Nuclear factor of activated T-cells 5 (NFAT5) has recently been described to control the phenotype of vascular smooth muscle cells (VSMCs). Although an increase in wall stress or stretch (e.g. elicited by hypertension) is a prototypic determinant of the VSMC phenotype, the impact of this biomechanical force on the activity of NFAT5 is unknown.

To reveal the function of NFAT5 and to explore potential signal transduction pathways leading to its activation in stretch-stimulated VSMCs, these cells were exposed to cyclic stretch and subjected to immunofluorescence analyses. Under these conditions NFAT5 translocates to the nucleus which was most prominent after 24 hours and declined thereafter. Translocation of NFAT5 to the nucleus required activation of c-Jun N-terminal kinase as well as that of a palmitoyltransferase. By employing DNA microarray analyses, we identified the matrix molecule tenascin-C as a prominent transcriptional target of NFAT5 under these conditions that stimulates migration of VSMCs. Analyses of isolated mouse femoral arteries exposed to hypertensive perfusion conditions verified that NFAT5 translocation to the nucleus is followed by an increase in tenascin-C abundance in the vessel wall.

Collectively, our data suggest for the first time that biomechanical stretch controls the activity of NFAT5 both in native and cultured human VSMCs where it regulates the expression of genes promoting migration of these cells. This may support a shift towards the synthetic phenotype in VSMCs and thus promote maladaptive vascular remodeling processes such as hypertension induced arterial stiffening.