title: Captopril suppresses post-transplantation angiogenic activity in rat allograft coronary vessels.
abstract: BACKGROUND
  The development of transplant coronary artery disease is associated with neovascularization in the thickened neointima. We previously reported that captopril inhibits neointimal proliferation in a rat allograft model. We postulated that angiogenic inducers are upregulated post-transplantation and captopril ameliorates transplant coronary artery disease by suppressing the angiogenic activity of coronaries.
  
  
  METHODS
  Animals received no treatment or captopril (50 mg/kg/day). Allograft hearts were analyzed at post-transplantation Days 0, 14, and 21 and angiogenic inducer, plasma platelet-activating factor, determined. The conditioned media from coronaries and myocardium were tested for vascular endothelial growth factor, thrombospondin-1 and angiogenic activity using an endothelial migration assay and rat corneal neovascularization assay.
  
  
  RESULTS
  The captopril-treated group had reduced plasma platelet-activating factor and coronary media revealed earlier upregulation of thrombospondin-1 secretion, diminished vascular endothelial growth factor and no angiogenic activity. At Day 0, the coronary and myocardial conditioned medium had inhibitory activity due to thrombospondin-1, and circulating levels of platelet-activating factor were negligible. By 21 days post-transplantation, plasma platelet-activating factor was elevated and the conditioned medium from untreated coronaries had significantly higher angiogenic activity due to increased vascular endothelial growth factor whereas the myocardium remained non-angiogenic.
  
  
  CONCLUSIONS
  After transplantation, coronary vessels switch to an angiogenic phenotype and vascular endothelial growth factor contributes to the high angiogenic activity, possibly exacerbated by high circulating levels of platelet-activating factor. The ability of captopril to modulate angiogenic mediators and maintain the allograft coronary to its normal anti-angiogenic phenotype may be one mechanism by which it suppresses transplant coronary artery disease.
authors.affiliation: Department of Pathology, Children's Memorial Hospital and Institute for Education and Research, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. scrawford@northwestern.edu
authors.forename: Susan E
authors.initials: SE
authors.lastname: Crawford
authors.forename: Constantine
authors.initials: C
authors.lastname: Mavroudis
authors.forename: Carl L
authors.initials: CL
authors.lastname: Backer
authors.forename: Xuemei
authors.initials: X
authors.lastname: Huang
authors.forename: Yan
authors.initials: Y
authors.lastname: Mu
authors.forename: Olga V
authors.initials: OV
authors.lastname: Volpert
authors.forename: Veronica
authors.initials: V
authors.lastname: Stellmach
authors.forename: Elfriede
authors.initials: E
authors.lastname: Pahl
authors.forename: Lijun
authors.initials: L
authors.lastname: Huang
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002216:Captopril / Q000494:pharmacology* / Q000627:therapeutic use; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000187:drug effects; D003315:Cornea / Q000098:blood supply / Q000187:drug effects; D003324:Coronary Artery Disease / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D016027:Heart Transplantation / Q000009:adverse effects*; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010972:Platelet Activating Factor / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D010972:Platelet Activating Factor; D042461:Vascular Endothelial Growth Factor A; D002216:Captopril