LXR?/estrogen receptor-? signaling in lipid rafts preserves endothelial integrity.

ABSTRACT: Liver X receptors (LXR) are stimulated by cholesterol-derived oxysterols and serve as transcription factors to regulate gene expression in response to alterations in cholesterol. In the present study, we investigated the role of LXRs in vascular endothelial cells (ECs) and discovered that LXR? has nonnuclear function and stimulates EC migration by activating endothelial NOS (eNOS). This process is mediated by estrogen receptor-? (ER?). LXR activation promoted the direct binding of LXR? to the ligand-binding domain of ER? and initiated an extranuclear signaling cascade that requires ER? Ser118 phosphorylation by PI3K/AKT. Further studies revealed that LXR? and ER? are colocalized and functionally coupled in EC plasma membrane caveolae/lipid rafts. In isolated aortic rings, LXR activation of NOS caused relaxation, while in mice, LXR activation stimulated carotid artery reendothelialization via LXR?- and ER?-dependent processes. These studies demonstrate that LXR? has nonnuclear function in EC caveolae/lipid rafts that entails crosstalk with ER?, which promotes NO production and maintains endothelial monolayer integrity in vivo.

SUBMITTER: Ishikawa T 

PROVIDER: S-EPMC3726156 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature