Physical exercise reduces transplant arteriosclerosis in a mouse aorta transplantation model

Abstract

Transplant arteriosclerosis limits long-term outcome after heart transplantation. The underlying mechanism of transplant arteriosclerosis remains alloreactivity, but it is also influenced by nonimmunologic cofactors. Physical exercise has well-established effects on the prevention of native arteriosclerosis. We hypothesized that physical exercise would reduce the development of transplant arteriosclerosis in an allogeneic transplantation setting. Segments of the thoracic aorta from C57.Bl6 (H2b) or C3H.HeJ (H2k) mice were transplanted into the abdominal aortas of CBA.Ca mice (H2k), representing a major or minor alloantigen mismatch, respectively. Three days after surgery, recipient mice were assigned to either the control or physical exercise (consisting of 2×45 minutes of treadmill training per day) groups. Transplant arteriosclerosis was assessed and quantified by histology on day 28 after vessel transplantation. Endothelial cell integrity and function in histology sections and peripheral blood was assessed. All animals developed transplant arteriosclerosis with more severe luminal occlusion in the major alloantigen mismatch setting. Animals undergoing physical exercise developed significantly less severe transplant arteriosclerosis in both the major (P<.0001) and minor (P<.0001) antigen mismatches than their respective control groups without physical exercise. CD31(+) endothelial cells were present in significantly higher numbers in the grafts and circulating in peripheral blood in the exercise groups compared with their respective control. Above that, we found enhanced endothelial nitric oxide synthase-positive cells in both exercise groups compared with the untreated groups (P=.01 and P=.02, respectively). Physical exercise has a protective effect against the development of transplant arteriosclerosis. This could be due to enhanced endothelial cell regeneration and function in the graft.