Background: Transient receptor potential (TRP) ion channels play a central role in pressure- induced myogenic vasoconstriction. However, their role in early phases of pressure-induced vascular remodelling is not known. Here we have analysed the role of TRPs in an early event of vascular remodelling, the redistribution of the focal adhesion protein zyxin to the nucleus in pressurized or stretched endothelial cells (EC) and smooth muscle cells (SMC). Methods: In situ perfusion of freshly isolated mouse femoral arteries was done using a Pressure Myograph System (DMT). Human primary cultured ECs and mouse SMCs were exposed to cyclic stretch using a computer-assisted Flexercell strain device. Stretch-induced changes in gene expression were analysed by Western blot, ELISA, immunohistochemistry, DNA microarray and RT-PCR analysis. Results: A stretch-/pressure-induced dissociation of zyxin from focal adhesions and its migration to the nucleus was observed both in the native and cultured cells. In the nucleus, zyxin orchestrates endothelial cell gene expression in a complex manner. Its translocation to the nucleus in ECs requires the subsequent stretch-induced release of both endothelin-1 (ET-1) and atrial natriuretic peptide (ANP), the trigger for which is unknown at present. We hypothesized that TRP-mediated influx of calcium ions is the initial event responsible for the redistribution of zyxin in these cells. Indeed, stretch-induced zyxin translocation was absent in arteries and cultured SMCs isolated from TRP knock out mice. Moreover, inhibition of stretch-induced zyxin- mediated endothelial cell gene expression by the TRP inhibitor gadolinium (50 mM) was reversed by exposure to the down-stream effectors ET-1 (10 nM) or ANP (1 nM). Conclusions: TRP channel activity is a crucial up-stream event in stretch-induced nuclear translocation of the focal adhesion protein zyxin. In the nucleus, zyxin orchestrates endothelial and smooth muscle cell gene expression in response stretch.