Fluid shear stress induces a biphasic response of human monocyte chemotactic protein 1 gene expression in vascular endothelium.

Abstract

The focal distribution of atherosclerotic lesions in the arterial tree is related to the local shear stress generated by blood flow, but the molecular basis of the atherogenic response of endothelial cells in these lesion-prone areas is still unclear. We report that shear stress mediates a biphasic response of monocyte chemotactic protein 1 (MCP-1) gene expression in vascular endothelial cells (EC). Northern blot analysis indicated that the level ofMCP-1 mRNA in human umbilical vein EC (HUVEC) subjected to a shear stress of 16 dynes/cm2 (1 dyne = 10 MN) for 1.5 hr increased by 2-to 3-fold when compared with static cells. The MCP-1 gene expression decreased to the basal level at 4 hr and then declined further to become completely quiescent at 5 hr after the onset of shear. Once the gene expression was fully suppressed, it remained quiescent even after static incubation for 1.5 hr and would not respond to reshearing after this static incubation. However, if the postshearing incubation extended from 1.5 to 24 hr, the MCP-1 mRNA returned to the basal level and was then able to increase after the reapplication of shear stress. Nuclear run-on experiments showed that the shear-induced increased MCP-1 mRNA in HUVEC was regulated at the transcriptional level. By using cycloheximide, it was shown that de novo protein synthesis was not necessary for the induction of MCP-1 by shear stress. The biphasic response of MCP-1 gene expression was found in experiments in which the applied shear stress was 6, 16, or 32 dynes/cm2, and it was observed not only in HUlVEC but also in HeLa cells, glioma cell lines, and skin fibroblasts. This in vitro study demonstrates that the response of MCP-1 gene to shear stress represents an immediate early gene activation and suggests that this gene is probably suppressed in EC that have been exposed to a constant shear stress.Atherosclerotic lesions show a focal pattern of distribution in the arterial tree; they have a predilection in regions such as bends and bifurcations where the blood flow is disturbed with flow separation and where the wall shear stress is low and unsteady (1, 2). Studies of experimental atherosclerosis in animal models also indicate that risk factors such as hyperlipidemia, smoking, and hypertension enhance the occurrence of lesions in these regions by superimposing their effects on the fundamental predilection resulting from hemodynamic forces (3). We have previously demonstrated that the endothelial cells (EC) in these prelesion areas have a higher mitotic rate and a greater permeability to macromolecules such as low density lipoproteins (LDL) than EC in areas experiencing undisturbed laminar flow (4, 5). All of these findings suggest that hemodynamic forces play a key role in atherogenesis. However, the molecular mechanisms underlying these flow-induced atherogenic events in the endothelium at these lesion-prone areas are still unclear.Because of the difficulties of in vivo experiments, the flow chamber was used to study the production of prostacyclin in human umb...

Differential Expression of Splicing Variants of the Human Caldesmon Gene (CALD1) in Glioma Neovascularization versus Normal Brain Microvasculature

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Intussusceptive angiogenesis: Its emergence, its characteristics, and its significance

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