ABSTRACT
Title
Treatment with low-dose selective estrogen receptor α agonist is associated with heart and vascular protection in the absence of uterotrophic action
Authors
C. Bolego1, G.Rossoni2, C.Pinna3, E. Vegeto3, G.P.Fadini4, R.M.Gaion1, A. Cignarella1.
1Dept. of Pharmacology and Anesthesiology, University of Padova;2Dept. of Pharmacology, Chemotherapy, and Medical Toxicology and 3Dept. of Pharmacological Sciences, University of Milan; and 4Dept of Clinical and Experimental Medicine, Padua University Hospital.
1Dept. of Pharmacology and Anesthesiology, University of Padova;2Dept. of Pharmacology, Chemotherapy, and Medical Toxicology and 3Dept. of Pharmacological Sciences, University of Milan; and 4Dept of Clinical and Experimental Medicine, Padua University Hospital.
Abstract
In spite of experimental and epidemiological studies suggesting a cardiovascular protective role for estrogens, results from clinical trials have disputed the protective role of menopausal hormone therapy (MHT) in cardiovascular health. Results from our group and others have demonstrated that the beneficial cardiovascular effects of estrogens are mainly mediated by activation of ERα (Cignarella et al, 2010). This is also the main ER isoform expressed in the uterus, responsible for unwanted effects associated with MHT. Few available data address the modulation of cardiovascular function by in vivo treatment with ERα selective agonists as well as the effects of such a treatment in different target tissues. The aim of our study was to analyse the action profile of ERα selective agonists by assessing both cardiovascular-endothelial and endometrial effects of in vivo treatment with the ERα selective agonist propyl pyrazole triol (PPT) compared with 17β-estradiol (E2) in ovariectomized (OVX) rats. Four weeks postovariectomy, equimolar doses of PPT and E2 in subcutaneous implants were administered for 5 days. As expected, uterus weight dropped by 70% in untreated OVX animals. In E2-treated OVX rats uterus weight was similar to that of control animals, while PPT did not affect this parameter. Similar results were obtained in OVX mice. Both treatments restored the rapid vasorelaxation of aortic tissue to estrogenic agents that was impaired in OVX animals, and prevented coronary hyperresponsiveness to angiotensin II in isolated heart preparations. Accordingly, multiple endpoints of myocardial ischemia-reperfusion injury exacerbated by ovariectomy returned to baseline following treatment with PPT and E2. These protective effects were linked to increased in vivo levels of endothelial progenitor cells (EPCs). The function of human EPCs was also enhanced in vitro after PPT treatment. In sharp contrast to E2, PPT treatment had no effect on uterine histomorphology except for vessel density, and failed to up-regulate classic estrogen target genes. The dissection of effects on vascular reactivity and uterine morphology was maintained following increased exposure to PPT at a higher dose for longer time. Hence, these data provide the first in vivo evidence for tissue-specific ERα activation. By conferring cardiovascular protection dissected from unwanted uterotrophic effects, ERα-selective agonists may represent a potential safer alternative to natural hormones.