Circadian System and Melatonin Hormone: Risk Factors for Complications during Pregnancy

Abstract

Pregnancy is a complex and well-regulated temporal event in which several steps are finely orchestrated including implantation, decidualization, placentation, and partum and any temporary alteration has serious effects on fetal and maternal health. Interestingly, alterations of circadian rhythms (i.e., shiftwork) have been correlated with increased risk of preterm delivery, intrauterine growth restriction, and preeclampsia. In the last few years evidence is accumulating that the placenta may have a functional circadian system and express the clock genes Bmal1, Per1-2, and Clock. On the other hand, there is evidence that the human placenta synthesizes melatonin, hormone involved in the regulation of the circadian system in other tissues. Moreover, is unknown the role of this local production of melatonin and whether this production have a circadian pattern. Available information indicates that melatonin induces in placenta the expression of antioxidant enzymes catalase and superoxide dismutase, prevents the injury produced by oxidative stress, and inhibits the expression of vascular endothelial growth factor (VEGF) a gene that in other tissues is controlled by clock genes. In this review we aim to analyze available information regarding clock genes and clock genes controlled genes such as VEGF and the possible role of melatonin synthesis in the placenta.

Figure 1

Molecular Circuit of Circadian Oscillator. See details in the text. Positive regulation of clock genes Bmal1 and Clock stimulate promoter of negative regulators Per 1-2, Cry 1-2 and controlled clock genes Hexokinase and VEGF.

Figure 2

Signaling of MT1 and MT2. Both are G protein-coupled receptors. MT1 is associated with Gi protein and inhibition of adenylyl cyclase. MT2 receptor is associated with PKC stimulation and increase of calcium associated with IP3 (for details see Dubocovich et al. [11]).

Figure 3

Autocrine and paracrine effects of melatonin over circadian system and enzyme of synthesis of melatonin localized in trophoblast and endothelial cells.