title: Targeting VEGFR1 on endothelial progenitors modulates their differentiation potential.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Sorbonne Paris Cité, Université Paris Descartes, Paris, France.
authors.forename: Clément
authors.initials: C
authors.lastname: d'Audigier
authors.forename: Benoit
authors.initials: B
authors.lastname: Gautier
authors.forename: Alexis
authors.initials: A
authors.lastname: Yon
authors.forename: Jean-Meidi
authors.initials: JM
authors.lastname: Alili
authors.forename: Coralie L
authors.initials: CL
authors.lastname: Guérin
authors.forename: Solène M
authors.initials: SM
authors.lastname: Evrard
authors.forename: Anne
authors.initials: A
authors.lastname: Godier
authors.forename: Skerdi
authors.initials: S
authors.lastname: Haviari
authors.forename: Marie
authors.initials: M
authors.lastname: Reille-Serroussi
authors.forename: Florent
authors.initials: F
authors.lastname: Huguenot
authors.forename: Blandine
authors.initials: B
authors.lastname: Dizier
authors.forename: Nicolas
authors.initials: N
authors.lastname: Inguimbert
authors.forename: Delphine
authors.initials: D
authors.lastname: Borgel
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.forename: Catherine
authors.initials: C
authors.lastname: Boisson-Vidal
authors.forename: Carmen
authors.initials: C
authors.lastname: Roncal
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Michel
authors.initials: M
authors.lastname: Vidal
authors.forename: Pascale
authors.initials: P
authors.lastname: Gaussem
authors.forename: David M
authors.initials: DM
authors.lastname: Smadja
mesh_terms: D000818:Animals; D006348:Cardiac Surgical Procedures; D002454:Cell Differentiation / Q000187:drug effects; D054443:Cell Migration Assays; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D003114:Colony-Forming Units Assay; D003324:Coronary Artery Disease / Q000097:blood / Q000473:pathology; D004338:Drug Combinations; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006614:Hindlimb / Q000098:blood supply / Q000473:pathology; D006801:Humans; D007511:Ischemia / Q000473:pathology; D007797:Laminin / Q000378:metabolism; D008565:Membrane Proteins / Q000097:blood; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011509:Proteoglycans / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
chemical_list: D004338:Drug Combinations; D007797:Laminin; D008565:Membrane Proteins; C098069:PIGF protein, human; D011509:Proteoglycans; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; D040281:Vascular Endothelial Growth Factor Receptor-1