LXRβ/estrogen receptor-α signaling in lipid rafts preserves endothelial integrity
Tomonori Ishikawa, … , Philip W. Shaul, Michihisa Umetani
Tomonori Ishikawa, … , Philip W. Shaul, Michihisa Umetani
Published July 8, 2013
Citation Information: J Clin Invest. 2013;123(8):3488-3497. https://doi.org/10.1172/JCI66533.
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Research Article Vascular biology Article has an altmetric score of 14

LXRβ/estrogen receptor-α 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 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.

Authors

Tomonori Ishikawa, Ivan S. Yuhanna, Junko Umetani, Wan-Ru Lee, Kenneth S. Korach, Philip W. Shaul, Michihisa Umetani

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Figure 7

LXRβ activation promotes reendothelialization in mice in an ERα–dependent manner.

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LXRβ activation promotes reendothelialization in mice in an ERα–dependen...
(A and B) Reendothelialization of the carotid artery was evaluated in male Lxra/b+/+, Lxra/b–/–, Lxra–/–, and Lxrb–/– mice fed a diet containing either vehicle or T1317. (C and D) Reendothelialization experiments were performed in Era+/+ mice, in Era+/+ mice treated with ICI, and in Era–/– mice fed a diet containing either vehicle or T1317. Four days after perivascular electric injury, mice were injected with Evans blue dye and the area of intimal surface dye incorporation was quantified. (A and C) Intimal surfaces of representative carotid arteries are shown. (B and D) Remaining area of denudation (arbitrary pixel units of blue stain) was quantified, and summary data are expressed as percentage of vehicle-treated Lxra/b+/+ or Era+/+ controls (mean ± SEM; n = 6–7 per group; *P < 0.05 vs. vehicle treatment).