Targeting VEGFR1 on endothelial progenitors modulates their differentiation potential

Angiogenesis. 2014 Jul;17(3):603-16. doi: 10.1007/s10456-013-9413-2. Epub 2014 Jan 14.


Objectives: We studied whether plasma levels of angiogenic factors VEGF and placental growth factor (PlGF) in coronary artery disease patients or undergoing cardiac surgery are modified, and whether those factors modulate endothelial progenitor's angiogenic potential.

Methods and results: A total of 143 patients' plasmas from two different studies were analyzed (30 coronary artery disease patients, 30 patients with stable angina, coupled with 30 age and sex-matched controls; 53 patients underwent cardiac surgery). Among factors screened, only PlGF was found significantly increased in these pathological populations. PlGF-1 and PlGF-2 were then tested on human endothelial-colony-forming cells (ECFCs). We found that PlGF-1 and PlGF-2 induce VEGFR1 phosphorylation and potentiate ECFCs tubulogenesis in vitro. ECFCs VEGFR1 was further inhibited using a specific small interfering RNA (siRNA) and the chemical compound 4321. We then observed that the VEGFR1-siRNA and the compound 4321 decrease ECFCs tubulogenesis potential in vitro. Finally, we tested the compound 4321 in the preclinical Matrigel(®)-plug model with C57Bl/6J mice as well as in the murine hindlimb ischemia model. We found that 4321 inhibited the plug vascularization, attested by the hemoglobin content and the VE-Cadherin expression level and that 4321 inhibited the post-ischemic revascularization.

Conclusion: PlGF plasma levels were found increased in cardiovascular patients. Disrupting PlGF/VEGFR1 pathway could modulate ECFC-induced tubulogenesis, the cell type responsible for newly formed vessels in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiac Surgical Procedures
  • Cell Differentiation* / drug effects
  • Cell Migration Assays
  • Cell Proliferation / drug effects
  • Collagen / metabolism
  • Colony-Forming Units Assay
  • Coronary Artery Disease / blood
  • Coronary Artery Disease / pathology
  • Drug Combinations
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Hindlimb / blood supply
  • Hindlimb / pathology
  • Humans
  • Ischemia / pathology
  • Laminin / metabolism
  • Membrane Proteins / blood
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic / drug effects
  • Phosphorylation / drug effects
  • Proteoglycans / metabolism
  • RNA, Small Interfering / metabolism
  • Recombinant Proteins / pharmacology
  • Stem Cells / drug effects
  • Stem Cells / metabolism*
  • Vascular Endothelial Growth Factor A / blood
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism*


  • Drug Combinations
  • Laminin
  • Membrane Proteins
  • PIGF protein, human
  • Proteoglycans
  • RNA, Small Interfering
  • Recombinant Proteins
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • matrigel
  • Collagen
  • Vascular Endothelial Growth Factor Receptor-1