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EDITORIAL FOCUS
Department of Pharmacology, University of California, San Diego, California
ENDOTHELIAL CELLS THAT LINE the inner wall of blood vessels secrete many vasoactive factors including nitric oxide (vasorelaxant) and endothelin-1 (vasoconstrictor) that contribute to the regulation of vascular tone and blood pressure (21). Endothelial cells respond to various humoral agents, including inflammatory mediators, such as interleukin-1 and prostaglandins, to regulate the permeability of the endothelium and allow passage of leukocytes (16). In addition, endothelial cells are involved in hemostatic mechanisms that include the adhesion of platelets in response to injury and are a source of tissue factor involved in clot formation (19). Consequently endothelial dysfunction contributes to many clinical disorders, including hypertension, atherosclerosis, and thrombosis (7).
To investigate endothelial cell function in a simplified and manipulable system, the use of homogenous populations of endothelial cells grown in tissue culture has been developed. However, whereas such cultures are maintained in an environment intended to mimic their in vivo setting, static cultures lack a critical feature that can influence their phenotype: tonic, low magnitude mechanical stress that is imposed on endothelial cells in vivo from the flow of blood, pressure fluctuations, and pulsatile stretch and contraction of the surrounding smooth muscle (see Fig. 1). Most prior studies with endothelial cells have not considered the role of such dynamic events in cell physiological studies and relatively little data have documented differences between static and dynamic cultures. Thus the article by McIntire et al. (Ref. 20), published in the current issue, is important because it highlights the effect of mechanical stressors on endothelial cell function by demonstrating that different types of mechanical stress (cyclic strain or fluid agitation "motion control") can produce opposing effects, depending on the vascular bed of origin of endothelial cells that are studied in culture.
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Cyclic strain can be imposed on endothelial cells in culture by growing the cells on a flexible membrane that is inserted in a chamber with one side of the chamber oscillating. Such a force stretches the membrane in one plane but also agitates the fluid, thus necessitating a "motion control" whereby an identical chamber is used but the oscillating wall is not attached to the membrane. McIntire et al. used such a device in their study to assess the effects of fluid agitation and cyclic strain on two types of endothelial cells-human umbilical vein endothelial cells (HUVEC) and human aortic endothelial cells (HAEC), representative of venous and arterial endothelial cell types, respectively. Since arterial endothelium in vivo is exposed to higher cyclic strain than is venous endothelium, the authors hypothesized that HAEC would be conditioned to ROS-stimulating activities of cyclic strain and thus produce less ROS in response to cyclic strain than would HUVEC. This was indeed found to be the case but, surprisingly, the motion control proved more effective at increasing ROS in HAEC than HUVEC. Since the cyclic strain treatment includes a fluid agitation component, McIntire et al. conclude that cyclic strain, per se (i.e., without fluid motion), is protective against oxidative stress in HAEC.
These results raise many questions, including the following: what is the mechanosensory signal transduction mechanism? How is ROS generated in response to mechanical stimuli? How does cyclic strain protect HAEC against oxidative stress? Studies by Schumacker et al. have shown that mechanically stimulated ROS production from endothelial cells is sensitive to mitochondrial inhibitors (2). In addition, mitochondria-derived ROS stimulates phosphorylation of focal adhesion kinase, a cytoskeletal component involved in anchoring mitochondria to the plasma membrane, in response to mechanical stretch (1). Such results implicate a role for mitochondria in mechanical stress-induced ROS production.
Coronary artery bypass grafts from veins are more sensitive to atherosclerosis than are arterial grafts (14). This suggests that arterial endothelia are intrinsically different from venous endothelia because they do not simply adapt to the elevated ROS levels associated with the increase in cyclic strain associated with an arterial locale. An approach to identifying the differences between venous and arterial endothelia is the use of gene expression profiling by the use of cDNA microarrays. Indeed, such analyses have revealed substantial differences in gene expression among different types of endothelial cells (5, 11, 17). McIntire et al. (8) have already made progress in the assessment of gene expression and have identified gene transcripts that change in response to cyclic strain in HUVEC. Identification of the genes in HAEC responsible for its protection against elevated ROS may provide novel therapeutic strategies to target diseases processes in which ROS have been implicated such as atherogenesis.
It is clear from the current article in focus that mechanical stimuli effect endothelial cell function and that this is dependent on not only the type of mechanical stimuli (e.g., cyclical strain or fluid motion) but also the type of endothelial cell (e.g., arterial or venous). When experiments are performed on endothelial cells in culture, in addition to the typical "humoral agents" such as endothelin-1 and interleukin-1, mechanical stimuli should be considered as important in the regulation of endothelial cell function. A key conclusion of the study by McIntire et al.—and one that other investigators should consider—is whether traditional static cultures of endothelial cells could (or perhaps, should) be improved by making them dynamic so as to more accurately retain the physiology of endothelial cells in vivo. Of note in this regard, studies that have assessed nitric oxide production have suggested that the combination of cyclic strain, fluid shear stress and hydrostatic pressure—rather than any one alone—most accurately reflect physiological responses of endothelial cells (3).
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