Objective: Reelin and its receptor Apoer2 (apolipoprotein E receptor 2) play a prominent role in endothelial cell dysfunction by promoting leukocyte-endothelial cell adhesion, an important component of the inflammatory process underlying atherosclerosis. We, therefore, hypothesized that pharmacological depletion of circulating reelin represents a novel therapeutic strategy to impede the progression of atherosclerosis. Approach and Results: In vitro studies demonstrated that human plasma induced monocyte adhesion to endothelial cells, while reelin-depleted plasma had no effect on monocyte adhesion. Signaling analysis revealed that reelin activated a Dab2, PI3K (phosphoinositide 3-kinase), Akt (protein B kinase), and NF-κB (nuclear factor κB) cascade to promote the expression of adhesion markers (E-selectin, ICAM-1 [intercellular adhesion molecule 1], and VCAM-1 [vascular cell adhesion molecule 1]). Intravital microscopy confirmed decreased leukocyte-endothelial adhesion in mice treated with reelin antisense oligonucleotide. In vascular smooth muscle cells, reelin induced Stat3 phosphorylation to promote cell proliferation, which is another hallmark of atherosclerotic plaque progression. To investigate if reelin pharmaceutical depletion protects against atherosclerosis, low-density lipoprotein receptor-deficient (Ldlr-/-) mice fed with high-cholesterol diet were treated with either reelin antisense oligonucleotide or neutralizing antibody (CR-50) to systemically deplete circulating reelin. In both treatments, atherosclerotic plaque progression was markedly attenuated. These in vivo results suggest that reelin depletion decreases vascular adhesion and inhibits the recruitment of monocytes and consequently prevents plaque progression. Conclusions: These findings suggest that reelin inhibition may provide a novel therapeutic approach to counteract leukocyte or monocyte adhesion as well as extravasation and inhibit the progression of atherosclerosis. This strategy may also be relevant for other diseases that involve leukocyte or monocyte extravasation as a central pathological mechanism, such as multiple sclerosis or arthritis.
|Original language||English (US)|
|Number of pages||10|
|Journal||Arteriosclerosis, thrombosis, and vascular biology|
|State||Accepted/In press - 2021|
- endothelial cells
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine