CB1 receptor inhibition leads to decreased vascular AT1 receptor expression, inhibition of oxidative stress and improved endothelial function

Inhibition of the cannabinoid receptor CB₁ (CB₁-R) exerts numerous positive cardiovascular effects such as modulation of blood pressure, insulin sensitivity and serum lipid concentrations. However, direct vascular effects of CB₁-R inhibition remain unclear. CB₁-R expression was validated in vascular smooth muscle cells (VSMCs) and aortic tissue of mice. Apolipoprotein E-deficient (ApoE−/−) mice were treated with cholesterol-rich diet and the selective CB₁-R antagonist rimonabant or vehicle for 7 weeks. CB₁-R inhibition had no effect on atherosclerotic plaque development, collagen content and macrophage infiltration but led to improved aortic endothelium-dependent vasodilation and decreased aortic reactive oxygen species (ROS) production and NADPH oxidase activity. Treatment of cultured VSMC with rimonabant resulted in reduced angiotensin II-mediated but not basal ROS production and NADPH oxidase activity. CB₁-R inhibition with rimonabant and AM251 led to down-regulation of angiotensin II type 1 receptor (AT1-R) expression, whereas stimulation with the CB₁-R agonist CP 55,940 resulted in AT1-R up-regulation, indicating that AT1-R expression is directly regulated by the CB₁-R. CB₂-R inhibition had no impact on AT1-R expression in VSMC. Consistently, CB₁-R inhibition decreased aortic AT1-R expression in vivo. CB₁-R inhibition leads to decreased vascular AT1-R expression, NADPH oxidase activity and ROS production in vitro and in vivo. This antioxidative effect is associated with improved endothelial function in ApoE−/− mice, indicating beneficial direct vascular effects of CB₁-R inhibition.