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ENDOTHELIAL CANNABINOID RECEPTOR CB1 DEFICIENCY DECREASES OXLDL UPTAKE AND ATTENUATES VASCULAR INFLAMMATION IN ATHEROSCLEROSIS
Abstract
Background and Aims
The endocannabinoid system has emerged as an important lipid signaling system in atherosclerosis. Since endothelial dysfunction plays a critical role in atherosclerosis, we aimed to study the endothelial cell-specific role of CB1 in atherosclerotic plaque development.
Methods
We generated endothelial cell-specific CB1 knockout mice on ApoE-/- background and treated the mice with Western Diet (WD).
Results
Endothelial CB1 deficiency (EC-CB1-KO) attenuated plaque development in the aortic roots and abdominal aortas of female mice, accompanied by more stable plaque phenotype with increased collagen at advanced stage (16 weeks WD). However, the effect was not observed in male mice, suggesting that endothelial CB1 affects atherosclerosis in a sex-specific manner. Female EC-CB1-KO mice also had significantly lower aortic adhesion molecule ICAM-1 and VCAM-1 expression. Moreover, ex vivo imaging of perfused carotid arteries revealed less DIL-oxLDL uptake by CB1-deficient endothelium. Immunofluorescence staining revealed a significant reduction of aortic endothelial caveolin-1 (CAV-1) expression in female EC-CB1-KO mice, which might provide an explanation for reduced endothelial lipid uptake in EC-CB1-KO mice. Treatment of atherosclerotic mice with the peripheral CB1 antagonist JD-5037 reduced plaque progression, endothelial adhesion molecule and CAV-1 expression again only observed in females, but not males. Our in vivo findings are supported by ongoing mechanistic in vitro experiments using siRNA-CB1 silencing, CB1 agonists and antagonists in primary aortic endothelial cells.
Conclusions
In conclusion, our results indicate that endothelial CB1 promotes atherosclerosis by modulating endothelial oxLDL uptake and vascular inflammation, linked to a sex-specific regulation of CAV-1 expression.