Estrogen Protects Against Intracranial Aneurysm Rupture in Ovariectomized Mice

Tada, Yasuyuki; Wada, Kodai; Shimada, Kenji; Makino, Hiroshi; Liang, Elena I.; Murakami, Shoko; Kudo, Mari; Shikata, Fumiaki; Pena‐Silva, Ricardo A.; Kitazato, Keiko T.; Hasan, David; Kanematsu, Yasuhisa; Saijo, Nagahiro; Hashimoto, Tomoki

doi:10.1161/hypertensionaha.114.03300

Cited by 64 publications

(81 citation statements)

References 30 publications

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“…Previous studies have shown that estrogen‐deficient rodents produce more aneurysms and that estrogen supplementation reverses this effect 5, 6, 7, 8. These previous studies do not corroborate what we observe clinically.…”

Section: Discussioncontrasting

confidence: 99%

“…Approximately 70% to 75% of aneurysms occur in women,2 with postmenopausal women having the highest risk for aneurysm rupture 3, 4. Several studies have investigated estrogen deficiency and CA5, 6, 7, 8; however, the mechanism remains unknown. Understanding the mechanisms of aneurysms, particularly estrogen signaling, is needed to identify novel therapeutic targets.…”

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confidence: 99%

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Estrogen Deficiency Promotes Cerebral Aneurysm Rupture by Upregulation of Th17 Cells and Interleukin‐17A Which Downregulates E‐Cadherin

Hoh

Rojas

et al. 2018

JAHA

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BackgroundEstrogen deficiency is associated with the development of cerebral aneurysms; however, the mechanism remains unknown. We explored the pathway of cerebral aneurysm development by investigating the potential link between estrogen deficiency and inflammatory factors.Methods and ResultsFirst, we established the role of interleukin‐17 (IL‐17)A. We performed a cytokine screen demonstrating that IL‐17A is significantly expressed in mouse and human aneurysms (P=0.03). Likewise, IL‐17A inhibition was shown to prevent aneurysm formation by 42% (P=0.02) and rupture by 34% (P<0.05). Second, we found that estrogen deficiency upregulates T helper 17 cells and IL‐17A and promotes aneurysm rupture. Estrogen‐deficient mice had more ruptures than control mice (47% versus 7%; P=0.04). Estradiol supplementation or IL‐17A inhibition decreased the number of ruptures in estrogen‐deficient mice (estradiol 6% versus 37%; P=0.04; IL‐17A inhibition 18% versus 47%; P=0.018). Third, we found that IL‐17A‐blockade protects against aneurysm formation and rupture by increased E‐cadherin expression. IL‐17‐inhibited mice had increased E‐cadherin expression (P=0.003). E‐cadherin inhibition reversed the protective effect of IL‐17A inhibition and increased the rate of aneurysm formation (65% versus 28%; P=0.04) and rupture (12% versus 0%; P=0.22). However, E‐cadherin inhibition alone does not significantly increase aneurysm formation in normal mice or in estrogen‐deficient mice. In cell migration assays, E‐cadherin inhibition promoted macrophage infiltration across endothelial cells (P<0.05), which may be the mechanism for the estrogen deficiency/IL‐17/E‐cadherin aneurysm pathway.ConclusionsOur data suggest that estrogen deficiency promotes cerebral aneurysm rupture by upregulating IL‐17A, which downregulates E‐cadherin, encouraging macrophage infiltration in the aneurysm vessel wall.

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Section: Discussioncontrasting

confidence: 99%

mentioning

confidence: 99%

Estrogen Deficiency Promotes Cerebral Aneurysm Rupture by Upregulation of Th17 Cells and Interleukin‐17A Which Downregulates E‐Cadherin

Hoh

Rojas

et al. 2018

JAHA

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“…3 In an experimental intracranial aneurysm mouse model, estrogen prevented aneurysmal rupture in ovariectomized mice. 30 The protective effect of estrogen seemed to occur through activation of estrogen receptor-b, a predominant subtype of estrogen receptor in human intracranial aneurysms and cerebral arteries. Hormone replacement therapy (HRT) was associated with reduced risk of spontaneous SAH in postmenopausal women in most 19,22 but not all case control studies.…”

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confidence: 99%

Hormone replacement therapy and the risk of subarachnoid hemorrhage in postmenopausal women

Qureshi¹,

Malik²,

Saeed³

et al. 2016

JNS

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T he risk of intracranial aneurysm formation and subarachnoid hemorrhage (SAH) is higher in postmenopausal women compared with premenopausal women. 8,13,18,19,28 Reduced levels of estrogen in postmenopausal women may increase the risk of aneurysm formation and rupture by reduction in collagen and elastin content and reduced elasticity of arterial walls. 3 In an experimental intracranial aneurysm mouse model, estrogen prevented aneurysmal rupture in ovariectomized mice. 30The protective effect of estrogen seemed to occur through activation of estrogen receptor-b, a predominant subtype of estrogen receptor in human intracranial aneurysms and cerebral arteries. Hormone replacement therapy (HRT) was associated with reduced risk of spontaneous SAH in postmenopausal women in most 19,22 but not all case control studies. 25 The Women's Health Initiative (WHI) randomized trial 33 assessed the effect of estrogen plus progestin on ischemic and hemorrhagic stroke in 608 women 50-79 years of age with an average follow-up of 5.6 years. There was a nonsignificant protective effect on hemorrhagic stroke (HR 0.82, 95% CI 0.43-1.56). However, the study was underpowered because there were only 10 SAH events among the randomized patients. A meta-analysis 24 found a small nonsignificant protective effect of HRT on risk of SAH (HR 0.8, 95% CI 0.57-1.04).We performed this study to determine the effect of abbreviatioNs HRT = hormone replacement therapy; RR = relative risk; SAH = subarachnoid hemorrhage; SE = standard error; WHI = Women's Health Initiative. obJective The incidence of subarachnoid hemorrhage (SAH) increases after menopause. Anecdotal data suggest that hormone replacement therapy (HRT) may reduce the rate of SAH and aneurysm formation in women. The goal of this study was to determine the effect of HRT on occurrence of SAH in a large prospective cohort of postmenopausal women. methods The data were analyzed for 93,676 women 50-79 years of age who were enrolled in the observational arm of the Women's Health Initiative Study. The effect of HRT on risk of SAH was determined over a period of 12 ± 1 years (mean ± SD) using Cox proportional hazards analysis after adjusting for potential confounders. Additional analysis was performed to identify the risk associated with "estrogen only" and "estrogen and progesterone" HRT among women. results Of the 93,676 participants, 114 (0.1%) developed SAH during the follow-up period. The rate of SAH was higher among women on active HRT compared with those without HRT used (0.14% vs 0.11%, absolute difference 0.03%, p < 0.0001). In unadjusted analysis, participants who reported active use of HRT were 60% more likely to suffer an SAH (RR 1.6, 95% CI 1.1-2.3). Compared with women without HRT use, the risk of SAH continued to be higher among women reporting active use of HRT (RR 1.5, 95% CI 1.0-2.2) after adjusting for age, systolic blood pressure, cigarette smoking, alcohol consumption, body mass index, race/ethnicity, diabetes, and cardiovascular disease. The risk of SAH was nonsignificantly h...

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“…Hormon estrogen juga dapat mencegah rupturnya aneurisma serebral melalui aktivasi reseptor estrogen-β yang merupakan subtipe reseptor estrogen yang dominan pada pembuluh darah otak (Tada et al, 2014).…”

Section: Metodeunclassified

Perbedaan Kadar Kolesterol Total Antara Penderita Stroke Iskemik Dan Stroke Hemoragik

Aini¹,

Pujarini²,

Nirlawati³

2017

Biomedika

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Estrogen Protects Against Intracranial Aneurysm Rupture in Ovariectomized Mice

Cited by 64 publications

References 30 publications

Estrogen Deficiency Promotes Cerebral Aneurysm Rupture by Upregulation of Th17 Cells and Interleukin‐17A Which Downregulates E‐Cadherin

Estrogen Deficiency Promotes Cerebral Aneurysm Rupture by Upregulation of Th17 Cells and Interleukin‐17A Which Downregulates E‐Cadherin

Hormone replacement therapy and the risk of subarachnoid hemorrhage in postmenopausal women

Perbedaan Kadar Kolesterol Total Antara Penderita Stroke Iskemik Dan Stroke Hemoragik

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