EXPOSURE TO SHEAR-STRESS ALTERS ENDOTHELIAL ADHESIVENESS - ROLE OF NITRIC-OXIDE

Background Shear stress increases the release of nitric oxide (NO) by endothelial cells (ECs). We and others have provided evidence that end othelium-derived NO inhibits monocyte adhesion to the vessel wall. We therefore hypothesized that previous exposure to shear stress would in hibit endothelial adhesiveness for monocytes by virtue of its effect t o increase NO release. Methods and Results Confluent monolayers of bov ine aortic endothelial cells, human aortic endothelial cells, or human venous endothelial cells were exposed to laminar fluid flow. Culture media were collected for measurement of NO (by chemiluminescence) and the prostacyclin metabolite 6-ketoprostaglandin F-1 alpha. NOx and 6-k eto-prostaglandin F1 alpha accumulated in the conditioned medium durin g laminar fluid flow from 30 minutes to 24 hours in a time-dependent f ashion. In another set of studies, ECs previously exposed to pow or to static conditions were washed with Hanks' buffer and exposed to THP-1 cells for 30 minutes. Adherent cells were counted by microscopy. Prev ious exposure to flow reduced endothelial adhesiveness for monocytes b y 50% (P<.05). The effect of flow on endothelial adhesiveness occurred within 30 minutes. This effect was abrogated by nitro-L-arginine (an antagonist of NO synthesis), as well as by tetraethylammonium ion (an antagonist of the flow-activated potassium channel); the effects of th ese inhibitors were reversed by the NO donor SPM-5185. Although the cy clo-oxygenase inhibitor Indomethacin totally inhibited the flow-induce d production of prostacyclin by ECs, it minimally affected adherence o f THP-1 cells. The early effect of flow on endothelial adhesiveness wa s not mediated by alterations in the expression of the endothelial adh esion molecules VCAM-1 or ICAM-1 as assessed by fluorescent activated cell sorting. Conclusions Shear stress alters endothelial adhesiveness for monocytes; at early time points, this effect is largely due to ho w-stimulated release of NO and, to a lesser extent, prostacyclin. This effect of flow occurs within 30 minutes and is probably due to altera tions in the signal transduction or activation state (rather than the expression) of endothelial adhesion molecules;