Endothelial cannabinoid CB1 receptor deficiency reduces shear stress-induced arterial inflammation and lipid uptake

Area of Science:

• Cardiovascular Biology
• Metabolic Disease Research
• Endothelial Cell Signaling

Background:

• Peripheral cannabinoid CB1 receptor antagonists show promise for metabolic diseases.
• The role of endothelial CB1 signaling in atherosclerosis is not well understood.

Purpose of the Study:

• To investigate the role of endothelial CB1 signaling in atherosclerosis and metabolic dysfunction.
• To determine if endothelial CB1 antagonism can be a therapeutic strategy for atherosclerosis.

Main Methods:

• Examined endothelial CB1 expression in human atherosclerotic plaques.
• Utilized endothelial-specific Cnr1 deletion and peripheral CB1 antagonism in mouse models.
• Assessed atherosclerosis, vascular permeability, lipid uptake, and metabolic parameters.

Main Results:

• Endothelial CB1 is present in human plaques and induced by shear stress, promoting inflammation and lipid uptake.
• Endothelial CB1 deletion or antagonism reduced atherosclerosis, decreased low-density lipoprotein uptake, and improved metabolic parameters.
• Effects were more pronounced in female mice, potentially due to estrogen signaling.

Conclusions:

• Endothelial CB1 is a pro-atherogenic factor that regulates vascular lipid transport.
• Targeting endothelial CB1 offers a potential therapeutic approach for atherosclerosis and related metabolic disorders.
• Endothelial CB1's pro-atherogenic role is sex-biased, suggesting differential therapeutic efficacy.