title: Vascular endothelial growth factor enhances cardiac allograft arteriosclerosis.
abstract: BACKGROUND
  Cardiac allograft arteriosclerosis is a complex process of alloimmune response, chronic inflammation, and smooth muscle cell proliferation that includes cross talk between cytokines and growth factors.
  
  
  RESULTS
  Our results in rat cardiac allografts established alloimmune response as an alternative stimulus capable of inducing vascular endothelial growth factor (VEGF) mRNA and protein expression in cardiomyocytes and graft-infiltrating mononuclear inflammatory cells, which suggests that these cells may function as a source of VEGF to the cells of coronary arteries. Linear regression analysis of these allografts with different stages of arteriosclerotic lesions revealed a strong correlation between intragraft VEGF protein expression and the development of intimal thickening, whereas blockade of signaling downstream of VEGF receptor significantly reduced arteriosclerotic lesions. In addition, in cholesterol-fed rabbits, intracoronary perfusion of cardiac allografts with a clinical-grade adenoviral vector that encoded mouse VEGF(164) enhanced the formation of arteriosclerotic lesions, possibly secondary to increased intragraft influx of macrophages and neovascularization in the intimal lesions.
  
  
  CONCLUSIONS
  Our findings suggest a positive regulatory role between VEGF and coronary arteriosclerotic lesion formation in the allograft cytokine microenvironment.
authors.affiliation: Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. Karl.Lemstrom@helsinki.fi
authors.forename: Karl B
authors.initials: KB
authors.lastname: Lemström
authors.forename: Rainer
authors.initials: R
authors.lastname: Krebs
authors.forename: Antti I
authors.initials: AI
authors.lastname: Nykänen
authors.forename: Jussi M
authors.initials: JM
authors.lastname: Tikkanen
authors.forename: Roope K
authors.initials: RK
authors.lastname: Sihvola
authors.forename: Eva M
authors.initials: EM
authors.lastname: Aaltola
authors.forename: Pekka J
authors.initials: PJ
authors.lastname: Häyry
authors.forename: Jeanette
authors.initials: J
authors.lastname: Wood
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.forename: Petri K
authors.initials: PK
authors.lastname: Koskinen
mesh_terms: D000208:Acute Disease; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D002908:Chronic Disease; D004195:Disease Models, Animal; D018450:Disease Progression; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D022761:Gene Transfer, Horizontal; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000009:adverse effects* / Q000276:immunology / Q000473:pathology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000473:pathology; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D008264:Macrophages / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010793:Phthalazines / Q000494:pharmacology; D011725:Pyridines; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor; D014162:Transfection; D016042:Transplantation, Heterotopic; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D008222:Lymphokines; D010793:Phthalazines; D011725:Pyridines; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C404768:vatalanib; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor