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...
Abstract-The vascular consequences of estrogen treatment may be driven by its initiation timing. We tested the hypothesis that the duration of ovarian hormone deprivation before estrogen reintroduction affects the role of estrogen as mediator of endothelial function and vascular relaxation in nondiseased vessels. Rats were ovariectomized and implanted with 17-estradiol (E 2 ) or oil capsules 1, 4, and 8 months after surgery. After the longest hypoestrogenicity period, acetylcholine-mediated aortic relaxation was attenuated and insensitive to E 2 administration despite endothelial integrity. Whereas no rapid vasorelaxant responses were elicited by an estrogen receptor (ER) -selective agonist, responses to E 2 and an ER␣ selective agonist waned postovariectomy at any given time and were restored by E 2 treatment after 1 and 4 months but not 8 months postovariectomy. Accordingly, endothelial ER␣ mRNA and protein expression declined Ϸ6-fold after prolonged hypoestrogenicity and was restored by estrogen replacement starting 1 month but not 8 months postovariectomy. Furthermore, the amount of active phosphorylated endothelial NO synthase rose significantly after E 2 replacement after 1 and 4 months but not 8 months postovariectomy. The present findings document that the functional impairment of the ER␣/endothelial NO synthase signaling network after an extended period of hypoestrogenicity was not restored by E 2 administration, providing experimental support to early initiation of estrogen replacement with preferential ER␣ targeting to improve cardiovascular outcomes. Key Words: endothelium Ⅲ hormones Ⅲ pharmacology Ⅲ NO synthase Ⅲ receptors I n spite of a large body of preclinical studies attesting beneficial actions of estrogenic treatment on the cardiovascular system, large clinical trials of hormone therapy so far have failed to improve clinical outcomes (reviewed in Reference 1). In attempting to explain the apparent discrepancy between experimental and clinical results, the timing of treatment initiation has been deemed a critical factor. The timing hypothesis proposes that the earlier an estrogenic treatment starts, the more likely it is of being successful, because the time since menopause is a major risk factor for the development and progression of atherosclerosis. 2,3 This is consistent with observations that cyclic or permanent changes in circulating concentrations of estrogen in premenopausal and postmenopausal women, respectively, affect vascular responses. 4,5 Of note, estrogen deprivation in rats time-dependently impairs endothelial function, as assessed by the loss of acetylcholine-mediated dilation, but this response is restored by early 17-estradiol (E 2 ) replacement. 6 In addition, estrogen affects endothelial vasomotor responses per se. 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 o...
Estrogen is known to affect vascular function and diabetes development, but the relative contribution of estrogen receptor (ER) isoforms is unclear. The aim of this study was to determine how individual ER isoforms modulate inflammatory enzymes in the vascular wall of control and streptozotocin (STZ)-injected rodents. Primary cultures of rat aortic smooth muscle cells (SMCs) were stimulated with inflammatory agents in the presence or absence of increasing concentrations of the ER␣ and ER-selective agonists 4,4Ј,4ЈЈ-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) and diarylpropionitrile (DPN), respectively. The production of inducible nitric-oxide synthase (iNOS), a classical indicator of vascular inflammation, was significantly reduced by PPT in control but not diabetic SMCs, whereas it was further enhanced by DPN treatment in both groups. This distinct action profile was not related to changes in ER transcriptional activity. However, extracellular signal-regulated kinase 1/2 signaling was activated by DPN but not by PPT in cytokine-treated SMCs. In cultured aortic rings from both normoglycemic and STZ-diabetic mice, pharmacological activation of ER␣ attenuated cytokine-driven iNOS induction by 30 to 50%. Vascular iNOS levels were decreased consistently when adding 1 nM 17-estradiol to aortic tissues from ER-but not ER␣-knockout mice. These findings suggest a possible role for ER␣-selective ligands in reducing vascular inflammatory responses under normo-and hyperglycemic conditions. Recent large-scale clinical trials found a significantly lower incidence of diabetes in postmenopausal women on hormone replacement therapy despite no improvement in vascular outcomes (Kanaya et al., 2003; Margolis et al., 2004). The mechanisms accounting for this outcome, however, are largely unknown, although estrogen is increasingly recognized as an important regulator of glucose homeostasis Le May et al., 2006). Because the endogenous hormone binds to its receptors with identical affinity, the metabolic effects of individual estrogen receptor (ER) isoforms, ER␣ and ER, are hard to differentiate and appear to be tissue-and speciesspecific. In accordance, there is little information as to how ER␣ and ER affect the course and timeline of diabetic vascular dysfunction, which ultimately results in macrovascular complications of clinical relevance. We previously demonstrated that anti-inflammatory activity of estrogen is impaired in vascular smooth muscle cells (SMCs) from streptozotocin (STZ)-diabetic rats, which display ER overexpression with respect to normoglycemic controls (Maggi et al., 2003). The biological significance of ER overexpression in vascular cells from diabetic rats is unclear. There have been concerns that ER-selective agonists may be diabetogenic , whereas they are effective anti-inflammatory agents in selected in vivo models of inflammation (Harris, 2007).Inducible nitric-oxide synthase (iNOS) is a well established marker of vascular inflammation (Bardell and MacLeod, 2001;Nagareddy et al., 200...
Previous studies reported the ability of raloxifene to acutely relax arterial and venous vessels, but the underlying mechanisms are controversial. Anti-inflammatory effects of the drug have been reported in nonvascular tissues. Therefore, the aim of this study was to investigate the nature of short-and longterm effects of raloxifene on selected aspects of vascular function in rat aorta. Isometric tension changes in response to raloxifene were recorded in aortic rings from ovariectomized female rats that underwent estrogen replacement, whereas long-term experiments were performed in isolated aortic smooth muscle cells (SMCs). Raloxifene (0.1 pM-0.1 M) induced acute vasorelaxation through endothelium-and nitric oxide (NO)-dependent, prostanoid-independent mechanisms. The relaxant response to raloxifene was significantly weaker than that to 17-estradiol and was sensitive to neither the nonselective estrogen receptor antagonist ICI 182,780 [7,4,5,5,sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol] nor a selective estrogen receptor (ER) ␣ antagonist. This rapid vasorelaxant effect was retained in aortic rings from rats treated with 0.1 mg/kg, but not 1 mg/kg, lipopolysaccharide, 4 h before sacrifice. In cultured aortic SMCs, raloxifene treatment (1 nM-1 M) for 24 h reduced inducible NO synthase activation in response to cytokines. This effect was prevented by the selective ER␣ antagonist and was associated with upregulation of ER␣ protein levels, which dropped markedly upon cytokine stimulation. These findings illustrate the relevance of classic ER-dependent pathways to the vascular anti-inflammatory effects rather than to the nongenomic vasorelaxation induced by raloxifene and may assist in the design of novel ER isoform-selective estrogen-receptor modulators targeted to the vascular system.Raloxifene is a selective estrogen-receptor modulator (SERM) approved for use in osteoporosis and has been suggested to be cardioprotective in women at high risk for coronary heart disease (Barrett-Connor et al., 2002), although these results were from post hoc analyses. In fact, the results of the recently completed RUTH (Raloxifene Use for The Heart) study indicate that treatment with raloxifene does not significantly affect the risk of coronary events in postmenopausal women at risk for coronary disease (Barrett-Connor et al., 2006). Thus, a more detailed understanding of raloxifene pharmacological action in vascular tissues is required to better define and unravel potential benefits of treatment with raloxifene and other SERMs.A certain number of studies have examined the direct effects of raloxifene on the vessel wall. It has been consistently shown that the drug acutely relaxes different arterial (Figtree et al., 1999;Tsang et al., 2004;Chan et al., 2005;Leung et al., 2005) and venous (Bracamonte et al., 2002;Chan et al., 2005) vessels from different animal species. A variety of underlying mechanisms, however, can be involved, including enhanced endothelial NO production (Figtree et al., 1999;Bracamonte et al., 200...
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