Heterogeneity in Endothelial Responsiveness to Cytokines, Molecular Causes, and Pharmacological Consequences

Microvascular endothelial cells play an essential role in inflammatory diseases. Functional heterogeneity between microvascular segments in normal organ homeostasis has been appreciated for a long time, and more recent studies have revealed heterogeneity in endothelial reactivity to inflammatory stimuli as well. This review summarizes the state-of-the-art knowledge regarding endothelial cell responses to the proinflammatory cytokines tumor necrosis factor alpha, interleukin-1 beta, and the bacterial product lipopolysaccharide. It focuses on similarities and differences in reactivity between endothelial cell subsets in vitro and endothelial cells in their pathophysiological environment in vivo, and culminates into a mainly theoretical model of possible intracellular control mechanisms that can assist to ultimately explain the molecular causes of endothelial heterogeneity. The last part of this review contains some pharmacological considerations, and, with the aim to further unravel the molecular basis of in vivo endothelial heterogeneity, descriptions of new techniques that will be essential to achieve this.