title: Effects of vascular endothelial growth factor on endothelin-1 production by human lung microvascular endothelial cells in vitro.
abstract: OBJECTIVE
  Increased endothelin-1 (ET-1) is a hallmark of pulmonary arterial hypertension (PAH), and contributes to its pathogenesis. The factors controlling ET-1 in PAH are poorly understood. Combined with other stimuli, vascular endothelial growth factor (VEGF) blockade results in PAH-like lesions in animal models, and has been associated with PAH in humans. The effects of VEGF on ET-1 production by human lung blood microvascular endothelial cells (HMVEC-LBl) are unknown.
  
  
  METHODS
  We exposed HMVEC-LBl in-vitro to human VEGF-121 (40 ng/mL) in serum-free medium for 7h, in the absence or presence of the VEGF receptor antagonist, SU5416 (3 and 10 μM). ET-1 production was measured in the supernatant. Phosphorylation of VEGF receptor 2 (VEGFR2) was measured by Western blotting after exposure to VEGF without or with SU5416 for 5 and 10 min.
  
  
  RESULTS
  VEGF effectively caused VEGFR2 phosphorylation, which was blocked by SU5416. VEGF decreased ET-1 production by at least 29%. In the absence of VEGF, SU5416 increased ET-1 production, by 16% at 10 μM, and SU5416 was able to completely abolish the VEGF effect on ET-1 production.
  
  
  CONCLUSIONS
  VEGF may promote vascular health by decreasing ET-1 production in HVMEC-LBl. Blockade of VEGF signaling by SU5416 increases ET-1 levels. The role of VEGF in modulating endothelin production in PAH deserves further study.
authors.affiliation: Lady Davis Research Institute and Center for Pulmonary Vascular Disease, Division of Cardiology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Star
authors.affiliation: Lady Davis Research Institute and Center for Pulmonary Vascular Disease, Division of Cardiology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Michele
authors.initials: M
authors.lastname: Giovinazzo
authors.affiliation: Department of Pathology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Esther
authors.initials: E
authors.lastname: Lamoureux
authors.affiliation: Lady Davis Research Institute and Center for Pulmonary Vascular Disease, Division of Cardiology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada. Electronic address: david.langleben@mcgill.ca.
authors.forename: David
authors.initials: D
authors.lastname: Langleben
mesh_terms: D015153:Blotting, Western; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D019332:Endothelin-1 / Q000096:biosynthesis*; D055427:Growth Differentiation Factor 2 / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008168:Lung / Q000098:blood supply*; D055806:Microvessels / Q000166:cytology*; D010766:Phosphorylation / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: D019332:Endothelin-1; D055427:Growth Differentiation Factor 2; D007211:Indoles; D011758:Pyrroles; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C116890:Semaxinib; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: Endothelial cell; Endothelin-1; Pulmonary hypertension; SU5416; Vascular endothelial growth factor