Captopril suppresses post-transplantation angiogenic activity in rat allograft coronary vessels.
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.
Crawford
Susan E
SE
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
Mavroudis
Constantine
C
Backer
Carl L
CL
Huang
Xuemei
X
Mu
Yan
Y
Volpert
Olga V
OV
Stellmach
Veronica
V
Pahl
Elfriede
E
Huang
Lijun
L
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
D000806:Angiotensin-Converting Enzyme Inhibitors; D010972:Platelet Activating Factor; D042461:Vascular Endothelial Growth Factor A; D002216:Captopril