Improvement of endothelial dysfunction by selective estrogen receptor-alpha stimulation in ovariectomized SHR.
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.
Widder
Julian
J
Medizinische Klinik der Julius-Maximilians-Universität, Würzburg, Germany.
Pelzer
Theo
T
von Poser-Klein
Christine
C
Hu
Kai
K
Jazbutyte
Virginija
V
Fritzemeier
Karl-Heinrich
KH
Hegele-Hartung
Christa
C
Neyses
Ludwig
L
Bauersachs
Johann
J
D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000503:physiopathology; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism; D046508:Culture Techniques; D004730:Endothelium, Vascular / Q000503:physiopathology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D005260:Female; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D008840:Microfilament Proteins; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D010052:Ovariectomy; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011960:Receptors, Estrogen / Q000819:agonists*; D012694:Serine / Q000378:metabolism; D014664:Vasodilation; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D008840:Microfilament Proteins; D010750:Phosphoproteins; D011960:Receptors, Estrogen; D000098662:Vasodilator-Stimulated Phosphoprotein; D012694:Serine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat