Critical Care Epidemiological studies consistently demonstrate higher sepsis syndrome incidence in males vs. females. This finding may result from female resistance to endothelial dysfunction during pathophysiologic stress. In turn, superior female endothelial function may be mediated by beneficial effects of estrogens on nitric oxide (NO) and oxidative metabolism. We are studying mechanisms of endothelial dysfunction in sepsis syndrome, and the relationship between these mechanisms and clinical outcomes. Specifically, a prospective cohort study is underway analyzing the effects of gonadal hormones, oxidative stress, and NO metabolism on endothelial function and outcomes in sepsis syndrome patients. Complementing this observational study, we are conducting an epidemiologic study utilizing a prospectively collected ICU database containing over 20,000 septic patients to assess the independent effect of gender on sepsis syndrome mortality. Recent data suggest that the vasodilator NO is transported in blood, not rapidly consumed as previously assumed. These data indicate that NO is liberated in vascular beds characterized by hypoxia or endothelial dysfunction, effecting vasodilation. Thus, intravascular NO transport may be a protective mechanism matching blood flow to metabolic need. We are investigating the role of various blood components in permitting circulatory nitric oxide transport, in vitro. We are also applying and testing the concepts of intravascular NO transport and delivery in the aforementioned cohort study. Together, these clinical, epidemiologic, and physiologic studies complete the translational investigation loop that forms the backbone of this research enterprise.