Estrogen replacement inhibits intimal hyperplasia and the accumulation andeffects of transforming growth factor beta(1)

Background. The role of estrogens in providing atheroprotection has been we ll documented in both epidemiologic and experimental studies. This phenomen on has traditionally been attributed to the beneficial lipid-modifying effe cts of estrogens. Previous studies have used models of either diet- or inju ry-induced atherosclerosis. As such, the interrelationship between estrogen s, lipids, and atherosclerosis remains unclear. We hypothesized that estrog ens are atheroprotective independent of changes in serum lipids by directly influencing the accumulation and effects of the peptide growth factor tran sforming growth factor beta(1) (TGF-beta(1)). Material and methods. Thirteen female sheep (8 years old) were randomized t o sham, ovariectomy, or ovariectomy with 17 beta-estradiol replacement. Ser um lipid levels were serially measured. At 9 months, necropsy was performed with histologic morphometric analysis of the aortoiliac bifurcation, Level s of TGF-beta(1) were determined in serum and aortic tissue. Human aortic s mooth muscle cells were isolated and cultured. Results. Serum triglyceride, lipoprotein a, and total, low-density lipoprot ein, and high-density lipoprotein cholesterol levels were similar and norma l between groups. Ovariectomy resulted in aortoiliac intimal hyperplasia co mpared with sham (P < 0.001) and hormone replacement (P < 0.001) groups. Co mpared with ovariectomy, estrogen replacement attenuated aortic accumulatio n of TGF-beta(1) (P < 0.02). In vitro, estradiol potentiated TGF-beta(1) in hibition of human vascular smooth muscle cell (VSMC) proliferation and incr eased TGF-beta(1) release in stimulated VSMCs (P < 0.001). Conclusions. Without dietary manipulation, ovarian ablation induces aortic intimal hyperplasia in the ewe. Estradiol abrogates this response independe ntly of its effects on serum lipids. Hormone replacement decreases the accu mulation of TGF-beta(1), suggesting that estrogens may provide atheroprotec tion both by modifying local production and by modulating the influence of TGF-beta(1), on VSMC growth. (C) 1998 Academic Press.