Endocannabinoids modulate Gq/11 protein-coupled receptor agonist-induced vasoconstriction via a negative feedback mechanism

Abstract

Abstract Objectives The endocannabinoid (eCB) system centrally and peripherally regulates cardiovascular parameters, including blood pressure, in health and disease. The relationship between Gq/11 protein-coupled receptor activation, regulation of eCBs release (mainly 2-arachidonoylglycerol) and subsequent CB1 receptor activation was initially observed in the central nervous system. Here, we review the latest findings from systemic physiological studies which include for the first time data from pulmonary arteries. We present evidence for direct CB1-dependent cannabinoid ligand-induced vasorelaxation, vascular expression of eCBs along with their degradation enzymes, and indicate the location of the described interaction. Key findings Endocannabinoids (mainly 2-arachidonoylglycerol), acting via CB1 receptors, evoke vasodilatory effects and may modulate responses of vasoconstrictors for Gq/11 protein-coupled receptors including angiotensin II, thromboxane A2, phenylephrine, noradrenaline in systemic or pulmonary arteries. However, the role of the endothelium in this interaction is not well-established, and the precise vascular location of eCB system components remains unclear, which contributes to discrepancies in the interpretation of results when describing the above-mentioned relationship. Summary Endocannabinoid's negative feedback is responsible for diminishing agonist-induced vasoconstriction, which may be clinically important in the treatment of arterial and pulmonary hypertension. Further research is required to establish the importance of the eCB system and its downstream signalling pathways.