title: Vascular endothelial growth factor inhibits mitogen-induced vascular smooth muscle cell proliferation.
abstract: BACKGROUND
  Delivery of vascular endothelial growth factor (VEGF) protein or gene transfer has been shown to accelerate re-endothelialization and attenuate neointimal hyperplasia in various arterial injury models, including balloon injury, stent implantation, and vein grafts. In addition to stimulating re-endothelialization, we hypothesize that VEGF has further vascular protective functions to prevent neointimal hyperplasia by directly inhibiting mitogen-induced proliferation of vascular smooth muscle cells (VSMCs) via the mitogen-activated protein kinase pathway.
  
  
  METHODS
  Human aortic VSMCs were seeded and serum starved for 24 h. The cells were then stimulated with a mitogen, recombinant human platelet derived growth factor at 20 ng/mL together with 0, 10, 20, 30, 40, 50 ng/mL recombinant human VEGF. A proliferation assay was used to quantitate bromodeoxyuridine uptake into newly synthesized DNA. Western immunoassay was used to quantify extracellular signal-regulated kinase (ERK) 2 protein and phosphorylation of retinoblastoma and ERK 1/2 protein.
  
  
  RESULTS
  VEGF inhibited bromodeoxyuridine incorporation into mitogen-induced VSMC in a dose-dependent manner, reaching statistical significance at concentrations of 30 (P < 0.05), 40 (P < 0.05), and 50 ng/mL (P < 0.01). Densitometry of western immunoblots revealed an inhibition of phosphorylation of retinoblastoma at VEGF concentrations of 40 and 50 ng/mL and ERK 1/2 phosphorylation at concentrations of 30, 40 and 50 ng/mL.
  
  
  CONCLUSIONS
  In addition to stimulating re-endothelialization, VEGF appears to have a vascular protective function by directly inhibiting VSMC proliferation. This effect occurs in the absence of endothelial cells and via the mitogen-activated protein kinase pathway. VEGF may serve as an important modulator of mitogen-induced VSMC proliferation after vascular injury.
authors.affiliation: Division of Vascular Surgery and UCLA Gonda (Goldschmird) Diabetes Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Amir H
authors.initials: AH
authors.lastname: Dorafshar
authors.forename: Niren
authors.initials: N
authors.lastname: Angle
authors.forename: Michael
authors.initials: M
authors.lastname: Bryer-Ash
authors.forename: Danshan
authors.initials: D
authors.lastname: Huang
authors.forename: Michael M
authors.initials: MM
authors.lastname: Farooq
authors.forename: Hugh A
authors.initials: HA
authors.lastname: Gelabert
authors.forename: Julie A
authors.initials: JA
authors.lastname: Freischlag
mesh_terms: D001011:Aorta / Q000166:cytology / Q000187:drug effects; D001973:Bromodeoxyuridine; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D007700:Kinetics; D008222:Lymphokines / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D011994:Recombinant Proteins; D016160:Retinoblastoma Protein; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D001973:Bromodeoxyuridine