Editors' ChoicePhysiology

Protecting the Endothelium

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Science Signaling  13 Aug 2013:
Vol. 6, Issue 288, pp. ec190
DOI: 10.1126/scisignal.2004608

In endothelial cells (ECs), liver X receptors (LXRα and LXRβ) can be activated in response to oxysterols derived from endogenous cholesterol or by synthetic agonists to inhibit atherosclerosis. Estrogen promotes reendothelialization and inhibits inflammation after vascular injury through its receptor ERα. Ishikawa et al. found that LXRβ interacts directly with ERα in ECs to promote cell migration, vasodilation, and reendothelialization. ERα and LXRβ coimmunoprecipitated from cultured human EA.hy926 ECs, an interaction that was increased by the LXR agonist T0901317 (T1317) or estrogen (E2). In vitro assays indicated that this interaction required a 30–amino acid region within the ligand-binding domain of ERα. Scratch assays revealed that the LXR agonists T1317 or GW3965 stimulated EC migration independently of proliferation, to a similar extent to that caused by E2 treatment. Agonist- or E2-induced migration was abrogated by treatment with a nonselective nitric oxide synthase (NOS) inhibitor but not by treatment with inhibitors of inducible NOS (iNOS) or neuronal NOS (nNOS), indicating that endothelial NOS (eNOS) mediates LXR- and ER-induced migration. E2 stimulated cell migration in primary ECs isolated from wild-type or Lxra/b–/– mice; however, whereas T1317 induced migration in Lxra–/– ECs, it did not stimulate migration in Lxrb–/– or Lxra/b–/– ECs. Further, in the presence of E2, T1317 did not have an additive or synergistic effect on migration, and a general (ICI) or an α-specific, but not a β-specific, ER antagonist prevented T1317-induced migration, indicating that activation of LXRβ induces EC migration through ERα. LXR agonists (and, as expected, E2) induced the phosphorylation and activation of the kinase Akt and that of its target eNOS. Akt activation in response to either treatment was inhibited by ICI or overexpression of an inactive mutant (S118A) ERα. In contrast, knockdown of LXRβ prevented Akt activation in response to LXR agonists but not to E2, suggesting that the LXRβ-mediated mechanism is dependent on ERα but that ER signaling is independent of LXRβ. E2 or T1317 had a vasodilatory effect on isolated rat aortic rings, which was inhibited by the nonselective NOS inhibitor. E2 or T1317 induced reendothelialization of denuded carotid arteries in wild-type or Lxra–/– mice but not Lxrb–/–, Lxra/b–/–, Era–/–, or ICI-treated mice. Together the data suggest that activation of LXRβ promotes the integrity of the endothelial monolayer through ERα.

T. Ishikawa, I. S. Yuhanna, J. Umetani, W.-R. Lee, K. S. Korach, P. W. Shaul, M. Umetani, LXRβ/estrogen receptor-α signaling in lipid rafts preserves endothelial integrity. J. Clin. Invest. 123, 3488–3497 (2013). [PubMed]