Loss of Reelin protects against atherosclerosis by reducing leukocyte-endothelial cell adhesion and lesion macrophage accumulation

Yinyuan Ding, Linzhang Huang, Xunde Xian, Ivan S. Yuhanna, Catherine R. Wasser, Michael Frotscher, Chieko Mineo, Philip W. Shaul, Joachim Herz

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

The multimodular glycoprotein Reelin controls neuronal migration and synaptic transmission by binding to apolipoprotein E receptor 2 (Apoer2) and very low density lipoprotein receptor (Vldlr) on neurons. In the periphery, Reelin is produced by the liver, circulates in blood, and promotes thrombosis and hemostasis. To investigate if Reelin influences atherogenesis, we studied atherosclerosisprone low-density lipoprotein receptor-deficient (Ldlr-/-) mice in which we inducibly deleted Reelin either ubiquitously or only in the liver, thus preventing the production of circulating Reelin. In both types of Reelin-deficient mice, atherosclerosis progression was markedly attenuated, and macrophage content and endothelial cell staining for vascular cell adhesion molecule'1 (VCAM-1) and intercellular adhesion molecule'1 (ICAM-1) were reduced at the sites of atherosclerotic lesions. Intravital microscopy revealed decreased leukocyte-endothelial adhesion in the Reelin-deficient mice. In cultured human endothelial cells, Reelin enhanced monocyte adhesion and increased ICAM1, VCAM1, and E-selectin expression by suppressing endothelial nitric oxide synthase (eNOS) activity and increasing nuclear factor kB (NF-kB) activity in an Apoer2-dependent manner. These findings suggest that circulating Reelin promotes atherosclerosis by increasing vascular inflammation, and that reducing or inhibiting circulating Reelin may present a novel approach for the prevention of cardiovascular disease.

Original languageEnglish (US)
Article numberRA29
JournalScience Signaling
Volume9
Issue number419
DOIs
StatePublished - Mar 15 2016

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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