Gender‐differences in leukocyte activation in vivo: role of endothelium‐derived mediators

Endothelial‐derived mediators, particularly nitric oxide (NO) and prostacyclin (PGI 2 ), are potent inhibitors of leukocyte activation. Since endothelial mediators are gender‐specific (Scotland et al [2005] Circulation , 111 , 796), we studied leukocyte activation in male and female mice lacking endothelial NO (eNOS −/− ) or PGI 2 (COX‐1 −/− ). Intravital microscopy was used to assess leukocyte activation in vivo in mesenteric post‐capillary venules of wild‐type (WT), eNOS −/− , and COX‐1 −/− mice (11–15g) under basal or inflammatory conditions (IL‐1β; 5ng i.p.; 90min.). Basal leukocyte rolling was low and similar in male and female WT (n=4). In eNOS −/− , basal leukocyte rolling was raised in males only (P<0.05; n=8). Basal rolling was also (P<0.05) elevated in COX‐1 −/− but no gender‐difference was observed (n=8). IL‐1β (P<0.05) elevated leukocyte activation in WT, eNOS −/− and COX‐1 −/− males but had no significant effect in females of any genotype. Thus, basal and IL‐1β‐stimulated leukocyte activation in male, but not female, mice is dependent predominantly on endothelial NO. PGI 2 also contributes to regulation of basal leukocyte rolling, but no gender difference is apparent. In contrast, IL‐1β has no effect on leukocyte rolling in females of any genotype, intimating the existence of gender‐specific anti‐inflammatory mechanisms. As EDHF is the predominant endothelium‐derived mediator in the mesenteric vascular bed of female mice, enhanced activity of EDHF might underlie these gender‐differences in leukocyte activation. Supported by the Wellcome Trust and British Heart Foundation