Wall stress initiates the nuclear export and degradation of phosphorylated myocardin in vascular smooth muscle cells

Abstract

Myocardin controls the expression of genes stabilizing the contractile phenotype of vascular smooth muscle cells (SMC) by binding to the CArG box of serum response factor. Despite its crucial role in the development of the embryonic vasculature, its impact on the phenotype of adult SMCs still is poorly understood. We observed a significant decrease in myocardin abundance in SMCs of mouse arteries upon in vivo exposure to increased wall stress (e.g. hypertension), accompanied by downregulation of target genes such as calponin and an increase in proliferation. In SMCs of isolated mouse arteries myocardin level strongly decreased upon a supraphysiological increase in transmural pressure. Subsequent analyses of human cultured SMCs exposed to enhanced stretch, suggested that this biomechanical force elicits the nuclear export of phosphorylated myocardin. Followed by its proteasomal degradation in the cytoplasm.These findings suggest that increased wall stress triggers the nuclear export of myocardin and its proteasomal degradation in arterial SMCs through an as yet unknown mechanism. This process may determine the switch towards the synthetic phenotype and thus control the onset of arterial remodeling.