Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA366

Poster Communications

NFAT5/TonEBP - a mechanoresponsive transcription factor that controls arterial remodeling

M. Zappe1, A. Feldner1, C. Arnold1, D. Komljenovic2, C. Sticht1, C. De La Torre1, M. Hecker1, W. Neuhofer1, T. Korff1

1. Heidelberg University, Heidelberg, Germany. 2. DKFZ, Heidelberg, Germany.

Cells are continuously exposed to mechanical stress that may wreak havoc if exceeding physiological levels. Consequently, cell type-specific mechanisms strengthening their integrity or evading harmful stressors are indispensable. In arteries, vascular smooth muscle cells (VSMCs) respond to an increase in wall stress by reorganizing the arterial architecture which - in the long run - causes detrimental arterial hypertrophy and stiffening. In this context, transcriptional determinants controlling cellular stress responses have been insufficiently studied. We identified the transcription factor ‘nuclear factor of activated T-cells 5' (NFAT5) as a regulatory element of mechanical stress responses and intended to further characterize its impact on the VSMC phenotype in vitro and in vivo. Biomechanical stress downregulated NFAT5 isoform A in VSMCs (3-fold, p<0.05, n=3) while isoform C was upregulated (1.8-fold, p<0.05, n=3). Analyses of corresponding Flag-tagged NFAT5 proteins revealed that isoform C but not A enters the nucleus of mechanoactivated VSMCs (10.3-fold vs. isoform A, p<0.001, n=3). On the functional level, overexpression of NFAT5c stimulated VSMC migration and proliferation. The relevance of these observations for biomechanically evoked arterial remodeling was investigated in mice allowing for induction of SMC-specific genetic ablation of Nfat5. As evidenced by transcriptome studies, loss of Nfat5 in mouse VSMCs impairs expression of gene products controlling cell cycle, cytoskeletal dynamics and cellular adhesion. SMC-specific Nfat5 deficiency did not alter the general vascular architecture and blood pressure levels under baseline conditions or DOCA/salt-induced hypertension. However, proliferation of VSMCs and thickening of the arterial wall was attenuated during hypertension-mediated arterial remodeling (2.4-fold, p<0.05, n=5). These findings identify NFAT5 as physiologically relevant mechanoresponsive transcriptional determinant regulating the activation of VSMCs in the biomechanically stressed arterial wall during pressure-mediated arterial remodeling.

Where applicable, experiments conform with Society ethical requirements