The Acute Estrogenic Dilation of Rat Aorta Is Mediated Solely by Selective Estrogen Receptor-α Agonists and Is Abolished by Estrogen Deprivation

Abstract

Estrogen is known to induce rapid vasodilatory response in isolated arteries. Because estrogen is a nonselective receptor agonist, the involvement of estrogen receptor (ER) subtypes in acute estrogenic responses has remained elusive. Acute administration of the selective ER␣ agonist 4,4Ј,4Љ-(4-propyl-[ 1 H]pyrazole-1,3,5-triyl) tris-phenol (PPT) to precontracted aortic rings from intact female rats dose-dependently induced an ER-dependent vascular relaxation fully overlapping to that induced by 17␤-estradiol. By contrast, the selective ER␤ agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) had no acute effect on vasomotion. This short-term vasorelaxant action of PPT was abolished by the NO synthase inhibitor N -nitro-L-arginine methyl ester and by endothelium removal. In aortic tissues from ovariectomized (OVX) rats, however, neither 17␤-estradiol nor PPT induced acute vascular relaxation. The effect of PPT was restored in preparations from estrogen-replaced OVX rats, whereas DPN remained ineffective even after estrogen replacement. PPT acted through an ER-dependent mechanism, as shown by impaired response in the presence of the anti-estrogen ICI 182,780 (7␣,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol). Accordingly, isolated rat aortic endothelial cells expressed both ER␣ and ER␤. These data show that selective ER␣ but not ER␤ agonists reproduced the acute vasodilation of estrogen via a receptor-mediated pathway in the aorta from intact as well as 17␤-estradiolreplaced OVX rats. This beneficial effect was undetectable in tissues from OVX rats. Selective pharmacological targeting of ER subtypes may thus represent a novel and promising approach in the treatment of vascular disease.The vascular wall is clearly one of the target organs of estrogens. A number of studies have shown that estrogens modulate vasomotor responses after both acute application and in vivo short-or long-term treatment (for review, see Mendelsohn and Karas, 1999;Cignarella et al., 2001). Although different mechanisms have been reported (Shaw et al., 2001), such effects seem to be mediated by specific estrogen receptors (ERs) that are located on the plasma membrane as well as intracellularly. So far, two ER subtypes have been described: ER␣ and ER␤. Both subtypes are found in vascular smooth muscle (Register and Adams, 1998;Hodges et al., 2000;Maggi et al., 2003) and human endothelial cells (Caulin-Glaser et al., 1996). Although similar, the two ER isoforms are distinct gene products with nonoverlapping functions. They are coexpressed in most tissues but increasing evidence suggests that ER␣ and ER␤ mediate opposite effects in a kind of yin-yang manner (Gustafsson, 2003).The relative contribution of each ER subtype to vascular responses has been difficult to investigate because the physiological ER ligand 17␤-estradiol (E 2 ) has no binding affinity preference for ER␣ and ER␤. Selective ER agonists have now become available, the most widely used being 4,4Ј,4Љ-(4-propyl-[1 H]pyrazole-1,3,5-triyl) tris-phen...

17β-Estradiol modulates vasoconstriction induced by endothelin-1 following trauma-hemorrhage

“…They observed that in rat aortic rings contracted with KCl, the ER-␤ agonist DPN produced significantly greater relaxations than the ER-␣ agonist PPT. In contrast, Bolego et al (6) reported that aortic rings isolated from E 2 -treated ovariectomized rats responded with higher potency to an ER-␣ agonist than an ER-␤ agonist. The apparent discrepancy between the results of Bolego et al (6) and our findings may be related to the use of different sexes, treatment regimen, and differences in ER-subtype predominance and/or connecting downstream mechanisms that can modify responses to ER agonists.…”

Prolonged Ovarian Hormone Deprivation Impairs the Protective Vascular Actions of Estrogen Receptor αAgonists

“…13 In this regard, we demonstrated previously that ER␣-selective agonists, unlike ER␤-selective agonists, induce acute vascular relaxation in the aorta from intact female or E 2 -replaced ovariectomized (OVX) rats. 7 Such an activity, however, is undetectable in preparations from untreated OVX rats, suggesting that physiological levels of circulating E 2 are essential for rapid vascular responses to be induced. 7,14 This likely occurs through regulation of the levels of ER and cellular effectors thereof, such as endothelial NO synthase (eNOS) after E 2 administration.…”

“…12 The 2 ER isoforms not only are differentially modulated by circulating hormones but also mediate distinct actions in the vascular wall. In fact, ER␣ conveys both short-term effects including endothelial dilation 7 and long-term anti-inflammatory actions of E 2 . 13 In this regard, we demonstrated previously that ER␣-selective agonists, unlike ER␤-selective agonists, induce acute vascular relaxation in the aorta from intact female or E 2 -replaced ovariectomized (OVX) rats.…”

“…We demonstrated previously that ovariectomy abolishes acute estrogen dilation, which is restored by timely E 2 replacement. 7 Thus, vascular relaxation is a primary target of estrogen action in the vessel wall. This is known to occur through rapid stimulation of NO production and modulation of NO synthase genes.…”

Pharmacology in Health Foods: Improvement of Vascular Endothelial Function by French Maritime Pine Bark Extract (Flavangenol)

“…Some flavonoids derived from natural compounds, such as genistein, daidzein, and apigenin, have been shown to compete with 17β-estradiol for binding to the estrogen receptor, acting as phytoestrogens (25). Thus, the vasorelaxant activities of Flavangenol may result from the activation of the estrogen receptor, which is known to induce the enhancement of the eNOS activity (26,27) and NO-mediated vasorelaxation (28). However, preincubation with the estrogen-receptor antagonist ICI 182,780 did not modify the vasorelaxant responses to Flavangenol.…”