Differential effects of 17β-estradiol, conjugated equine estrogen, and raloxifene on mRNA expression, aggregation, and secretion in platelets

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Abstract
Changes in platelet functions could contribute to thrombotic risk associated with estrogen treatments. This study was designed to test the hypothesis that three clinically relevant estrogenic treatments affect platelet function comparably. Adult female pigs were ovariectomized and randomized to either no treatment or treatment with oral 17β-estradiol (2 mg/day), conjugated equine estrogen (0.625 mg/day), or raloxifene (60 mg/day) for 4 wk. Platelet turnover, aggregation, and secretion were assessed before and after treatment. Platelet turnover and mRNA increased significantly only in pigs treated with 17β-estradiol. Expression of estrogen receptors increased with ovariectomy and decreased with all treatments. Platelet aggregation and secretion of ATP, platelet-derived growth factor, and matrix metalloproteinase-2 increased with ovariectomy. All treatments reduced both aggregation and secretion. Expression of mRNA for constitutive endothelial nitric oxide synthase (eNOS), but not eNOS protein, increased with ovariectomy. Only eNOS mRNA decreased with all treatments, but only treatment with 17β-estradiol increased secretion of nitric oxide from intact platelets. Platelets from 17β-estradiol-treated animals caused relaxation of coronary arteries, which was sensitive to inhibition of nitric oxide. Although three different estrogenic treatments reversed increases in platelet aggregation caused by ovariectomy, only 17β-estradiol increased platelet RNA and release of platelet-derived nitric oxide. These differences reflect transcriptional and posttranscriptional regulation of protein synthesis in bone marrow megakaryocytes and circulating platelets.