title: Ultrastructural evidence of early endothelial damage in coronary arteries of rat cardiac allografts.
abstract: BACKGROUND
  Events that occur early after transplantation, particularly immune recognition of allo-endothelium, initiate transplant vascular disease (TVD). Previous work suggests an important compromise of endothelial integrity as the allo-immune milieu evolves, although mechanisms by which integrity is altered remain unclear. Increased vascular permeability caused by endothelial damage may allow inflammatory cells, lipoproteins, other proteins, and plasma fluid to enter the sub-endothelial space, thereby contributing to the initiation of atherosclerosis. In this study, we examined endothelial integrity in coronary arteries and the proximal aorta after cardiac transplantation in rats.
  
  
  METHODS
  We used Lewis-to-Lewis and Lewis-to-F344 rat heterotopic cardiac transplant models. We studied the effects of cyclosporine (5mg/kg/day) therapy compared with saline-treated controls. En face silver nitrate staining was performed to demonstrate endothelial cell borders and gaps. We used scanning electron microscopy to extend silver nitrate findings and to further define the presence and nature of endothelial disruptions. We used transmission electron microscopy to further characterize immune cell identity and interaction with endothelium.
  
  
  RESULTS
  Syngrafts and cyclosporine-treated allografts showed normal-looking endothelium similar to that observed in arteries from native hearts. However, saline-treated allografts displayed progressive endothelial destruction, including large intercellular gaps, missing cells, and areas of bare extracellular matrix. Exfoliated surfaces were covered by platelets at various stages of adhesion, activation, and spreading. Similarly, we observed numerous leukocytes as either adherent to the endothelial lining or transmigrating into the sub-endothelial space. Cessation of cyclosporine therapy was associated with the development of similar abnormalities.
  
  
  CONCLUSIONS
  Our findings indicate that, especially when immunosuppression is insufficient, early endothelial damage may promote vascular permeability and thereby initiate TVD.
authors.affiliation: University of British Columbia McDonald Research Laboratories, iCAPTUR4E Centre, Department of Pathology and Laboratory Medicine, St. Paul's Hospital, Providence Health Care, Vancouver, British Columbia, Canada.
authors.forename: John C K
authors.initials: JC
authors.lastname: Lai
authors.forename: Erin M
authors.initials: EM
authors.lastname: Tranfield
authors.forename: David C
authors.initials: DC
authors.lastname: Walker
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dyck
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kerjner
authors.forename: Sylvia
authors.initials: S
authors.lastname: Loo
authors.forename: Dean
authors.initials: D
authors.lastname: English
authors.forename: Donald
authors.initials: D
authors.lastname: Wong
authors.forename: Paul C
authors.initials: PC
authors.lastname: McDonald
authors.forename: Mohammed H
authors.initials: MH
authors.lastname: Moghadasian
authors.forename: Janet E
authors.initials: JE
authors.lastname: Wilson
authors.forename: Bruce M
authors.initials: BM
authors.lastname: McManus
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology*; D003331:Coronary Vessels / Q000473:pathology*; D016572:Cyclosporine / Q000627:therapeutic use; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000648:ultrastructure*; D005990:Glycerol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016027:Heart Transplantation / Q000473:pathology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D014677:Pharmaceutical Vehicles; D051381:Rats; D011917:Rats, Inbred Lew; D016622:Silver Staining; D013501:Surface-Active Agents / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; D014677:Pharmaceutical Vehicles; D013501:Surface-Active Agents; C000515:cremophor EL; D016572:Cyclosporine; D005990:Glycerol