title: Vascular endothelial growth factor-D is overexpressed in human cardiac allograft vasculopathy and diabetic atherosclerosis and induces endothelial permeability to low-density lipoproteins in vitro.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF)-D is a member of the VEGF family, which can induce angiogenesis and lymphangiogenesis. We have previously demonstrated a role for VEGF-A in cardiac allograft vasculopathy (CAV). Our experiments profile the expression and localization of VEGF-D in human native atherosclerosis (NA), diabetes mellitus with atherosclerosis (DM) and CAV, and we investigate its ability to induce low-density lipoprotein (LDL) permeability in human cardiac microvascular endothelial cells (HCMEC).
  
  
  METHODS
  VEGF-D mRNA and protein expression was characterized in coronary arteries and intramyocardial arterioles in NA, DM and CAV using in situ hybridization and immunohistochemical staining. Transendothelial electrical resistance (TER) measurements and immunocytochemical staining for platelet and endothelial cell adhesion molecule-1 and zonula occludens-1 were used to assess endothelial barrier and tight junctional integrity. LDL permeability in response to treatment with VEGF-D was measured using fluorometry in confluent HCMEC.
  
  
  RESULTS
  Image quantitation demonstrated significant increases in VEGF-D immunoreactivity in the media of coronary arteries and intramyocardial arterioles of CAV cases, and in the intima and media of coronary arteries of DM cases. Treatment with VEGF-D, in vitro, significantly increased LDL passage through HCMEC monolayers. In conjunction, treatment with VEGF-D significantly decreased TER measurements 2 hours post-treatment and induced the formation of intercellular gaps through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent pathway.
  
  
  CONCLUSIONS
  VEGF-D is overexpressed in the arteries of CAV and DM cases. Treatment with VEGF-D can disrupt HCMEC tight junctions, resulting in the formation of intercellular gaps, and can also significantly increase LDL permeability through confluent monolayers.
authors.affiliation: UBC James Hogg Research Centre, Institute for Heart + Lung Health, St Paul's Hospital, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Wong
authors.forename: Donald
authors.initials: D
authors.lastname: Wong
authors.forename: Honglin
authors.initials: H
authors.lastname: Luo
authors.forename: Bruce M
authors.initials: BM
authors.lastname: McManus
mesh_terms: D000293:Adolescent; D000328:Adult; D001160:Arterioles / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000378:metabolism*; D003331:Coronary Vessels / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019108:Tight Junctions / Q000502:physiology; D017539:Tunica Intima / Q000378:metabolism; D017540:Tunica Media / Q000378:metabolism; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D008077:Lipoproteins, LDL; D042643:Vascular Endothelial Growth Factor D; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3