Abstract
Vascular cells are continuously exposed to mechanical stress that may wreak havoc if exceeding physiological levels. Consequently, mechanisms facing such a challenge are indispensable and contribute to the adaptation of the cellular phenotype. To this end, vascular smooth muscle cells (VSMCs) activate mechanoresponsive transcription factors promoting their proliferation and migration to initiate remodeling the arterial wall. In mechanostimulated VSMCs, we identified nuclear factor of activated T-cells 5 (NFAT5) as transcriptional regulator protein and intended to unravel mechanisms controlling its expression and nuclear translocation. In cultured human VSMCs, blocking RNA synthesis diminished both baseline and stretch-induced NFAT5 mRNA expression while inhibition of the proteasome promoted accumulation of the NFAT5 protein. Detailed PCR analyses indicated a decrease in expression of NFAT5 isoform A and an increase in isoform C in mechanoactivated VSMCs. Upon overexpression, only NFAT5c was capable to enter the nucleus in control- and stretch-stimulated VSMCs. As evidenced by analyses of NFAT5c mutants, nuclear translocation required palmitoylation, phosphorylation at Y143 and was inhibited by phosphorylation at S1197. On the functional level, overexpression of NFAT5c forces its accumulation in the nucleus as well as transcriptional activity and stimulated VSMC proliferation and migration. These findings suggest that NFAT5 is continuously expressed and degraded in resting VSMCs while expression and accumulation of isoform C in the nucleus is facilitated during biomechanical stress to promote an activated VSMC phenotype.
Highlights
Arteries provide a hierarchically organized network for the distribution of blood throughout the organism and are exposed to variable physical forces as generated by blood flow and blood pressure
We revealed that nuclear factor of activated T-cells 5 (NFAT5) is activated in vascular smooth muscle cells (VSMCs) exposed to biomechanical stretch (Hodebeck et al, 2014) to control the expression of gene products such as the cytoskeletal filament kappa-actin and the extracellular matrix protein tenascin C
Wall stress is well tolerated and to the most part absorbed by components of the extracellular matrix such as elastic fibers which transform the biomechanical load into reversible structural changes
Summary
Arteries provide a hierarchically organized network for the distribution of blood throughout the organism and are exposed to variable physical forces as generated by blood flow and blood pressure. Disturbed (non-laminar) blood flow and chronically elevated blood pressure are leading causes of arteriosclerosis and arterial remodeling (Intengan and Schiffrin, 2000; AlGhatrif and Lakatta, 2015) which are thought to be preceded by the mechanoactivation of vascular endothelial and smooth muscle cells. The latter retained the ability to switch their phenotype from quiescent/contractile to activated/synthetic which discriminates. This is accompanied by their proliferation which drives arterial thickening (Intengan and Schiffrin, 2001; AlGhatrif and Lakatta, 2015)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
