Effects of hemodynamic forces on gene expression and signal transduction in endothelial cells.

Abstract

Vascular endothelial cells respond to mechanical forces, such as shear stress, by expressing a number of immediate early genes. One of these genes encodes monocyte chemotactic protein-l (MCP-1, Shyy et al., 1994), which plays a significant role in atherogenesis. This presentation summarizes the work done in our laboratory on the effects of shear stress on signal transduction and on the expression of the MCP-1 gene. Human umbilical vein endothelial cells and many other cell types respond to arterial level of shear stress (lo-30 dynes/cm2) with a transient increase of MCP-1 gene expression that peaks at 1.5 h (Shyy et al., 1994). Sequential deletion of the 5’ promoter region of the MCP-1 gene and site-specific mutation of the &-elements show that one of the two copies of the putative TPA-responsive elements (TRE), with the sequence TGACTCC, is critical for shearstress induction of the MCP-1 gene (Shyy et al., 1994). Transactivation assays indicate that activating protein1 (AP1, composed of Jun-Fos heterodimer or Jun-Jun homodimer) is the nuclear binding protein responsible for shear activation of MCP-1. The signal transduction pathways leading to the activa-