Although pressure-induced vascular remodeling is a major problem in many cardiovascular diseases, molecular mechanisms are not understood. The focal adhesion protein zyxin seems to play a central role in this adaptive process as it is involved in the changes in cellular phenotype at the onset of remodeling. In this study we have analyzed the events leading to the pressure- induced activation of zyxin.

Primary human umbilical vein endothelial cells (EC) were cultured on flexible membranes and subjected to cyclic strain in a computer-assisted device. Real time RT-PCR, Western blot, ELISA and IFA were used to assay mRNA and protein levels as well as protein localization. Cyclic stretch of EC results in a secretion of Endothelin-1 (ET-1) followed by an ET-1-dependent release of atrial natriuretic peptide (ANP). This release is mediated by the B-type ET-1 receptor as pre-incubation with the receptor-specific ET-1 antagonist BQ788 leads to complete inhibition of ANP release. Autocrine ANP-induced activation of protein kinase G finally leads to a dissociation of zyxin from focal adhesions and nuclear accumulation of the protein. In the nucleus, zyxin controls stretch-induced gene expression.

Analogous to the heart, the endothelial ANP ET-1 system detects increases in vascular wall tension and mediates the cellular response to this stimulus.