Seminar Series on Fluids and Transport Processes in Biological Systems Chien Abstract

Molecular Basis of Mechano-chemical Transduction in Endothelial Cells

Vascular endothelial cells (ECs) perform many important functions, including the control of molecular permeability, the modulation of vascular smooth muscle contractility, and the production, secretion, and metabolism of biochemical substances. Thus, ECs play significant roles in regulating vascular functions in health and disease. This presentation focuses on the effects of shear stress and flow pattern on signal transduction and the consequent gene expression and functional responses of ECs.

Shear stress can modulate EC functions by activating sequentially the mechano-sensors, intracellular signaling pathways, specific transcription factors, and gene and protein expressions. We found that vascular endothelial growth factor receptor (VEGFR, which is a receptor tyrosine kinase) on the luminal side of ECs and integrins (e.g., avb3 and a5b1) on the abluminal side can serve as mechano-sensors. Other potential EC membrane mechano-sensors are G-proteins, ion channels, and intercellular junction proteins. The activation of these mechano-sensors by shear stress leads to the triggering of phosphorylation cascades of signaling molecules. For example, the Ras-MEKK-JNK signaling pathway mediates the shear stress-activation of the expression of monocyte chemotactic protein-1 (MCP-1) gene and protein in response to shear stress.

A sustained application of laminar shear stress results in only a transient activation of the Ras-MEKK-JNK signaling pathway and a transient MCP-1 expression followed by its down-regulation. Furthermore, sustained laminar shear stress activates the genes that inhibit vessel wall growth, e.g., the genes causing cell cycle arrest.

When ECs are subjected to complex flow patterns simulating these seen in the branch points, the down-regulation of MCP-1 in response to sustained flow does not occur. Thus, there is a sustained activation of genes such as MCP-1 in the areas with complex flow, especially the flow reattachment area, which has a low shear stress and a high shear stress gradient. Furthermore, EC mitosis and apoptosis are accelerated in the areas with complex flow. Such accelerated cell turnover leads to an enhanced macromolecular permeability. Therefore, the temporal and spatial variations in shear stress and flow pattern play important roles in endothelial functions such as leukocyte chemoattraction and macromolecular permeability.

The results of such interdisciplinary studies help to enhance our understanding of the fundamental process of mechano-chemical transduction, and the pathophysiological mechanisms of cardiovascular diseases. [an error occurred while processing this directive]