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Examination of endothelial integrity in a rat cardiac transplant model : implications for the pathogenesis of transplant vascular disease Lai, John Chi Keung

Abstract

Background: One of the major complications associated with solid organ transplantation is a progressive form of allo-atherosclerosis known as transplant vascular disease (TVD), an expression of chronic allograft rejection. Events occurring early post-transplantation, particularly immune recognition of alloendothelium, initiate TVD. Previous work has suggested an important compromise of endothelial integrity as the allo-immune milieu evolves, although mechanisms by which integrity is altered remain to be resolved. Increased vascular permeability due to endothelial damage may allow entrance of inflammatory cells, lipoproteins, other proteins and plasma fluid into the subendothelial space, thereby contributing to the initiation of atherosclerosis in thoroughfare arteries. In this study, endothelial integrity in coronary arteries and proximal aorta was examined following cardiac transplantation in rats. Hypothesis: Altered endothelial integrity, as reflected in structural changes, is present in the rat allograft cardiac transplant model. Methods: Lewis-to-Lewis and Lewis-to-F-344 rat heterotopic cardiac transplants were examined at 1, 4, 21 and 42 days post-transplantation. The effects of cyclosporine treatment (5mg/kg/day) on maintaining endothelial integrity were studied and compared with control saline treated animals. At the light microscopy level, en face silver nitrate staining was performed to demonstrate endothelial cell borders and gaps. Scanning electron microscopy was used to extend silver nitrate findings and to further define the presence and nature of endothelial disruptions. Transmission electron microscopy was performed to further characterize endothelial integrity, immune cell identity and interaction with endothelium, and disease progression. Results: Syngrafts and cyclosporine treated allografts showed normal looking endothelium similar to that observed in arteries from native and control 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, numerous leukocytes were observed a s either adherent to the endothelial lining or transmigrating into the sub-endothelial space. Cessation of cyclosporine therapy was associated with development of similar abnormalities. Conclusion: These findings suggest that early endothelial damage may promote vascular permeability and thereby initiate TVD, especially when immunosuppression is insufficient.

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