Supraphysiological Role of Melatonin Over Vascular Dysfunction of Pregnancy, a New Therapeutic Agent?

Abstract

Hypertension can be induced by the disruption of factors in blood pressure regulation. This includes several systems such as Neurohumoral, Renin-angiotensin-aldosterone, the Circadian clock, and melatonin production, which can induce elevation and non-dipping blood pressure. Melatonin has a supraphysiological role as a chronobiotic agent and modulates vascular system processes via pro/antiangiogenic factors, inflammation, the immune system, and oxidative stress regulation. An elevation of melatonin production is observed during pregnancy, modulating the placenta and fetus’s physiological functions. Their impairment production can induce temporal desynchronization of cell proliferation, differentiation, or invasion from trophoblast cells results in vascular insufficiencies, elevating the risk of poor fetal/placental development. Several genes are associated with vascular disease and hypertension during pregnancy via impaired inflammatory response, hypoxia, and oxidative stress, such as cytokines/chemokines IL-1β, IL-6, IL-8, and impairment expression in endothelial cells/VSMCs of HIF1α and eNOS genes. Pathological placentas showed differentially expressed genes (DEG), including vascular genes as CITED2, VEGF, PL-II, PIGF, sFLT-1, and sENG, oncogene JUNB, scaffolding protein CUL7, GPER1, and the pathways of SIRT/AMPK and MAPK/ERK. Additionally, we observed modification of subunits of NADPH oxidase and extracellular matrix elements, i.e., Glypican and Heparanase and KCa channel. Mothers with a low level of melatonin showed low production of proangiogenic factor VEGF, increasing the risk of preeclampsia, premature birth, and abortion. In contrast, melatonin supplementation can reduce systolic pressure, prevent oxidative stress, induce the activation of the antioxidants system, and lessen proteinuria and serum level of sFlt-1. Moreover, melatonin can repair the endothelial damage from preeclampsia at the placenta level, increasing PIGF, Nrf-2, HO-1 production and reducing critical markers of vascular injury during the pregnancy. Melatonin also restores the umbilical and uterine blood flow after oxidative stress and inhibits vascular inflammation and VCAM-1, Activin-A, and sEng production. The beneficial effects of melatonin over pathological pregnancies can be partially observed in normal pregnancies, suggesting the dual role of/over placental physiology could contribute to protection and have therapeutic applications in vascular pathologies of pregnancies in the future.

Melatonin reduces IL‐33 and TSLP expression in human nasal epithelial cells by scavenging ROS directly

“… 12 Some studies postulate that melatonin has significant potential in treating various diseases because of its powerful antioxidant and anti‐inflammatory effects. 13 , 14 , 15 , 16 , 17 However, there are no studies on the use of melatonin in the treatment of CRS.…”

“…Current studies suggest that melatonin reduces inflammatory responses or their adverse effects by mainly reducing oxygen free radicals, promoting antioxidant processes, and producing excess nitric oxide 12 . Some studies postulate that melatonin has significant potential in treating various diseases because of its powerful antioxidant and anti‐inflammatory effects 13–17 . However, there are no studies on the use of melatonin in the treatment of CRS.…”

Heat Stress-Induced Fetal Intrauterine Growth Restriction Is Associated with Elevated LPS Levels Along the Maternal Intestine–Placenta–Fetus Axis in Pregnant Mice

“…The failure of vascular system formation has been widely shown to have a relationship with placental impairment . VEGF is an angiogenic factor that can effectively induce the growth of new blood vessels and is necessary for angiogenesis and endothelial cell proliferation. − However, excessive VEGF signaling interferes with normal placental angiogenesis resulting in vascular leakage. − Another critical limited factor in nutrient supply efficiency is the abundance and activity of those transporters located on placental trophoblast epithelial cells during pregnancy. The absence or insufficiency of the transport system directly restricts fetal access to nutrients necessary for intrauterine development .…”

Cited2 is a key regulator of placental development and plasticity

“…Required for the regulation of hepatic gluconeogenesis [50,156] Downregulation mediates high glucose-induced endoplasmic reticulum stress-dependent apoptosis [51] Upregulated in vascular tissue of patients with obesity and type 2 diabetes [157] Impairs insulin signaling in endothelial cells [158] Decreased in heart tissue of maternal diabetic-exposed embryos [58] Increased expression in adipose-derived stem cells from diabetic patients, which exhibit decreased proliferation and wound healing abilities [159] Inflammation Potent repressor of macrophage proinflammatory activation [23] Myeloid deficiency significantly increases macrophage and neutrophil recruitment [32] Restrains signal transducer and activator of transcription 1 (STAT1) and interferon regulatory factor 1 (IRF1) signaling in macrophages and limits development of atherosclerotic plaques [73] Deficiency results in enhanced placenta interferon-responsive gene expression [44] Pregnancy related disorders Lower levels in cumulus cells are associated with higher rates of oocyte fertilization and embryo implantation [161] Dysregulated in the placenta from mothers with hypertension [160] Upregulated in placentas from women with severe preeclampsia [61] Upregulated in placentas from growth restricted fetuses [87] Decreased expression in endoplasmic-reticulum stress-induced BeWo choriocarcinoma cells (note: CITED2 may be restricted to the transformed character of the cells and not their trophoblast origin) [62] Cardiovascular disease Essential for heart development [20,21,26,27,44,162] Mutations contribute to congenital heart disease [24,[28][29][30][52][53][54][55][56][57] Lung development Dysregulation results in aberrations in lung development…”