Murine model of accelerated transplant arteriosclerosis.
To define the role of specific gene deletions and mutations in the development of transplant arteriosclerosis, we generated an accelerated model of the disease in mice. Carotid arteries were transplanted between B.10A(2R) (H-2h2) donor mice and C57BL/6J (H-2b) recipients and compared with arteries isografted between H-2b mice. Immunosuppressive drugs were not used. Within 7 days, the allografted carotid artery formed a neointima composed of mononuclear leukocytes (CD45+) that were predominantly monocytes or macrophages (ie, CD11b+ cells with single-lobed nuclei). CD4+ and CD8+ cells were present as well. By 30 days, the neointima became exuberant, and mononuclear leukocytes were largely replaced by smooth muscle cells. Cells staining for proliferating-cell nuclear antigen were abundantly present in the intima at both early and late time points, indicating the proliferation of mononuclear leukocytes and smooth muscle cells. The area of the intima increased from day 7 to day 30 (P < .0005), as did the number of nuclei (P = .0005), but the density of the nuclei decreased (P = .02), suggesting the formation of extracellular matrix. Six of the eight isografts formed no neointima, and in samples from the remaining two, a single layer of smooth muscle neointimal cells covered just a portion of the vessel circumference. This model, which reproduces many of the features of human transplant arteriosclerosis but at an accelerated pace, should prove useful for determining the roles in transplant arteriosclerosis of genes that code for components of immunologic and inflammatory responses.
Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, Mass.
C
C
Shi
M E
ME
Russell
C
C
Bianchi
J B
JB
Newell
E
E
Haber
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology; D016027:Heart Transplantation / Q000009:adverse effects*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D013997:Time Factors; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic; D017539:Tunica Intima / Q000473:pathology; D017540:Tunica Media / Q000473:pathology