Pressure-induced vascular remodeling is a major problem in cardiovascular disease. However, although the result of this process, i.e., formation of a neointima or hypertrophic media and a fixed increase in total arterial resistance have long been described in detail, the early signaling events leading to the onset of vascular remodeling are not understood.

We have analyzed wall tension-induced signaling in human primary cultured endothelial and smooth muscle cells exposed to increased wall tension using a computer-assisted Flexercell strain device. The mechanotransducing protein zyxin and wall tension-induced IL-8 expression were the main read outs. Zyxin-phosphorylation was analyzed by 2D gel electrophoresis combined with the transfection-based expression of phosphorylation-incompetent zyxin isoforms. Real time RT-PCR, Western blot, ELISA and IFA were used to assay mRNA and protein levels as well as protein localization.

Increases in wall tension resulted in a hierarchical chain of signaling events involving TRP-mediated sodium/calcium influx, the consecutive release of endothelin-1 (ET-1) and atrial natriuretic peptide (ANP) and, finally, a protein kinase G-induced phosphorylation of zyxin at specific serine residues. This phosphorylation caused the dissociation from focal adhesion contacts followed by a nuclear accumulation of the protein. In the nucleus, zyxin controlled the wall tension-induced changes in endothelial transcription patterns in response to wall tension in a highly complex way.

Interestingly, paracrine endothelial wall tension-induced signaling as the first step in pressure-induced vascular closely resembles the systemic atrio-renal ANP signaling pathway only differing in the final effector mechanism.