Abstract
Objective:Previous work indicated that E-selectin mediates transient interactions between leukocytes and cytokine-activated endothelium in vitro. Here we examine the role of E-selectin in blood leukocyte interactions with microvascular endothelium in vivo. Methods:E-selectin-deficient (E−/−mice were produced by gene targeting. The effect of this null mutation on leukocyte-endothelial interactions was determined by intravital microscopy before and 4 to 5 hours after local administration of the proinflammatory cytokine tumor necrosis factor α (TNFα) in dermal microvessels with low blood flow (dorsal skin-fold chambers, intact ear skin), and after endotoxin activation in exteriorized mesenteric microvessels with higher blood flow. Results:E−/−mice were viable, fertile with normal circulating leukocyte and platelet profiles. Approximately 60% of circulating leukocytes rolled in dermal microvessels of both normal (E+/+) and E−/−mice without inflammatory stimulation. After local administration of TNFα, rolling increased modestly and equivalently in both genotypes. The main effect of TNFα was a dramatic increase in leukocyte stable adhesion and, unlike rolling, this manifestation of endothelial activation was significantly reduced in E−/−animals. This reflected fewer dermal microvessels supporting higher adhesion densities in E−/−mice, and a similar trend was observed in mesenteric microvessels. Conclusions:E-selectin plays a previously unappreciated role in facilitating and/or mediating stable adhesion of leukocytes to inflamed microvascular endothelium.