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.