SERMS PREVENT NEOINTIMA FORMATION AFTER VASCULAR INJURY

Abstract

P772 Aims: Vascular intimal dysplasia and remodelling are characteristic features, not only after percutaneuous transluminal angioplasty and bypass surgery, but also in chronic allograft rejection (allograft arteriosclerosis). Moreover, most renal transplants are lost to death with function, mainly for cardiovascular reasons (accelerated atherosclerosis). The vasculoprotective properties of estrogen have been demonstrated in the primary prevention of age-related cardiovascular disease in women, as well as in experimental restenosis and allograft arteriosclerosis. Estrogen’s vasculoprotective effects can be differentiated from its sex-related side-effects with estrogen receptor subtype-selective ligands. We investigate here whether selective estrogen receptor modulators (SERM) preserve estrogens beneficial effects on the vascular wall without inducing growth of the uterus. Methods: Two clinically used (tamoxifen, raloxifene) and two novel (ospemifene, fispemifene) SERMs effects on neointima formation and uterine growth were explored in ovariectomized female Wistar rats at 7, 14, and 28 days after aorta denudation injury. Effects on rat smooth muscle cell (SMC) and aortic explant proliferation and migration were investigated in cell culture conditions. 17β-estradiol (E2) served as positive, and vehicle and a pure antiestrogen ICI 182,780 (ICI) as negative controls. Results: All compounds dose-dependently (from 0.0025 to 25 mg/kg/d s.c.) inhibited neointimal thickening at 7 days post-denudation in the following order: E2>tamoxifen>raloxifene>ospemifene>fispemifene>ICI. E2, tamoxifen, and raloxifene also significantly reduced SMC replication in the intima. At 28 days (2.5 mg/kg/d), E2 (p=0.01), tamoxifen (p=0.0002), and ospemifene (p=0.0008) reduced intimal nuclei number and intimal area by 40-80%, while raloxifene, fispemifene, and ICI had no effect. E2 (4-fold, p=0.005) and the SERMs (2 to 3-fold) also significantly enhanced reendothelialization at 28 days. Replacing the drug at 14 days with vehicle induced no rebound effect at 28 days in any of the groups, and furthermore, resulted in a significantly smaller neointima with raloxifene, fispemifene, and ICI. All SERMs inhibited replication, and all but fispemifene the migration of vascular SMC and cells from aortic explants in vitro. Finally, only estradiol dose-dependently (r=0.775, p<0.0001) increased the weight of the uterus above that of normal rats. Conclusions: SERMs have beneficial estrogen agonist effects in the injured vascular wall through their regulation of vascular SMC function and reendothelialization. Early intervention is especially important in preventing the injury response. In vivo treatment with tamoxifen and ospemifene inhibits neointimal thickening equal to E2. A favorable side-effect profile makes ospemifene a promising new SERM with beneficial effects on bone, breast, and the cardiovascular system.