Functional crosstalk between the vanilloid and endocannabinoid systems in modulating vascular tone: implications for (neuro)vascular disorder therapy

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BACKGROUND: The endocannabinoid system (ECS) exerts its effects through cannabinoid (CB) receptors and/or transient receptor potential vanilloid 1 (TRPV1) channels. Additionally, capsaicin, a TRPV1 agonist, can also activate CB receptors to modulate vascular tone and pain pathways. As capsaicin-induced vasodilation appears to be mediated by TRPV1-independent mechanisms, we investigated whether capsaicin exerts vascular modulation through the activation of CB receptors, and the possible role of TRPV1 as a modulator of the ECS. METHODS: Human coronary arteries (HCAs; males, n = 16; 53 ± 4 years; females, n = 14; 56 ± 2 years) were used to evaluate: (i) the responses to capsaicin in the absence or presence of the antagonists capsazepine (TRPV1), AM6545 (CB1 receptor), AM630 (CB2 receptor), O-1918 (putative endothelial CB receptor) or cannabidiol (GPR55 receptor); and (ii) the effect of capsazepine on responses to anandamide (AEA, CB1/CB2 receptor agonist), arachidonyl-2’-chloroethylamide (ACEA, CB1 receptor agonist), and WIN 55,212-2 (CB2 receptor agonist). In a different set of experiments, the effect of AM6545 on responses to AEA or ACEA was investigated in HCAs with or without capsaicin pretreatment. RESULTS: In HCAs from both males and females, capsaicin induced concentration-dependent vasorelaxation. This response was inhibited only by AM6545 and O-1918. Moreover, the vasorelaxation induced by AEA and ACEA, but not by WIN 55,212-2, was inhibited by capsazepine and AM6545. Finally, TRPV1 desensitisation induced a significant decrease in the maximum responses to AEA or ACEA in HCAs from females, but not in HCAs from males. CONCLUSIONS: Capsaicin-induced vasodilation is mediated by CB1 and the putative endothelial CB receptors, without the involvement of CB2 receptors. Moreover, TRPV1 channels may play a role in modulating AEA- and ACEA-induced vasodilation as capsazepine inhibited the induced responses. Additionally, the role of TRPV1 channels in modulating ECS differs between males and females, suggesting an important role for sex hormones. Therefore, the interaction between the ECS and vanilloid system could offer new treatment targets for (neuro)vascular disorders, including migraine, by sharing a signalling pathway to modulate vascular tone.

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