LXRβ/estrogen receptor-α signaling in lipid rafts preserves endothelial integrity

J Clin Invest. 2013 Aug;123(8):3488-97. doi: 10.1172/JCI66533. Epub 2013 Jul 8.

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 LXRβ has nonnuclear function and stimulates EC migration by activating endothelial NOS (eNOS). This process is mediated by estrogen receptor-α (ERα). LXR activation promoted the direct binding of LXRβ to the ligand-binding domain of ERα and initiated an extranuclear signaling cascade that requires ERα Ser118 phosphorylation by PI3K/AKT. Further studies revealed that LXRβ and ERα 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 LXRβ- and ERα-dependent processes. These studies demonstrate that LXRβ has nonnuclear function in EC caveolae/lipid rafts that entails crosstalk with ERα, which promotes NO production and maintains endothelial monolayer integrity in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / cytology
  • Caveolae / metabolism
  • Cell Line
  • Cell Movement
  • Cell Nucleus / metabolism
  • Endothelial Cells / enzymology*
  • Endothelial Cells / metabolism
  • Endothelium, Vascular / cytology
  • Enzyme Activation
  • Estrogen Receptor alpha / metabolism*
  • Humans
  • In Vitro Techniques
  • Liver X Receptors
  • Male
  • Membrane Microdomains / metabolism*
  • Mice
  • Mice, Knockout
  • Nitric Oxide Synthase Type III
  • Orphan Nuclear Receptors / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Receptor Cross-Talk
  • Signal Transduction
  • Vasodilation

Substances

  • Estrogen Receptor alpha
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • estrogen receptor alpha, human
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt