Reference : Improvement of endothelial dysfunction by selective estrogen receptor-alpha stimulati...
Scientific journals : Article
Human health sciences : Cardiovascular & respiratory systems
Improvement of endothelial dysfunction by selective estrogen receptor-alpha stimulation in ovariectomized SHR.
Widder, Julian [> >]
Pelzer, Theo [> >]
von Poser-Klein, Christine [> >]
Hu, Kai [> >]
Jazbutyte, Virginija [> >]
Fritzemeier, Karl-Heinrich [> >]
Hegele-Hartung, Christa [> >]
Neyses, Ludwig mailto [University of Luxembourg > Research Office]
Bauersachs, Johann [> >]
Yes (verified by ORBilu)
United States
[en] Animals ; Aorta/enzymology/physiopathology ; Cell Adhesion Molecules/chemistry/metabolism ; Culture Techniques ; Endothelium, Vascular/physiopathology ; Estrogen Antagonists/pharmacology ; Estrogen Receptor alpha ; Female ; Hypertension/metabolism/physiopathology ; Microfilament Proteins ; Nitric Oxide Synthase/metabolism ; Nitric Oxide Synthase Type III ; Ovariectomy ; Phosphoproteins/chemistry/metabolism ; Rats ; Rats, Inbred SHR ; Receptors, Estrogen/agonists ; Serine/metabolism ; Vasodilation
[en] Both known estrogen receptors, ERalpha and ERbeta, are expressed in blood vessels. To gain further insight into the role of ERalpha in a functional setting, we investigated the effect of the novel highly selective ERalpha agonist Cpd1471 on vascular reactivity in ovariectomized spontaneously hypertensive rats (SHR). After ovariectomy or sham operation, 12-week-old female SHR received either 17beta-estradiol (E2, 2 microg/kg body wt per day), the selective ERalpha agonist Cpd1471 (30 microg/kg body wt per day), or placebo. Acetylcholine-induced endothelium-dependent vasorelaxation was significantly blunted in aortas from ovariectomized rats (Rmax, 53%+/-3% versus sham, 79%+/-2%; P<0.001). Treatment with E2 or Cpd1471 significantly augmented acetylcholine-induced relaxation in ovariectomized rats (Rmax, 70%+/-2%; resp, 73%+/-2%). Endothelium-independent relaxation induced by sodium nitroprusside was not different among the four groups. The contractile response induced by the nitric oxide (NO) synthase inhibitor Nomega-nitro-l-arginine, an index of basal NO formation, was significantly lower in ovariectomized rats compared with sham-operated animals (53+/-2% versus 77%+/-5%; P<0.01) and was normalized by both E2 (70%+/-2%) and Cpd1471 (70%+/-3%). Aortic endothelial NO synthase (eNOS) expression and phosphorylation of the vasodilator-stimulated phosphoprotein, an index of NO/cGMP-signaling, was reduced in ovariectomized SHR and normalized by E2 and Cpd1471. In SHR after ovariectomy, endothelium-dependent NO-mediated vasorelaxation and eNOS expression are attenuated. The novel selective ERalpha agonist Cpd1471 prevented these pathophysiological changes to a similar extent as E2. Thus, the pharmacological principle of selective ERalpha activation mediates positive vascular effects.

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