Upregulation of estrogen receptor α and mediation of 17β-estradiol vasoprotective effects via estrogen receptor α in basilar arteries in rats after experimental subarachnoid hemorrhage

2008 ◽  
Vol 109 (1) ◽  
pp. 92-99 ◽  
Author(s):  
Huei-Chuan Shih ◽  
Chih-Lung Lin ◽  
Shu-Chuan Wu ◽  
Aij-Lie Kwan ◽  
Yi-Ren Hong ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Estrogen Receptor ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Estrogen Receptor Α ◽  
Male Rats ◽  
Enos Expression ◽  
Basilar Arteries ◽  
17Β Estradiol ◽  
Oxide Synthase

Object The authors previously demonstrated that 17β-estradiol benzoate (E2) treatment prevents subarachnoid hemorrhage (SAH)–induced cerebral vasospasm and preserves endothelial nitric oxide synthase (eNOS) in male rats. Changes in the expression of estrogen receptor (ER) subtypes ERα and -β and their roles in the E2-mediated preservation of eNOS in SAH remain unknown. In the present study the effects of SAH on the expression of ERα and -β in the cerebral arteries were clarified, and the receptor roles in the E2-mediated preservation of eNOS expression in SAH were differentiated. Methods A 2-hemorrhage SAH model was induced by 2 autologous blood injections into the cisterna magna of adult male rats. The effect of SAH on ERα and -β expression was evaluated. Other rats subcutaneously received implanted Silastic tubes containing corn oil with E2 and daily injections of various doses of an ERα- (methyl-piperidinopyrazole [MPP]) or ERβ-selective antagonist (R,R-tetrahydrochrysene) after the first hemorrhage. The protein levels of ERα, ERβ, eNOS, and inducible nitric oxide synthase (iNOS) from basilar arteries were examined using Western blot analysis, and their mRNAs were evaluated by reverse transcription–polymerase chain reaction. Results The ERα but not the ERβ was upregulated in the basilar artery after SAH. Treatment with MPP eliminated E2-mediated effects in SAH, relieved cerebral vasospasm, preserved eNOS expression, and suppressed iNOS expression. Conclusions Estrogen receptor α is upregulated in the basilar artery after SAH. Note that E2 exerts its protective effects through ERα-dependent pathways to relieve cerebral vasospasm and preserve eNOS expression. A selective ERα agonist may be the drug of choice for the treatment of patients with SAH.

Salutary effects of 17β-estradiol on T-cell signaling and cytokine production after trauma-hemorrhage are mediated primarily via estrogen receptor-α

2007 ◽  
Vol 292 (6) ◽  
pp. C2103-C2111 ◽  
Author(s):  
Takao Suzuki ◽  
Tomoharu Shimizu ◽  
Huang-Ping Yu ◽  
Ya-Ching Hsieh ◽  
Mashkoor A. Choudhry ◽  
...  
Keyword(s):  
T Cells ◽  
Estrogen Receptor ◽  
T Cell ◽  
Signaling Pathways ◽  
Cytokine Production ◽  
Estrogen Receptor Α ◽  
Male Rats ◽  
17Β Estradiol ◽  
Ifn Γ ◽  
Cell Cytokine Production

Although 17β-estradiol (E2) administration following trauma-hemorrhage prevents the suppression in splenocyte cytokine production, it remains unknown whether the salutary effects of 17β-estradiol are mediated via estrogen receptor (ER)-α or ER-β. Moreover, it is unknown which signaling pathways are involved in 17β-estradiol's salutary effects. Utilizing an ER-α- or ER-β-specific agonist, we examined the role of ER-α and ER-β in E2-mediated restoration of T-cell cytokine production following trauma-hemorrhage. Moreover, since MAPK, NF-κB, and activator protein (AP)-1 are known to regulate T-cell cytokine production, we also examined the activation of MAPK, NF-κB, and AP-1. Male rats underwent trauma-hemorrhage (mean arterial pressure 40 mmHg for 90 min) and fluid resuscitation. ER-α agonist propyl pyrazole triol (PPT; 5 μg/kg), ER-β agonist diarylpropionitrile (DPN; 5 μg/kg), 17β-estradiol (50 μg/kg), or vehicle (10% DMSO) was injected subcutaneously during resuscitation. Twenty-four hours thereafter, splenic T cells were isolated, and their IL-2 and IFN-γ production and MAPK, NF-κB, and AP-1 activation were measured. T-cell IL-2 and IFN-γ production was decreased following trauma-hemorrhage, and this was accompanied with a decrease in T-cell MAPK, NF-κB, and AP-1 activation. PPT or 17β-estradiol administration following trauma-hemorrhage normalized those parameters, while DPN administration had no effect. Since PPT, but not DPN, administration following trauma-hemorrhage was as effective as 17β-estradiol in preventing the T-cell suppression, it appears that ER-α plays a predominant role in mediating the salutary effects of 17β-estradiol on T cells following trauma-hemorrhage, and that such effects are likely mediated via normalization of MAPK, NF-κB, and AP-1 signaling pathways.

scholarly journals Endothelial Nitric Oxide Synthase Gene Single-Nucleotide Polymorphism Predicts Cerebral Vasospasm after Aneurysmal Subarachnoid Hemorrhage

2008 ◽  
Vol 28 (6) ◽  
pp. 1204-1211 ◽  
Author(s):  
Robert M Starke ◽  
Grace H Kim ◽  
Ricardo J Komotar ◽  
Zachary L Hickman ◽  
Eric M Black ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Subarachnoid Hemorrhage ◽  
Nitric Oxide Synthase ◽  
Cerebral Vasospasm ◽  
Endothelial Nitric Oxide Synthase ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Enos Gene ◽  
Single Nucleotide ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Vasospasm is a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). Studies have shown a link between single-nucleotide polymorphisms (SNPs) in the endothelial nitric oxide synthase (eNOS) gene and the incidence of coronary spasm and aneurysms. Alterations in the eNOS T-786 SNP may lead to an increased risk of post-aSAH cerebral vasospasm. In this prospective clinical study, 77 aSAH patients provided genetic material and were followed for the occurrence of vasospasm. In multivariate logistic regression analysis, genotype was the only factor predictive of vasospasm. The odds ratio (OR) for symptomatic vasospasm in patients with one T allele was 3.3 (95% confidence interval (CI): 1.1 to 10.0, P=0.034) and 10.9 for TT. Patients with angiographic spasm were 3.6 times more likely to have a T allele (95% CI: 1.3 to 9.6, P=0.013; for TT: OR 12.6). Patients with severe vasospasm requiring endovascular therapy were more likely to have a T allele (OR 3.5, 95% CI: 1.3 to 9.5, P=0.016; for TT: OR 12.0). Patients with the T allele of the eNOS gene are more likely to have severe vasospasm. Presence of this genotype may allow the identification of individuals at high risk for post-aSAH vasospasm and lead to early treatment and improved outcome.

scholarly journals Estrogen Modulates Endothelial and Neuronal Nitric Oxide Synthase Expression via an Estrogen Receptor β-Dependent Mechanism in Hypothalamic Slice Cultures

Endocrinology ◽  
2005 ◽  
Vol 146 (7) ◽  
pp. 2933-2941 ◽  
Author(s):  
Sarah Gingerich ◽  
Teresa L. Krukoff
Keyword(s):  
Nitric Oxide ◽  
Estrogen Receptor ◽  
Female Rats ◽  
Inhibitory Effects ◽  
17Β Estradiol ◽  
Hypothalamic Slice ◽  
Blood Pressure Responses ◽  
Induced Changes ◽  
Oxide Synthase ◽  
Brain Nitric Oxide

Abstract Although it is evident that estrogen has important physiological effects in the brain, the signaling mechanisms mediating these effects remain unclear. We recently showed that estrogen mediates attenuated blood pressure responses to psychological stress in ovariectomized female rats through brain nitric oxide (NO). An area likely to mediate these effects is the hypothalamic paraventricular nucleus (PVN), because here NO exerts inhibitory effects on autonomic output to the periphery. Because little is known about how estrogen acts on the NO system in the PVN, our aim was to study the effects of estrogen on the NO system in the PVN of hypothalamic slices cultures. We show that 17β-estradiol (E2; 1 nm) increases endothelial NO synthase (eNOS) protein expression and decreases the numbers of neuronal NOS (nNOS)-positive neurons in the PVN after 8 and 24 h, respectively. Using the nonselective estrogen receptor (ER) antagonist, ICI 182,780 (10 nm), we determined that E2-induced changes in NOS expression in the PVN are ER dependent. Using the ERβ agonist, genistein (0.1 μm), we determined that activation of ERβ induces increased eNOS expression and a decreased number of nNOS-positive neurons. We used the selective ERα agonist, propyl-pyrazole-triol (10 nm), and antagonist, methyl-piperidino-pyrazole (1 μm), to exclude the possibility that ERα is involved in the E2-induced increase in eNOS and nNOS in the PVN. These results demonstrate that E2 induces changes in NOS expression in the PVN and that these effects are ERβ dependent.

scholarly journals Estrogen receptor α mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen

1999 ◽  
Vol 103 (3) ◽  
pp. 401-406 ◽  
Author(s):  
Zhong Chen ◽  
Ivan S. Yuhanna ◽  
Zoya Galcheva-Gargova ◽  
Richard H. Karas ◽  
Michael E. Mendelsohn ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Estrogen Receptor ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Estrogen Receptor Α ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Estrogen receptor-α predominantly mediates the salutary effects of 17β-estradiol on splenic macrophages following trauma-hemorrhage

2007 ◽  
Vol 293 (3) ◽  
pp. C978-C984 ◽  
Author(s):  
Takao Suzuki ◽  
Tomoharu Shimizu ◽  
Huang-Ping Yu ◽  
Ya-Ching Hsieh ◽  
Mashkoor A. Choudhry ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Signaling Pathways ◽  
Cytokine Production ◽  
Estrogen Receptor Α ◽  
Male Rats ◽  
Splenic Macrophage ◽  
Splenic Macrophages ◽  
Tnf Α ◽  
17Β Estradiol ◽  
Macrophage Cytokine

Although 17β-estradiol administration following trauma-hemorrhage prevents the suppression in splenic macrophage cytokine production, it remains unknown whether the salutary effects are mediated via estrogen receptor (ER)-α or ER-β and which signaling pathways are involved in such 17β-estradiol effects. Utilizing ER-α- or ER-β-specific agonists, this study examined the role of ER-α and ER-β in 17β-estradiol-mediated restoration of macrophage cytokine production following trauma-hemorrhage. In addition, since MAPK and NF-κB are known to regulate macrophage cytokine production, we also examined the activation of those signaling molecules. Male rats underwent trauma-hemorrhage (mean arterial pressure of 40 mmHg for 90 min) and fluid resuscitation. The ER-α agonist propyl pyrazole triol (PPT; 5 μg/kg), the ER-β agonist diarylpropionitrile (DPN; 5 μg/kg), 17β-estradiol (50 μg/kg), or vehicle (10% DMSO) was injected subcutaneously during resuscitation. Twenty-four hours thereafter, splenic macrophages were isolated, and their IL-6 and TNF-α production and activation of MAPK and NF-κB were measured. Macrophage IL-6 and TNF-α production and MAPK activation were decreased, whereas NF-κB activity was increased, following trauma-hemorrhage. PPT or 17β-estradiol administration after trauma-hemorrhage normalized those parameters. DPN administration, on the other hand, did not normalize the above parameters. Since PPT but not DPN administration following trauma-hemorrhage was as effective as 17β-estradiol in preventing the suppression in macrophage cytokine production, it appears that ER-α plays the predominant role in mediating the salutary effects of 17β-estradiol on macrophage cytokine production following trauma-hemorrhage and that such effects are likely mediated via normalization of MAPK but not NF-κB signaling pathways.

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