Abstract
Flow conditions critically regulate endothelial cell functions in the vasculature. Reduced shear stress resulting from disturbed blood flow can drive the development of vascular inflammatory lesions. On endothelial cells, the transmembrane chemokine CX3CL1/fractalkine promotes vascular inflammation by functioning as a surface-expressed adhesion molecule and by becoming released as soluble chemoattractant for monocytic cells expressing the receptor CX3CR1. Here, we report that endothelial cells from human artery, vein, or microvasculature constitutively express CX3CL1 when cultured under static conditions. Stimulation with TNFα under static or very low shear stress conditions strongly upregulates CX3CL1 expression. By contrast, CX3CL1 induction is profoundly reduced when cells are exposed to higher shear stress. When endothelial cells were grown and subsequently stimulated with TNFα under low shear stress, strong adhesion of monocytic THP-1 cells to endothelial cells was observed. This adhesion was in part mediated by transmembrane CX3CL1 as demonstrated with a neutralizing antibody. By contrast, no CX3CL1-dependent adhesion to stimulated endothelium was observed at high shear stress. Thus, during early stages of vascular inflammation, low shear stress typically seen at atherosclerosis-prone regions promotes the induction of endothelial CX3CL1 and monocytic cell recruitment, whereas physiological shear stress counteracts this inflammatory activation of endothelial cells.
Highlights
In the body, vascular endothelial cells are constantly exposed to blood flow
The importance of shear stress for endothelial cell functions is highlighted by pathological processes associated with reduced or absent laminar shear stress, which can occur in vascular beds that are prone to atherosclerosis
Endothelial CX3CL1 mRNA and Protein Expression Is Downregulated under Flow Conditions
Summary
Vascular endothelial cells are constantly exposed to blood flow. The resulting laminar shear stress on the endothelial surface can largely differ in large and small arteries or veins, respectively [1, 2]. Exposure to laminar flow typically leads to an alignment of the endothelial cells in the direction of the flow, cytoskeletal rearrangements, the formation of tight endothelial cell-to-cell contacts, reduced permeability, arrest of cell proliferation, and prolonged cell survival [3,4,5,6,7] These phenotypical characteristics are maintained by a transcriptional response to the flow conditions resulting in the altered expression of regulators of the vascular tone, endothelial surface molecules, and soluble mediators. At branch points and curved areas such as the carotid sinus, disturbed flow including flow reversal or turbulence may occur In these areas, the average shear stress is considerably lower and values below 1 dyn/cm can occur, which is 10 times lower than the average of 10 dyn/cm in the human vasculature and even 100 times lower compared to the microvasculature [1, 2, 13]. The adherent monocytes become activated and migrate into the vascular wall where they contribute to the lesion development by production of inflammatory mediators, by uptake of lipids, and by differentiation into macrophages and foam cells [14]
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