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

See allHide authors and affiliations

Science Signaling  15 Mar 2016:
Vol. 9, Issue 419, pp. ra29
DOI: 10.1126/scisignal.aad5578

Reelin in leukocytes for atherosclerosis

The secreted protein Reelin has important functions in the central nervous system and in the vascular system. Receptors for Reelin are found on the endothelial cells that line blood vessels, prompting Ding et al. to investigate if Reelin contributed to atherosclerosis. Mice globally deficient in Reelin or lacking Reelin produced by the liver were protected from diet-induced atherosclerosis. Reelin deficiency prevented leukocytes from adhering to endothelial cells, a critical first step in the inflammatory response that promotes atherosclerosis. Blocking this activity of Reelin on endothelial cells may prevent atherosclerosis or complement existing strategies.


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 atherosclerosis-prone 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 κB (NF-κB) 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.

View Full Text

Stay Connected to Science Signaling