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

Abstract

Inhibition of the cannabinoid receptor CB(1) (CB(1)-R) exerts numerous positive cardiovascular effects such as modulation of blood pressure, insulin sensitivity and serum lipid concentrations. However, direct vascular effects of CB(1)-R inhibition remain unclear. CB(1)-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 CB(1)-R antagonist rimonabant or vehicle for 7 weeks. CB(1)-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. CB(1)-R inhibition with rimonabant and AM251 led to down-regulation of angiotensin II type 1 receptor (AT1-R) expression, whereas stimulation with the CB(1)-R agonist CP 55,940 resulted in AT1-R up-regulation, indicating that AT1-R expression is directly regulated by the CB(1)-R. CB(2)-R inhibition had no impact on AT1-R expression in VSMC. Consistently, CB(1)-R inhibition decreased aortic AT1-R expression in vivo. CB(1)-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 CB(1)-R inhibition.

Angiotensin II-induced activation of central AT1 receptors exerts endocannabinoid-mediated gastroprotective effect in rats

“…The transactivation of cannabinoid CB1 receptors by Ang II is supported by the finding that showed an inhibitory effect of AM 251, inverse agonist of CB 1 receptors, on the hypertensive effect of Ang II injected directly into the hypothalamic paraventricular nucleus of anaesthetized rats (Gyombolai et al, 2012). Vice versa, AT 1 receptor expression may be directly regulated by CB 1 receptors, namely in cultured vascular smooth muscle cells inhibition of CB 1 receptor by rimonabant and AM 251 led to down-regulation of AT 1 receptor expression (Tiyerili et al, 2010).…”

Cannabinoid receptor 2 agonist ameliorates mesenteric angiogenesis and portosystemic collaterals in cirrhotic rats

“…receptor protein expression was significantly higher in BDL than in sham rats, providing direct evidence of CB 2 receptor up-regulation in portosystemic collateral vessels. CB receptors have been identified in various vessels, including rat aorta, 36 rat mesenteric vascular bed, 37 and human pulmonary artery. 38 However, the presence of CB receptors in the collateral vasculature and the up-regulated CB 2 receptor expression in cirrhosis have not been proven.…”

Cannabinoids and Atherosclerotic Coronary Heart Disease

“…An increase in AT1R expression secondary to CB1 agonism in turn leads to increased generation of ROS by VSMC. 39 The antioxidative effect of CB1 inhibition on VSMC was also shown to contribute to better endothelial function.…”