CB2 cannabinoid receptor stimulation attenuates TNF‐alpha‐induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte‐endothelial adhesion.

Targeting cannabinoid‐2 (CB2) receptors with selective agonists may represent a novel therapeutic avenue in various inflammatory diseases, but the mechanisms by which CB2 activation exerts its anti‐inflammatory effects and the cellular targets are elusive. Here, we investigated the effects of CB2‐receptor activation on TNF‐alpha‐induced signal transduction in human coronary artery endothelial cells in vitro and on endotoxin‐induced vascular inflammatory response in vivo. TNF‐alpha induced NF‐kappaB and RhoA activation and upregulation of adhesion molecules ICAM‐1 and VCAM‐1, increased expression of monocyte chemoattractant protein, enhanced transendothelial migration of monocytes, and augmented monocyte‐endothelial adhesion. Remarkably, all of the above‐mentioned effects of TNF‐alpha were attenuated by CB2 agonists. CB2 agonists also decreased the TNF‐alpha‐ and/or endotoxin‐induced ICAM‐1 and VCAM‐1 expression in isolated aortas and the adhesion of monocytes to aortic vascular endothelium. CB1 and CB2 receptors were detectable in human coronary artery endothelial cells by Western blotting, RT‐PCR, real‐time PCR, and immunofluorescence staining. Because the above‐mentioned TNF‐alpha‐induced phenotypic changes are critical in the initiation and progression of atherosclerosis and restenosis, our findings suggest that targeting CB2 receptors on endothelial cells may offer a novel approach in the treatment of these pathologies.