The pathological complications of atherosclerosis, namely heart attacks and strokes, are the leading cause of mortality in the Western world. Early atherosclerotic lesions develop preferentially in regions where the arterial wall is exposed to low and/or oscillatory fluid mechanical shear stress. Although the biological basis of this correlation remains unknown, dysfunction of vascular endothelial cells (ECs) is thought to be centrally involved. In response to shear stress, ECs exhibit humoral, metabolic, and structural responses; however, the specific nature of the response depends on the type of applied shear stress. While relatively high levels of steady shear stress lead to an anti-inflammatory, anti-adhesive, and hence atheroprotective EC phenotype, low and oscillatory shear stress result in a cellular profile that is pro-inflammatory and atherogenic. Although research over the past two decades has greatly enhanced our understanding of the EC signaling pathways induced by shear stress, the early events involved in shear stress sensing remain incompletely understood and the mechanisms by which ECs discriminate among different types of flow remain unknown.

Activation of flow-sensitive ion channels is among the most rapid flow responses in ECs; therefore, these channels have been proposed as candidate flow sensors. Sudden exposure of ECs to shear stress immediately activates inward-rectifying K⁺ channels, leading to cell membrane hyperpolarization. Simultaneously, flow stimulates outward-rectifying Cl^- channels whose activation antagonizes the K⁺ channel-mediated hyperpolarization and leads to membrane depolarization. In support of the proposed role of flow-activated ion channels as shear stress sensors, agents that block activation of these channels greatly attenuate or entirely abolish a number of downstream responses to shear stress in ECs including flow-mediated changes in gene expression and protein synthesis as well as shear stress-induced phosphorylation of the serine-threonine kinase Akt.

A key idea that is proposed is that flow-sensitive K⁺ and Cl^- channels are components of a complex mechanosensory system that endows ECs with the ability to discriminate among different levels and types of shear stress. In support of this construct, we have observed the following important differences between flow-sensitive K⁺ and Cl^- channels: 1) While both K⁺ and Cl^- channels are activated by very low levels of steady shear stress (0.1-0.3 dyne/cm²), peak current occurs at a shear stress of ~10-15 dyne/cm² for K⁺ channels and at a shear stress of ~3.5 dyne/cm² of Cl^- channels. Therefore, Cl^- channels exhibit maximal sensitivity at lower shear stress levels than K⁺ channels. 2) In response to shear stress, K⁺ channels are activated significantly more rapidly than Cl^- channels. 3) Oscillatory flow with a physiological frequency of 1 Hz fully activates K⁺ channels but fails to activate Cl^- channels. We hypothesize that the ratio of K⁺ current to Cl^- current elicited by a particular shear stress stimulus (and the effect of this ratio on cell membrane potential) constitutes a signal that ECs use to decipher the details of the amplitude and waveform of the imposed shear stimulus.

Another critical question to address is the mechanism(s) of activation of flow-sensitive ion channels. Our data using fluids of different viscosities suggest that the extent of activation of ion channels correlates with the magnitude of the applied shear stress rather than the applied shear rate. This suggests that ion channel activation is “direct” and is not a consequence of the altered delivery and/or removal (convective and/or diffusive transport) of specific fluid-borne agonists. It remains unclear how shear stress directly activates ion channels in ECs; however, the small sizes of the channels would argue against a channel conformational change as a direct result of the applied fluid mechanical force. Rather, a more likely pathway is channel gating through an effect of flow on cell membrane tension, membrane subdomains to which the channels are directly coupled, or even intracellular cytoskeletal elements.