Nuclear factor of activated T-cells 5 (NFAT5) was first described as an osmoprotective transcription factor in renal cells. Meanwhile, other functions of NFAT5 have been revealed in non-renal cells such as lymphocytes. Recent studies also implicate NFAT5 as an important transcription factor for the control of phenotype of vascular smooth muscle cells (VSMC).

Considering the fact that osmotic stress causes translocation of NFAT5 from the cytosol to the nucleus and that hypertension (i.e., an increase in wall stress hence stretch) is a prototypic determinant of the VSMC phenotype, we hypothesized that biomechanical stretch affects their phenotype by influencing the nuclear translocation of NFAT5. To substantiate this hypothesis, human umbilical artery smooth muscle cells were exposed to cyclic stretch and potential signal transduction pathways leading to the activation of NFAT5 analysed.

Our results show a significant translocation of NFAT5 to the nucleus upon stretch which was most prominent after 24 hours and declined thereafter. In agreement with this, femoral arteries isolated from DOCA-salt-treated (i.e, hypertensive) mice at day 10 revealed a down-regulation of NFAT5 in the native VSMCs. While the stretch-induced translocation of NFAT5 of the cultured VSMCs required the activation of c-Jun N-terminal kinase, this was inhibited by reactive oxygen species which play a critical role in hypertension-induced vascular remodelling processes.

Collectively, our data suggest that biomechanical stretch controls the activity of NFAT5 both in native and cultured VSMCs and may support their shift to the synthetic phenotype in response to stimuli causing a maladaptive remodelling of the vessel wall.