Ghrelin Stimulates Endothelial Cells Angiogenesis through Extracellular Regulated Protein Kinases (ERK) Signaling Pathway

Int J Mol Sci. 2018 Aug 26;19(9):2530. doi: 10.3390/ijms19092530.


Adipose tissue is hyper-vascularized. Vessels in adipose tissue not only supply nutrients and oxygen to nourish adipocytes, but also provide cytokines that regulate mass and function of adipose tissue. Understanding the fundamental mechanisms how vessels modulate adipocyte functions would provide new therapeutic options for treatment of metabolic disease and obesity. In recent years, researches about ghrelin are focused on glucose and lipid metabolism, but its effect on vascular function remains uncharacterized. In the present study, ghrelin receptor gene deletion mice (Ghsr-/- mice) were used to study ghrelin-regulated vascular metabolism in white adipose tissue. Ghsr-/- mice demonstrated lower food intake, lower body weight, and resistance to high-fat diet-induced obesity. The number of vessels in white adipose tissue was decreased in Ghsr-/- mice when compared with wild type mice fed with high-fat diet. To further define ghrelin effects in vitro, we used endothelial progenitor cells from wild type and Ghsr-/- mice as well as human umbilical vein endothelial cells in our experiments. We found that ghrelin stimulated endothelial cells angiogenesis and migration through the MEK-ERK signaling pathway. [d-Lys3]-GHRP-6 and PD98059 could reverse the effects of ghrelin on endothelial cells. Our study indicates that ghrelin activates its receptor on endothelial cells to promote angiogenesis and migration via a mechanism involving the extracellular regulated protein kinases (ERK) signaling pathway.

Keywords: ERK; angiogenesis; endothelial cells; ghrelin; migration.

MeSH terms

  • Adipose Tissue / metabolism
  • Animals
  • Body Weight
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Disease Models, Animal
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism*
  • Ghrelin / metabolism*
  • Ghrelin / pharmacology
  • Humans
  • MAP Kinase Signaling System*
  • Mice
  • Mice, Knockout
  • Neovascularization, Physiologic* / drug effects
  • Phosphorylation
  • Receptors, Ghrelin / antagonists & inhibitors
  • Receptors, Ghrelin / genetics
  • Receptors, Ghrelin / metabolism


  • Ghrelin
  • Ghsr1a protein, human
  • Receptors, Ghrelin