Cytomegalovirus infection enhances smooth muscle cell proliferation and intimal thickening of rat aortic allografts.

Abstract

Inbred DA (AG-B4, RT1 a) and WF (AG-B2, RT1') rats were used as donors and recipients of aortic allografts. The recipient rats were inoculated i.p. either on day 1 (early infection) or on day 60 (late infection) with iOs plaque-forming units of rat cytomegalovirus (RCMV). The control rats were left noninfected. The presence of viral infection was demonstrated by plaque assays from biopsies of the salivary glands, liver, and spleen at sacrifice. The rats received 300 gCi 13H Ithymidine by i.v. injection 3 h before sacrifice, and the grafts were removed at various time points for histology, immunohistochemistry, and autoradiography. RCMV infection significantly enhanced the generation of allograft arteriosclerosis. Infection at the time of transplantation had two important effects. First, the infection was associated with an early, prominent inflammatory episode and proliferation of inflammatory cells in the allograft adventitia. Second, the viral infection doubled the proliferation rate of smooth muscle cells and the arteriosclerotic alterations in the intima. In late infection the impact of RCMV infection on the allograft histology was nearly nonexistent. RCMV infection showed no effect in syngeneic grafts. These results suggest that early infection is more important to the generation of accelerated allograft arteriosclerosis than late infection, and that an acute alloimmune response must be associated with virus infection, to induce accelerated allograft arteriosclerosis. RCMVinfected aortic allografts, as described here, provide the first experimental model to investigate the interaction between the virus and the vascular wall of the transplant. (J. Clin. Invest. 1993. 92:549-558.)

Cytomegalovirus infection-enhanced allograft arteriosclerosis is prevented by DHPG prophylaxis in the rat.

“…13 In the DHPG prophylaxis group (Fig 3b), the early proliferative response of media cells was inhibited to half of that observed in RCMV-infected allografts, reaching 6±3 labeled nuclei at 7 days (P<.05) and 11±2 labeled nuclei at 14 days (P<.05). The same degree of inhibition was also observed in the DHPG treatment group, with Smooth muscle cells were isolated from 9-to 11-day-old DA rat thoracic aortas and seeded in 96-microtiter wells.…”

“…1994;90:1969-1978 Key Words * transplantation * ganciclovir * smooth muscle cells * growth substances * arterioscierosi M ajor risk factors for accelerated allograft arteriosclerosis, ie, chronic rejection, in heart transplant recipients include humoral and cellular immune responses,1-4 hyperlipidemia,5-7 and viral infections.8-1' We demonstrated with our rat aortic allograft model12 that rat cytomegalovirus (RCMV) infection doubles allograft arteriosclerosis. 13 The drug of choice for the treatment of CMV infection is 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG; ganciclovir).14 DHPG is an acyclic analogue of the natural 2'-deoxyguanosine. '5 The mechanism of action of this drug depends on the formation of a a direct antiproliferative effect on the secretory phenotype of vascular smooth muscle cells.…”

The Cell Biology of Cytomegalovirus: Implications for Transplantation

“…Atherogenesis CMV accelerates graft atherosclerosis clinically and in animal models of renal and cardiac transplantation (9,27,(104)(105)(106). Rat renal allograft recipients with CMV infection demonstrate atherosclerosis with intimal thickening of arteries, arterioles and medial necrosis of large arteries (9).…”

Mechanisms of Cytomegalovirus-Accelerated Vascular Disease: Induction of Paracrine Factors That Promote Angiogenesis and Wound Healing

“…Furthermore, HCMV infections are lifelong during which time the virus infects all of the cell types involved in TVS formation including SMC, EC, macrophages, and fibroblasts. Along these lines, HCMV evades the immune system by remaining latent in monocytes and HCMV reactivation in immunocompetent hosts is difficult to detect when clinically silent (Lemstrom et al 1993;Bruning et al 1994;Lemstrom et al 1995;Orloff 1999;Orloff et al 2000). These undeniable factors make it difficult to determine a temporal relationship between the virus infection and TVS, and because of obvious ethical reasons, human studies are impossible.…”