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

Cheng,Jiao; Yang,Hui‑Li; Gu,Chun‑Jie; Liu,Yu‑Kai; Shao,Jun; Zhu,Rui; He,Yin‑Yan; Zhu,Xiao‑Yong; Li,Ming‑Qing

doi:10.3892/ijmm.2018.4021

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

Authors:
- Jiao Cheng
- Hui‑Li Yang
- Chun‑Jie Gu
- Yu‑Kai Liu
- Jun Shao
- Rui Zhu
- Yin‑Yan He
- Xiao‑Yong Zhu
- Ming‑Qing Li
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Affiliations: Laboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, P.R. China, Center for Human Reproduction and Genetics, Suzhou Municipal Hospital, Suzhou, Jiangsu 215008, P.R. China, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China, Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, P.R. China
Published online on: December 10, 2018 https://doi.org/10.3892/ijmm.2018.4021
Pages: 945-955
Copyright: © Cheng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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