By virtue of its anatomic position at the interface of the bloodstream and the arterial wall, the vascular endothelium is constantly exposed to a complex and highly dynamic flow environment. Fluid mechanical forces, most notably shear stress, regulate vascular endothelial cell (EC) function through induction of humoral, metabolic, and structural responses. Beyond being responsive to shear stress, ECs have recently been shown to exhibit different responses when stimulated by steady vs. oscillatory flow. Although this observation is likely essential to understanding why early atherosclerotic lesions develop preferentially in arterial regions exposed to oscillatory flow, the mechanisms by which ECs distinguish among and respond differently to different types of flow remain unknown. Activation of flow-sensitive K and Cl channels is one of the most rapid endothelial responses to flow; therefore, these ion channels have been proposed as candidate flow sensors. In support of this idea, we have demonstrated that flow-sensitive ion channels regulate downstream responses to flow in ECs including changes in gene expression and protein synthesis. We have also used whole-cell patch clamping to demonstrate that flow-sensitive K channels respond differently to oscillatory flow from Cl channels. Additionally, we have formulated first-order mathematical models of flow-induced deformation of cell-surface and intracellular structures, and the results of this modeling provide insight into mechanisms by which ECs distinguish between steady and oscillatory flow. We propose that flow-sensitive ion channels form a part of an integrated mechanosensory system that allows ECs to discriminate among different types of flow.
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