INHIBITION OF MYOINTIMAL HYPERPLASIA AND MACROPHAGE INFILTRATION BY ESTRADIOL IN AORTA ALLOGRAFTS

A major cause of organ graft loss after heart transplantation is accelerated atherosclerosis. In this study we used aorta allografts and investigated the effect of estradiol-17-beta treatment on both the degree of myointimal hyperplasia and morphological changes evaluated by light and electron microscopy. Outbred New Zealand white male rabbits (2.7-3.5 kg) were fed cholesterol (0.5%) from one week prior to transplantation, and until sacrifice three weeks later. The donor abdominal aorta was transplanted end-to-end to the right carotid artery of the recipient animals. Immediately following surgery, cyclosporine (10 mg/kg/d s.c.) was administered to prevent graft rejection. The allograft recipients were randomly assigned to one of five groups and treated with cottonseed oil (placebo) or estradiol cypionate at 1, 10, 100, or 1000-mu-g/kg/d i.m. for 3 weeks. The aorta grafts were harvested and fixed for transmission electron microscopy and morphometry. The area of myointimal thickening was calculated as a percent of total vessel area (mean +/- SEM); the control group was 6.6 +/- 0.5% (n = 5). Estradiol treatment significantly inhibited (P < 0.05) myointimal hyperplasia at all doses. The vaues were 3.9 +/- 0.6% (n = 6) for 1-mu-g/kg/day; 4.4 +/- 0.7% (n = 5) for 10-mu-g/kg/day; 3.5 +/- 0.4% (n = 6) for 100-mu-g/kg/day; and 2.9 +/- 0.1% (n = 3) for 1000-mu-g/kg/day. Electron microscopic evaluation revealed that the four doses of estradiol protected the endothelium from the degenerative changes seen in all aorta allografts from the animals in the control group. Futhermore 10, 100, and 1000-mu-g/kg/day of estradiol prevented the appearance of vacuolized macrophages (foam cells) and also the vacuolization of smooth muscle cells that was observed in the aorta allografts from the control group and the group treated with 1-mu-g/kg/day of estradiol. We conclude that the inhibitory effect of estradiol on the development of graft atherosclerosis may be due to inhibition of smooth muscle cell proliferation and preservation of ultrastructurally normal endothelial cells. The inhibitory effect on foam cell production and a concomitant vacuolization of smooth muscle cells may play a lesser role. We suggest that estrogen replacement therapy may be beneficial in postmenopausal women with organ allografts.