Melatonin Membrane Receptors in the Vascular System: Function, Modulation and Clinical Relevance.

Melatonin (MEL) is a hormone whose secretion is regulated by daily and seasonal environmental light cycles. MEL production is strictly limited to the night and is inhibited by light. Besides exhibiting chronobiotic properties, MEL possesses vasoactive properties mediated by the plasma membrane melatonin receptors (MT1/MT2) and ion channels expressed in the vascular system. Therefore, it is important to understand the distribution and functions of these receptors in the vascular system. In this review, we analyzed 50 studies to map the expression of MT1/MT2 receptors in the vascular system and elucidate their mechanisms of action, modulation factors, and implications for vascular reactivity. The findings of this review indicate that MT1 and/or MT2 receptors are expressed heterogeneously across different vascular layers, including the cerebral vascular bed, caudal arteries of rats, mesenteric vascular bed, coronary arteries, aorta, and other vessels. In the cerebral vascular bed, the receptor expression is reduced during pathological conditions, advanced age, and the estrous cycle. Furthermore, MEL directly induces vasoconstriction by inhibiting cAMP and BKca channels via MEL membrane receptors. In rat caudal arteries, the receptor expression is regulated by conditions similar to those in the cerebral vascular bed. However, MEL demonstrated potentiating effects on pre-contracted vessels and vasorelaxant effects, probably via MT1 and MT2 receptors, respectively. The data obtained from the mesenteric vascular bed demonstrate that hypertension negatively modulates receptor expression and the vasorelaxant effect of MEL is mediated by the activation of both BKca channels and MEL receptors. In coronary arteries, MEL inhibits vasorelaxation. This effect is mediated by MT2 through the activation of BKca channels and stimulation of phosphodiesterase 5, which differs from the vasorelaxant effects observed in caudal arteries. The aorta is the only vessel in which the expression of these receptors has been investigated in humans, and is restricted to MT2. Furthermore, this is the only vessel in which the circadian profile of MT1 receptor expression has been analyzed in rats; however, no differences were observed between the evaluated phases. The expression of functionally active receptors was also detected in other vessels, such as the pulmonary, umbilical, and placental arteries. In general, we observed that MEL membrane receptors are widely expressed in the vascular system. The evidence obtained through this review suggests that the responses triggered by MEL in the vascular system vary depending on the vascular bed analyzed and hormone concentration. Furthermore, MT1 receptors likely mediate vasoconstrictor effects, whereas MT2 receptors mediate vasorelaxant effects. Additionally, there is a gap in the literature as very few studies have addressed the effects of circadian variations on the expression of these receptors, highlighting an important area for further research.