen am 03.04.2019
• Titel Quelle: Enthalten in: Federation of American Societies for Experimental BiologyThe FASEB journal
• Ort Quelle: Hoboken, NJ : Wiley, 1987
• Jahr Quelle: 2019
• Band/Heft Quelle: 33(2019), 3, Seite 3364-3377
• ISSN Quelle: 1530-6860
• DOI: doi:10.1096/fj.201801594R
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1662789475

Abstract

The arterial wall adapts to alterations in blood flow and pressure by remodeling the cellular and extracellular architecture. Biomechanical stress of vascular smooth muscle cells (VSMCs) in the media is thought to precede this process and promote their activation and subsequent proliferation. However, molecular determinants orchestrating the transcriptional phenotype under these conditions have been insufficiently studied. We identified the transcription factor, nuclear factor of activated T cells 5 (NFAT5; or tonicity enhancer-binding protein) as a crucial regulatory element of mechanical stress responses of VSMCs. Here, the relevance of NFAT5 for arterial growth and thickening is investigated in mice upon inducible smooth muscle cell (SMC)-specific genetic ablation of Nfat5. In cultured mouse VSMCs, loss of Nfat5 inhibits the expression of gene sets involved in the control of the cell cycle and the interaction with the extracellular matrix and cytoskeletal dynamics. In vivo, SMC-specific knockout of Nfat5 did not affect the general vascular architecture and blood pressure levels under baseline conditions. However, proliferation of VSMCs and the thickening of the arterial wall were inhibited during both flow-induced collateral remodeling and hypertension-mediated arterial hypertrophy. Whereas originally described as a hypertonicity-responsive transcription factor, these findings identify NFAT5 as a novel molecular determinant of biomechanically induced phenotype changes of VSMCs and wall stress-induced arterial remodeling processes.—Arnold, C., Feldner, A., Zappe, M., Komljenovic, D., De La Torre, C., Ruzicka, P., Hecker, M., Neuhofer, W., Korff, T. Genetic ablation of NFAT5/TonEBP in smooth muscle cells impairs flow- and pressure-induced arterial remodeling in mice.