Norepinephrine induces VEGF expression and angiogenesis by a hypoxia-inducible factor-1α protein-dependent mechanism

Int J Cancer. 2011 May 15;128(10):2306-16. doi: 10.1002/ijc.25589. Epub 2010 Oct 13.


A growing number of studies have demonstrated that physiological factors can influence the progression of several cancers via cellular immune function, angiogenesis and metastasis. Recently, stress-induced catecholamines have been shown to increase the expression of various cancer progressive factors, including vascular endothelial growth factor (VEGF), matrix metalloproteinases and interleukins. However, a detailed mechanism remains to be identified. In this study, we investigated the role of adrenergic receptors and hypoxia-inducible factor (HIF)-1α protein in catecholamine-induced VEGF expression and angiogenesis. Treatment of the cells with norepinephrine (NE) or isoproterenol induced VEGF expression and HIF-1α protein amount in a dose-dependent manner. Induction of VEGF expression by NE was abrogated when the cells were transfected with HIF-1α-specific siRNA. Similarly, adenylate cyclase activator forskolin and cyclic AMP-dependent protein kinase A inhibitor H-89 enhanced and decreased HIF-1α protein amount, respectively. More importantly, conditioned medium of NE-stimulated cancer cells induced angiogenesis in a HIF-1α protein-dependent manner. In addition, pretreatment of cells with propranolol, a β-adrenergic receptor (AR) blocker, completely abolished induction of VEGF expression and HIF-1α protein amount by NE in all of the tested cancer cells. However, treatment with the α1-AR blocker prazosin inhibited NE-induced HIF-1α protein amount and angiogenesis in SK-Hep1 and PC-3 but not MDA-MB-231 cells. Collectively, our results suggest that ARs and HIF-1α protein have critical roles in NE-induced VEGF expression in cancer cells, leading to stimulation of angiogenesis. These findings will help to understand the mechanism of cancer progression by stress-induced catecholamines and design therapeutic strategies for cancer angiogenesis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Base Sequence
  • Cell Line, Tumor
  • DNA Primers
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Neovascularization, Pathologic / chemically induced*
  • Norepinephrine / pharmacology*
  • Polymerase Chain Reaction
  • RNA, Small Interfering
  • Vascular Endothelial Growth Factor A / genetics*


  • DNA Primers
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Small Interfering
  • Vascular Endothelial Growth Factor A
  • Norepinephrine