Icariin stimulates angiogenesis by activating the MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways in human endothelial cells

Biochem Biophys Res Commun. 2008 Nov 14;376(2):404-8. doi: 10.1016/j.bbrc.2008.09.001. Epub 2008 Sep 16.


We investigated the molecular effect and signal pathway of icariin, a major flavonoid of Epimedium koreanum Nakai, on angiogenesis. Icariin stimulated in vitro endothelial cell proliferation, migration, and tubulogenesis, which are typical phenomena of angiogenesis, as well as increased in vivo angiogenesis. Icariin activated the angiogenic signal modulators, ERK, phosphatidylinositol 3-kinase (PI3K), Akt, and endothelial nitric oxide synthase (eNOS), and increased NO production, without affecting VEGF expression, indicating that icariin may directly stimulate angiogenesis. Icariin-induced ERK activation and angiogenic events were significantly inhibited by the MEK inhibitor PD98059, without affecting Akt and eNOS phosphorylation. The PI3K inhibitor Wortmannin suppressed icariin-mediated angiogenesis and Akt and eNOS activation without affecting ERK phosphorylation. Moreover, the NOS inhibitor NMA partially reduced the angiogenic activity of icariin. These results suggest that icariin stimulated angiogenesis by activating the MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways and may be a useful drug for angiogenic therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inducing Agents / pharmacology*
  • Endothelial Cells / drug effects*
  • Endothelial Cells / enzymology
  • Endothelial Cells / physiology
  • Enzyme Inhibitors / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Flavonoids / pharmacology*
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Signaling System / drug effects*
  • Neovascularization, Physiologic / drug effects*
  • Nitric Oxide Synthase Type III / antagonists & inhibitors
  • Nitric Oxide Synthase Type III / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism


  • Angiogenesis Inducing Agents
  • Enzyme Inhibitors
  • Flavonoids
  • Phosphoinositide-3 Kinase Inhibitors
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase Kinases
  • icariin