CB ₂ cannabinoid receptor agonists attenuate TNF-α-induced human vascular smooth muscle cell proliferation and migration

Background and purpose: Vascular smooth muscle proliferation and migration triggered by inflammatory stimuli are involved in the development and progression of atherosclerosis and restenosis. Cannabinoids may modulate cell proliferation in various cell types through cannabinoid 2 (CB ₂) receptors. Here, we investigated the effects of CB ₂ receptor agonists on TNF-α-induced proliferation, migration and signal transduction in human coronary artery smooth muscle cells (HCASMCs). Experimental approach: HCASMCs were stimulated with TNF-α. Smooth muscle proliferation was determined by the extent of BrdU incorporation and the migration was assayed by modified Boyden chamber. CB ₂ and/or CB ₁ receptor expressions were determined by immunofluorescence staining, western blotting, RT-PCR, real-time PCR and flow cytometry. Key results: Low levels of CB ₂ and CB ₁ receptors were detectable in HCASMCs compared to the high levels of CB ₂ receptors expressed in THP-1 monocytes. TNF-α triggered up to ∼80% increase (depending on the method used) in CB ₂ receptor mRNA and/or protein expression in HCASMCs, and induced Ras, p38 MAPK, ERK 1/2, SAPK/JNK and Akt activation, while increasing proliferation and migration. The CB ₂ agonists, JWH-133 and HU-308, dose-dependently attenuated these effects of TNF-α. Conclusions and implications: Since the above-mentioned TNF-α-induced phenotypic changes are critical in the initiation and progression of atherosclerosis and restenosis, our findings suggest that CB ₂ agonists may offer a novel approach in the treatment of these pathologies by decreasing vascular smooth muscle proliferation and migration.