Ion Channels in Shear Stress Sensing in Vascular Endothelium

Abstract

Endothelial cell (EC) responsiveness to fluid-mechanical shear stress is essential for normal vascular function and may play a role in the localization of early atherosclerotic lesions. Although ECs are known to be exquisitely sensitive to flow, the precise mechanisms by which ECs sense and respond to shear stress remain incompletely understood. The activation of flow-sensitive ion channels is one of the most rapid endothelial responses to shear stress; therefore, these ion channels have been proposed as candidate flow sensors. A central role for flowsensitive ion channels in EC shear sensing is supported by recent data demonstrating that blocking these ion channels profoundly affects downstream endothelial flow signaling. This chapter briefly describes the shear stress environment within medium and large arteries and highlights the wide array of EC responses induced by shear stress. Specific attention is focused on the differential responsiveness of ECs to different types of shear stress. The impact of shear stress on EC ion channels is described in detail, and a potential role for flow-sensitive ion channels in endowing ECs with the ability to distinguish among different types of flow is proposed. The chapter also addresses the implications of ion channel activation for overall endothelial responsiveness to flow, the potential mechanisms by which shear stress activates ion channels, and the remaining gaps in our understanding of shear stress-sensitive ion channels. Finally, suggestions are made for future research directions in this field. 9.1. Arterial Flow and Mechanotransduction in Vascular Endothelium 9.1.1. Central Importance of Endothelial Flow Sensing and Responsiveness The vascular endothelium, the innermost layer of cells lining the inner surfaces of all blood vessels, is capable of sensing and transducing mechanical forces ∗ Mechanical and Aeronautical Engineering, University of California, Davis, One Shields Avenue, Davis, CA 95616, abarakat@ucdavis.edu