Diabetes abolishes the vascular protective effects of estrogen in female rats

Bolego, Chiara; Cignarella, Andrea; Zancan, Valeria; Pinna, Christian; Zanardo, Rossella; Puglisi, L.

doi:10.1016/s0024-3205(98)00615-8

Cited by 37 publications

(24 citation statements)

References 28 publications

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“…Each group received subcutaneous implant of 2 silastic capsules containing 25 L of vehicle (peanut oil) or E 2 (235 g/mL; 0.86 mmol/L) for 5 days before sacrifice. 16,17 Plasma E 2 concentrations after treatment approached the normal rat proestrus level. 16 All of the procedures were performed in accordance with the guidelines for laboratory animal care of Milan University.…”

Section: Animal Protocolmentioning

confidence: 88%

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

et al. 2008

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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...

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Section: Animal Protocolmentioning

confidence: 88%

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

et al. 2008

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“…anesthesia. Four weeks later, the castrated animals received a subcutaneous implant of two silastic capsules containing 25 l of vehicle (peanut oil) or E 2 (5.87 g; 0.86 mM) for 5 days (Bolego et al, 1999;Cignarella et al, 2000). Plasma E 2 concentrations after this treatment approached the normal rat proestrus level (Lapchak, 1991).…”

Section: Methodsmentioning

confidence: 99%

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

Bolego

Cignarella²,

Sanvito³

et al. 2005

J Pharmacol Exp Ther

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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...

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“…In the general (nondiabetic) population, cardiovascular diseases are more frequent in men than in premenopausal women (21,22). However, diabetes may produce a greater impairment in the female cardiovascular system, with the result that the above difference between men and premenopausal women disappears in diabetic patients (23). Indeed, type 2 diabetes has been reported to negate the protective cardiovascular effects of female gender (24 -26).…”

Section: Introductionmentioning

confidence: 99%

Gender Differences in Endothelial Function in Aortas From Type 2 Diabetic Model Mice

et al. 2009

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Abstract. Type 2 diabetes mellitus is associated with high mortality and morbidity, mainly due to coronary artery disease and atherosclerosis, although female gender is a protective factor in the development of, for example, atherosclerosis and hypertension. Our main aim was to investigate gender differences in endothelial function in aortas from type 2 diabetic model mice. The nonfasting plasma glucose level was significantly elevated in diabetic mice (both males and females). The plasma insulin level was not different between controls and diabetics (either gender). The plasma adiponectin level was decreased by diabetes, and was lower in males. In control aortas (from males or females), the clonidine-induced relaxation was abolished by Aktinhibitor treatment. In diabetic males (versus both control males and diabetic females): a) the clonidine-and insulin-induced endothelium-dependent aortic relaxations were impaired, but the acetylcholine (ACh)-induced and sodium nitroprusside (SNP)-induced aortic relaxations were not, b) the norepinephrine (NE)-induced aortic contractile response was enhanced, c) systemic blood pressure was elevated, and d) the clonidine-stimulated Ser-473 phosphorylation of Akt in the aorta was decreased. These results suggest that endothelial functions dependent on the Akt pathway are abrogated by type 2 diabetes only in male mice.

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Diabetes abolishes the vascular protective effects of estrogen in female rats

Cited by 37 publications

References 28 publications

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

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

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

Gender Differences in Endothelial Function in Aortas From Type 2 Diabetic Model Mice

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