Estrogen enhances vasoconstrictive remodeling after injury in male rabbits

Francisco, Yoná Afonso; Dantas, Ana Paula; Carvalho, Maria Helena Catelli de; Laurindo, Frm

doi:10.1590/s0100-879x2005000900006

Cited by 5 publications

(4 citation statements)

References 18 publications

(20 reference statements)

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“…5). These findings somewhat agree with prior reports suggesting that the ER regulates eNOS transcription to some extent (31,33) and another that showed that in a rabbit iliac artery injury model, its regulation of iNOS transcription is more pronounced than its effects on eNOS mRNA levels (16).…”

Section: Discussionsupporting

confidence: 93%

Essential role of ER-α-dependent NO production in resveratrol-mediated inhibition of restenosis

Khandelwal

Hebert

Dugas

2010

American Journal of Physiology-Heart and Circulatory Physiology

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veratrol (Resv), a red wine polyphenol, is known to exhibit vascular protective effects and reduce vascular smooth muscle cell mitogenesis. Vascular smooth muscle cell proliferation is a critical factor in the pathogenesis of restenosis, the renarrowing of vessels that often occurs after angioplasty and/or stent implantation. Although Resv has been shown to be an estrogen receptor (ER) modulator, the role of the ER in Resv-mediated protection against restenosis has not yet been elucidated in vivo. Therefore, with the use of a mouse carotid artery injury model, our objective was to determine the role of ER in modulating Resv-mediated effects on neointimal hyperplasia. Female wild-type and ER-␣ Ϫ/Ϫ mice were administered a high-fat diet Ϯ Resv for 2 wk. A carotid artery endothelial denudation procedure was conducted, and the mice were administered a high-fat diet Ϯ Resv for an additional 2 wk. Resv-treated wild-type mice exhibited a dramatic decrease in restenosis, with an increased arterial nitric oxide (NO) synthase (NOS) activity and NO production. However, in the ER-␣ Ϫ/Ϫ mice, Resv failed to afford protection and failed to increase NO production, apparently because of a decreased availability of the NOS cofactor tetrahydrobiopterin. To verify the role of NO in Resvmediated effects, mice were coadministered Resv plus a nonselective NOS inhibitor, N G -nitro-L-arginine methyl ester (L-NAME). Cotreatment with L-NAME significantly attenuated the antirestenotic properties of Resv. These data thus suggest that Resv inhibits vascular proliferative responses after injury, predominately through an ER-␣-dependent increase in NO production. estrogen receptor; nitric oxide RESTENOSIS, or vessel renarrowing, is a major limiting factor in patients undergoing angioplasty and/or stent implantation (25). The primary cause for restenosis is neointimal formation, characterized by abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) from the media of the vessel wall to the intima (32). Thus the inhibition of VSMC proliferation can potentially inhibit restenosis. Several clinical studies have demonstrated an increased risk for developing cardiovascular disorders in postmenopausal compared with premenopausal women (29). This suggests an important role for estrogen and estrogen receptors (ERs) in the increased incidence of cardiovascular disorders in postmenopausal women. Several rodent studies have assessed the efficacy of 17␤-estradiol, a synthetic estrogen, in inhibiting restenosis. A mechanism by which the ERs modulate vascular function is via an ER-dependent increase in nitric oxide (NO) synthase (NOS) activity and NO production, occurring through both genomic and nongenomic mechanisms (2,8,26).According to the French paradox, epidemiological evidence demonstrating a decreased incidence in cardiovascular disorders among French populations consuming high amounts of saturated fat was associated with a daily consumption of red wine. Resveratrol (Resv) is a red wine polyphenol believed to be a key contribut...

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Section: Discussionsupporting

confidence: 93%

Essential role of ER-α-dependent NO production in resveratrol-mediated inhibition of restenosis

Khandelwal

Hebert

Dugas

2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…The increase of collagen type III in response to estrogen administration was found in hearts of aged and Dahl salt-sensitive rats (8,61). Similar estrogenic effects on collagen III were demonstrated in the arteries and other tissues of ovariectomized animals (7,10,15,24,36,47). The mechanisms of enhanced collagen type III expression due to estrogen treatment are still unknown, but they are likely related to the changes in MMPs and TIMPs expression that we Fig.…”

Section: Discussionsupporting

confidence: 77%

Estrogen improves TIMP-MMP balance and collagen distribution in volume-overloaded hearts of ovariectomized females

Voloshenyuk

Gardner

2010

American Journal of Physiology-Regulatory, Integrative and Comp

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Our previous studies demonstrate that 17␤-estradiol limits chronic volume overload-induced hypertrophy and improves heart function in ovariectomized rats. One possible cardioprotective mechanism involves the interaction between estrogen, estrogen receptors, and proteins of the extracellular matrix (ECM). The impact of estrogen deficiency and replacement on left ventricular (LV) hypertrophy and ECM protein expression was studied using five female rat groups: intact sham-operated, ovariectomized sham-operated, intact with volume overload, ovariectomized with volume overload, and ovariectomized with volume overload treated with estrogen. After 8 wk, LV protein extracts were evaluated by Western blot analysis for matrix metalloproteinase-2 (MMP-2) and MMP-9, MT1-MMP, tissue inhibitors of MMPs (TIMP)-1, TIMP-2, TIMP-3 and TIMP-4, collagens type I and III, and estrogen receptor ␣ and ␤ expression. MMP proteolytic activity was assessed by zymography. All volume-overloaded groups exhibited LV hypertrophy, which was associated with a loss of interstitial collagen and perivascular fibrosis. After 8 wk of volume overload, 70% of ovariectomized rats developed heart failure, in contrast to only one intact rat. A downregulation of MMP-2, estrogen receptor-␣ (ER␣), and ER␤, and upregulation of MMP-9 and MT1-MMP were found in the volume-overloaded hearts of ovariectomized rats. Estrogen treatment improved TIMP-2/MMP-2 and TIMP-1/MMP-9 protein balance, restored ER␣ expression, and prevented MMP-9 activation, perivascular collagen accumulation and development of heart failure. However, estrogen did not fully restore ER␤ expression and did not prevent the increase of MMP-9 expression or loss of interstitial collagen. These results support that estrogen limits undesirable ECM remodeling and LV dilation, in part, through modulation of ECM protein expression in volume-overloaded hearts of ovariectomized rats. extracellular matrix remodeling; ovariectomy; gender; hypertrophy; hormone; collagen; MT1-MMP; ventricle THE RISKS AND BENEFITS ASSOCIATED with estrogen replacement therapy remain uncertain. Conflicting results regarding the effect of estrogen replacement on the outcome of cardiovascular disease have been obtained from population studies, animal models, and clinical trials (2,16,20,21,32,33,61). The inconsistency of these findings demonstrates the lack of understanding of the mechanisms by which estrogen exerts its beneficial effects on the cardiovascular system. Using a rodent model, we demonstrated that hearts of intact female rats are resistant to chronic volume overload-induced adverse cardiac remodeling and dysfunction (12). This apparent cardioprotection is lost following ovariectomy (6). Estrogen replacement delays the development of left ventricular (LV) hypertrophy and dilation, and it prevents the onset of congestive heart failure (CHF) in ovariectomized rats with volume overload (13). However, the mechanisms of estrogen's protective effects in prevention of adverse myocardial remodeling remain unclear.Changes in extra...

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“…Other studies have suggested that E2 alters vessel structure in the periphery. It should be noted however that most of the studies documenting an effect E2 on vessel structure require some type of vessel injury (Liu et al 2002; Yuan et al 2002; Francisco et al 2005), hypertension (Garcia et al 2005; Garcia et al 2006) or aging (Zhang et al 2000). …”

Section: Discussionmentioning

confidence: 99%

Effect of high soy diet on the cerebrovasculature and endothelial nitric oxide synthase in the ovariectomized rat

Schreihofer

Deutsch

Lovekamp-Swan

et al. 2010

Vascular Pharmacology

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High soy (HS) diets are neuroprotective and promote vascular dilatation in the periphery. We hypothesized that a HS diet would promote vascular dilatation in the cerebrovasculature by mimicking estradiol's actions on the endothelial nitric oxide synthase (eNOS) system including increasing eNOS expression and decreasing caveolin-1 expression to increase nitric oxide (NO) production. Ovariectomized rats were fed HS or a soy-free diet (SF) ± low physiological estradiol (E2) for 4 weeks. Neither E2 nor HS altered middle cerebral artery (MCA) structure or vascular responses to acetylcholine, serotonin, or phenylephrine. Estradiol enhanced bradykinin-induced relaxation in an eNOS-dependent manner. Although E2 and HS increased eNOS mRNA expression in the brain and cerebrovasculature, they had no effect on eNOS protein expression or phosphorylation in the MCA. However, E2 decreased caveolin-1 protein in the MCA. In MCAs neither E2 nor HS altered estrogen receptor (ER) alpha expression, but E2 did reduce ER beta levels. These data suggest that HS diets have no effect on vascular NO production, and that E2 may modulate basal NO production by reducing the expression of caveolin-1, an allosteric inhibitor of NOS activity. However, the effects of E2 and HS on the cerebrovasculature are small and may not underlie their protective actions in pathological states.

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Estrogen enhances vasoconstrictive remodeling after injury in male rabbits

Cited by 5 publications

References 18 publications

Essential role of ER-α-dependent NO production in resveratrol-mediated inhibition of restenosis

Essential role of ER-α-dependent NO production in resveratrol-mediated inhibition of restenosis

Estrogen improves TIMP-MMP balance and collagen distribution in volume-overloaded hearts of ovariectomized females

Effect of high soy diet on the cerebrovasculature and endothelial nitric oxide synthase in the ovariectomized rat

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