title: Apoptosis of human macrophages by Flt-4 signaling: implications for atherosclerotic plaque pathology.
abstract: BACKGROUND
  Neointimal inflammation and angiogenesis are important contributors of progression and destabilization of the atherosclerotic plaque. While the role of vascular endothelial growth factor (VEGF) and its receptors VEGF-R1 (Flt-1) and VEGF-R2 (Flk-1) in this process has clearly been defined, expression of the VEGF-R3 (Flt-4) has only been documented on lymphatic and tumor endothelium. This study examined Flt-4 expression in human atherosclerotic plaque and explored its implications for atherosclerotic disease.
  
  
  RESULTS
  Carotid artery thrombendartherectomy specimens from 10 patients with unstable plaque were stained for Flt-4 and its specific growth factors VEGF-C and VEGF-D. Microvascular endothelial cells (MVEC) stained positive for VEGF-C and -D, but not for Flt-4. Interestingly, macrophages within inflammatory perivascular regions coexpressed Flt-4, VEGF-C and VEGF-D. In vitro studies confirmed the expression of Flt-4, VEGF-C and VEGF-D in human monocytes and cultured macrophages. Treatment of macrophages with VEGF-D induced apoptosis as determined by annexin V staining, by immunoblotting of activated caspase 3, and by the ratio of Bcl-2/Bax as well as by DNA fragmentation. Immunohistochemical studies of advanced human carotid atherosclerotic plaque confirmed the coexpression of Flt-4 with activated caspase 3 and TUNEL staining in macrophages, indicating an ongoing apoptotic process.
  
  
  CONCLUSIONS
  Human monocytes/macrophages express VEGF-C and -D and their receptor Flt-4 in vitro and in vivo within advanced atherosclerotic lesions. Flt-4, in turn, mediates monocyte/macrophage apoptosis and may this way alter plaque stability.
authors.affiliation: Medical Clinic II, Department of Cardiology, Dresden University of Technology, PO Box 95, Fetscherstr. 74, 01307 Dresden, Germany. alexanderschmeis@t-online.de
authors.forename: A
authors.initials: A
authors.lastname: Schmeisser
authors.forename: M
authors.initials: M
authors.lastname: Christoph
authors.forename: A
authors.initials: A
authors.lastname: Augstein
authors.forename: R
authors.initials: R
authors.lastname: Marquetant
authors.forename: M
authors.initials: M
authors.lastname: Kasper
authors.forename: R C
authors.initials: RC
authors.lastname: Braun-Dullaeus
authors.forename: R H
authors.initials: RH
authors.lastname: Strasser
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002340:Carotid Artery Diseases / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D053938:DNA Fragmentation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism / Q000494:pharmacology; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism / Q000494:pharmacology; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000032:analysis / Q000502:physiology*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D040321:Vascular Endothelial Growth Factor Receptor-3; D053148:Caspase 3