Introduction

Two essential functions of arterial endothelium are flow-mediated vasoregulation in response to acute changes in blood flow and vascular wall remodeling in response to chronic hemodynamic alterations [1, 2]. Both of these functions require arterial endothelial cells (ECs) to be capable of sensing the mechanical forces associated with blood flow and of transducing these forces into biochemical signals that mediate structural and functional responses. Mechanosensing and -transduction in arterial endothelium also play a critical role in the development and localization of atherosclerosis. The topography of early atherosclerotic lesions is highly focal and correlates with arterial regions that are exposed to low and/or oscillatory shear stress [3, 4]. There is mounting evidence that low and oscillatory shear stress elicit a pro-inflammatory and adhesive EC phenotype, whereas relatively high and nonreversing pulsatile shear stress induce a phenotype that is largely anti-inflammatory [5–9]. In light of the central role of EC inflammation in atherogenesis [9–14], the key to understanding the involvement of flow in the development of atherosclerosis may lie in determining the mechanisms governing the differential responsiveness of ECs to different types of flows.

The current concept of EC mechanotransduction postulates that it involves a sequential progression of events involving sensing of the mechanical stimulus, transduction of the stimulus to a biochemical signal, and cellular reaction and subsequent possible adaptation to the new mechanical environment [15–19]. Consistent with this construct, a number of candidate mechanosensors have been proposed. These include stretch- and flow-sensitive ion channels [20–27], cell-surface integrins at both the luminal and basal cell surfaces [19, 28], the cellular cytoskeletal network [15], subregions of the cell membrane or the entire membrane [29, 30], membrane-associated GTP-binding proteins (or G-proteins) [31, 32] and G-protein–coupled receptors [33], cell–cell junction constituents including platelet–EC adhesion molecule-1 (PECAM-1) [34], and the glycocalyx at the cell luminal surface [35–37]. The rationale for classifying these various structures as candidate mechanosensors is threefold: 1) They are associated with the cell membrane, where the effects of an externally applied force would likely be most immediately felt; 2) they generally respond very rapidly following the onset of the mechanical stimulus; and 3) interfering with the activation of these structures abrogates, or at least significantly diminishes, some of the downstream responses induced by the applied mechanical force. It remains unclear, however, how these various structures interact with one another to potentially form an integrated mechanosensory system.