Melatonin restricts the viability and angiogenesis of vascular endothelial cells by suppressing HIF-1α/ROS/VEGF

Abstract

Angiogenesis is an essential process involved in various physiological, including placentation, and pathological, including cancer and endometriosis, processes. Melatonin (MLT), a well-known natural hormone secreted primarily in the pineal gland, is involved in regulating neoangiogenesis and inhibiting the development of a variety of cancer types, including lung and breast cancer. However, the specific mechanism of its anti-angiogenesis activity has not been systematically elucidated. In the present study, the effect of MLT on viability and angiogenesis of human umbilical vein endothelial cells (HUVECs), and the production of vascular endothelial growth factor (VEGF) and reactive oxygen species (ROS), under normoxia or hypoxia was analyzed using Cell Counting kit 8, tube formation, flow cytometry, ELISA and western blot assays. It was determined that the secretion of VEGF by HUVECs was significantly increased under hypoxia, while MLT selectively obstructed VEGF release as well as the production of ROS under hypoxia. Furthermore, MLT inhibited the viability of HUVECs in a dose-dependent manner and reversed the increase in cell viability and tube formation that was induced by hypoxia/VEGF/H2O2. Additionally, treatment with an inhibitor of hypoxia inducible factor (HIF)-1α (KC7F2) and MLT synergistically reduced the release of ROS and VEGF, and inhibited cell viability and tube formation of HUVECs. These observations demonstrate that MLT may serve dual roles in the inhibition of angiogenesis, as an antioxidant and a free radical scavenging agent. MLT suppresses the viability and angiogenesis of HUVECs through the downregulation of HIF-1α/ROS/VEGF. In summary, the present data indicate that MLT may be a potential anticancer agent in solid tumors with abundant blood vessels, particularly combined with KC7F2.

Human Obesity Induces Dysfunction and Early Senescence in Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells

“…Interestingly, MSC from both obese and non-obese subjects decreased expression of p16, whereas p21 remained unchanged. In addition, VEGF, an important mediator of the pro-angiogenic function of endothelial cells (Cheng et al, 2019), and its expression falls in injured HUVEC (Wang et al, 2019;Wu et al, 2019), as we observed in our injured HUVEC model. Importantly, HUVEC VEGF gene expression was restored to control levels by co-incubation with MSC from non-obese subjects, whereas MSC from obese subjects failed to reinstate it.…”

Molecular Analysis of Fetal and Adult Primary Human Liver Sinusoidal Endothelial Cells: A Comparison to Other Endothelial Cells

“…Moreover, several pathways related to the degradation of serotonin, dopamine and melatonin, are hypoactive due to a decrease in the expression of two main enzymes, namely aryl sulfotransferase and mono-amine oxidase. This leads to relatively higher levels of these products, specifically in LSECs and to a decrease in angiogenesis [ 39 , 40 ] and a decrease in pro-inflammatory cytokines [ 41 ].…”

Clinical Trials for Use of Melatonin to Fight against COVID-19 Are Urgently Needed

“…In consideration of the common beneficial action of melatonin and attenuated metabolic processes caused by viral infections, there are reasonable imperatives to propose that this indoleamine may limit symptoms associated with viral infections, including COVID-19. Currently, it is known that severe inflammation induces multiple perturbations, such as enhanced endothelial cell apoptosis or elevation of the production of vascular endothelial growth factor (VEGF), which contributes to edema and the massive release of immune cells, while melatonin is an effective suppressor of VEGF in vascular endothelial cells [60]. Moreover, melatonin was found to be an ameliorating agent against sepsis-induced cardiomyopathy [61,62]; this effect may be also beneficial for some COVID-19 patients in whom an increased risk of sepsis and cardiac arrest accompany severe ALI/ARDS development.…”