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.
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- Vascular Endothelial Growth Factor A
- Surgery
- Rats, Inbred Lew
- Rats, Inbred F344
- Rats
- Platelet Activating Factor
- Neovascularization, Physiologic
- Male
- Heart Transplantation
- Endothelial Cells
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Vascular Endothelial Growth Factor A
- Surgery
- Rats, Inbred Lew
- Rats, Inbred F344
- Rats
- Platelet Activating Factor
- Neovascularization, Physiologic
- Male
- Heart Transplantation
- Endothelial Cells