Angiotensin II potentiates vascular endothelial growth factor-induced proliferation and network formation of endothelial progenitor cells

Hypertens Res. 2004 Feb;27(2):101-8. doi: 10.1291/hypres.27.101.


Bone marrow-derived endothelial progenitor cells (EPCs) in the peripheral blood of adult animals and adult humans have been shown to play a role in neovascularization into neovascular structures. On the other hand, angiotensin II (Ang II) plays a role in the development of many vascular diseases. To investigate whether Ang II affects human vascular endothelial growth factor (VEGF)-induced EPCs proliferation and network formation. Reverse transcription-polymelase chain reaction analysis demonstrated that Ang II induced a significant increase of VEGF receptor kinase domain-containing receptor (KDR) mRNA in a dose- and time-dependent manner; the maximal increase, which was 3-fold the control value, occurred after a 4-h stimulation. In addition, flow cytometric analysis revealed that Ang II up-regulated KDR protein expression in human EPCs. Both the angiotensin type 1 (AT1) receptor antagonist (valsartan: 200 nmol/l) and the PKC inhibitor, bisindolylmaleimide (GFX: 10 micromol/l) reduced Ang II-induced KDR mRNA expression to almost the control level. The culture assay showed that Ang II dose-dependently enhanced VEGF-induced EPC proliferation by activating AT1 receptors, which was also confirmed by the colorimetric MTS assay with the electron coupling reagent mathosulfate. Finally, in a Matrigel assay, EPCs treated with both Ang II and VEGF were shown to be more likely to integrate into the network formation than those treated with VEGF alone. In conclusion, our data indicate that Ang II potentiates VEGF-induced human EPCs proliferation and network formation through the up-regulation of KDR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / pharmacology*
  • Biocompatible Materials
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cells, Cultured
  • Collagen
  • Drug Combinations
  • Endothelium, Vascular / cytology*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiology
  • Gene Expression / drug effects
  • Gene Expression / physiology
  • Humans
  • Laminin
  • Leukocytes, Mononuclear / cytology
  • Neovascularization, Physiologic / physiology*
  • Protein Kinase C / metabolism
  • Proteoglycans
  • RNA, Messenger / analysis
  • Receptor, Angiotensin, Type 1 / metabolism
  • Stem Cells / cytology*
  • Stem Cells / drug effects
  • Stem Cells / physiology
  • Vascular Endothelial Growth Factor A / pharmacology
  • Vascular Endothelial Growth Factor Receptor-2 / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • Vasoconstrictor Agents / pharmacology*


  • Biocompatible Materials
  • Drug Combinations
  • Laminin
  • Proteoglycans
  • RNA, Messenger
  • Receptor, Angiotensin, Type 1
  • Vascular Endothelial Growth Factor A
  • Vasoconstrictor Agents
  • Angiotensin II
  • matrigel
  • Collagen
  • Vascular Endothelial Growth Factor Receptor-2
  • Protein Kinase C