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

Int J Mol Med. 2019 Feb;43(2):945-955. doi: 10.3892/ijmm.2018.4021. Epub 2018 Dec 10.


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.

MeSH terms

  • Biomarkers
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cells, Cultured
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hypoxia
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Melatonin / pharmacology*
  • Neovascularization, Physiologic / drug effects*
  • Reactive Oxygen Species / metabolism*
  • Vascular Endothelial Growth Factor A / metabolism*


  • Biomarkers
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Reactive Oxygen Species
  • Vascular Endothelial Growth Factor A
  • Melatonin