Arterial Wall Stress Controls NFAT5 Activity in Vascular Smooth Muscle Cells

Abstract

Background Nuclear factor of activated T‐cells 5 ( NFAT 5) has recently been described to control the phenotype of vascular smooth muscle cells ( VSMC s). Although an increase in wall stress or stretch (eg, elicited by hypertension) is a prototypic determinant of VSMC activation, the impact of this biomechanical force on the activity of NFAT 5 is unknown. This study intended to reveal the function of NFAT 5 and to explore potential signal transduction pathways leading to its activation in stretch‐stimulated VSMC s. Methods and Results Human arterial VSMC s were exposed to biomechanical stretch and subjected to immunofluorescence and protein‐biochemical analyses. Stretch promoted the translocation of NFAT 5 to the nucleus within 24 hours. While the protein abundance of NFAT 5 was regulated through activation of c‐Jun N‐terminal kinase under these conditions, its translocation required prior activation of palmitoyltransferases. DNA microarray and ChiP analyses identified the matrix molecule tenascin‐C as a prominent transcriptional target of NFAT 5 under these conditions that stimulates migration of VSMC s. Analyses of isolated mouse femoral arteries exposed to hypertensive perfusion conditions verified that NFAT 5 translocation to the nucleus is followed by an increase in tenascin‐C abundance in the vessel wall. Conclusions Collectively, our data suggest that biomechanical stretch is sufficient to activate NFAT 5 both in native and cultured VSMC s where it regulates the expression of tenascin‐C. This may contribute to an improved migratory activity of VSMC s and thus promote maladaptive vascular remodeling processes such as hypertension‐induced arterial stiffening.