Roles of Estrogen in the Formation of Intracranial Aneurysms in Ovariectomized Female Mice

Tada, Yasuyuki; Makino, Hiroshi; Furukawa, Hajime; Shimada, Kenji; Wada, Kodai; Liang, Elena I.; Murakami, Shoko; Kudo, Mari; Kung, David; Hasan, David; Kitazato, Keiko T.; Saijo, Nagahiro; Lawton, Michael T.; Hashimoto, Tomoki

doi:10.1227/neu.0000000000000528

Cited by 56 publications

(56 citation statements)

References 33 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%

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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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“…Other possible pathophysiological causes should be further actively explored. Our results may have practical implications for the on-going efforts to development of using estrogen, either alone or in combination with progestogen, to reduce the risk of screening detected cerebral aneurysms from rupture (11)(12)(13)(14). …”

Section: Discussionmentioning

confidence: 87%

“…Clinical trials show hormone replacement therapy (HRT) seems to be associated with a reduced risk for aneurysmal SAH (12,13). Experimental study also demonstrated a sex-specific hormonal factor may play a role in the pathogenesis of aneurysm formation and rupture (14,15). Because it is a relatively common cause of stroke in women under age 65 and because of its high morbidity and mortality, the excess of aneurysmal SAH in women remains a pressing question in stroke research.…”

Section: Introductionmentioning

confidence: 99%

A higher aneurysmal subarachnoid hemorrhage incidence in women prior to menopause: a retrospective analysis of 4,895 cases from eight hospitals in China

Wáng

Zhang

et al. 2016

Quant. Imaging Med. Surg.

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Background: Subarachnoid hemorrhage (SAH) from a ruptured cerebral aneurysm is a devastating disease.Despite the risk factors, including hypertension, cigarette smoking and alcohol use, are more common in men, aneurysmal SAH belongs to a few diseases which the incidence is higher in women than in men. Sex hormones, especially estrogen, might be protective against this condition. Hormone replacement therapy (HRT) seems to be associated with a reduced risk for aneurysmal SAH. This study aims to know the prevalence of aneurysmal SAH of men and women at different ages. Methods:The age and gender information of 4,895 case of aneurysmal SAH (3,016 females, 1,879 males) were collected retrospectively from eight institutions in mainland China. The prevalence of aneurysmal SAH of men and women at different ages was analyzed.Results: The data showed women had a higher incidence of aneurysmal SAH than men starting at late thirties, and men might have a higher incidence of aneurysmal SAH than women only before 37-year-old.Conclusions: Menopause may not be the only dominant factor causing higher incidence of aneurysmal SAH in women than in men. Quant Imaging Med Surg 2016;6(2):151-156 qims.amegroups.com the short-term and long-term risks of aneurysmal rupture with the risk associated with the intervention, whether it would be surgical clipping or endovascular management. Controversy remains regarding optimum management, and thorough assessments of the risks and benefits of contemporary management options, specific to aneurysm size, location, and many other aneurysm and patient factors, are needed. Endovascular management options continue to improve as micro-catheter technology advances and newer devices and embolic materials are developed. The most commonly used endovascular option is the Guglielmi detachable coil system. This system allows delivery of soft platinum coils into intracranial aneurysms. Overall, clinical trial data showed better recovery data with patients treated endovascularly than treated surgically (3). Findings from several studies also suggested that cerebral aneurysm rupture risk is reduced in patients taking aspirin (4). Recent data support long-term serial screening in individuals with a family history of aneurysmal SAH (5).Despite the risk factors, including hypertension, cigarette smoking and alcohol use, are more common in men, aneurysmal SAH belongs to a few diseases which the incidence is higher in women than in men (1-3,6,7). Women have a significantly higher risk for de novo cerebral aneurysm formation than men in a long-term follow-up study, being female is a significant independent risk factor for aneurysm growth; and women are more likely than men to have multiple cerebral aneurysms (7-9). It has been noted that the incidence was higher in younger men, whereas after the age of 55, the incidence was higher in women (2). Furthermore, earlier age at menopause may be associated with a greater risk of cerebral aneurysm (10). Therefore, a sex-specific hormonal factor may play a role in the pathogen...

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“…Epidemiological studies show that the female preponderance of intracranial aneurysms becomes significant only after the fourth or fifth decade, during the perimenopausal and postmenopausal periods. Moreover, estrogen has a protective effect against vascular injury [46] and hormone-replacement therapy has been shown to be a protective factor for subarachnoid hemorrhage [47].…”

Section: Epidemiological Aspectsmentioning

confidence: 99%

Carotid Intern Aneurysms

Waihrich¹,

Parente²,

Gonçalves³

et al. 2019

Carotid Artery - Gender and Health [Working Title]

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Cerebral aneurysms (CA) are acquired lesions, affecting 5-10% of the population, being about three times more common in women than in men. The absolute majority of CA is asymptomatic. However, in symptomatic cases, cerebral aneurysms present without about 80% of cases with severe intracranial hemorrhage, with mortality up to 50% and severe morbidity of up to 80%. At this point, the carotid siphon is particularly important because it is the blood gateway to the anterior cerebral circulation, being the most sinuous portion of the internal carotid artery, and because it houses about 30% of the intracranial aneurysm. The constant interactions of blood flow with carotid siphon curvatures are apparently intrinsically related to the epidemiology of these lesions in the various locations of the intracranial circulation and their presentation form. It is well established that a greater anterior knee angle has a significant independent relation with intracranial aneurysms located after carotid siphon, larger aneurysms, and greater risk of rupture. These findings may be associated with the hemodynamic interactions of blood flow and the curvature of carotid siphon. Little is known about the anatomical changes in carotid siphon and, consequently, the repercussions of the hemodynamic changes that the neurosurgical interventions mechanisms could entail. Devices such as intracranial stents, detachable coils, and even clips of aneurysms can modify the morphology of carotid siphon, and the knowledge of these consequences could be used to obtain better therapeutic results. In the last 10 years, a new device for the treatment of intracranial aneurysms has been presenting promising results, flow diverters stents (FDS), and its use to treat aneurysms in carotid siphon appears to cause morphological changes characterized by increased anterior and posterior angles. Specifically, the anterior angle increase was associated with better angiographic results. Aneurysms of the extracranial carotid artery (ECAA) are rare and little is known about its natural history. The etiology is diverse and most ECAA are asymptomatic, but they may progress to a pulsatile mass, cranial nerve compression, or cause a stroke. ECAA treatment is still controversial and a better insight into natural history and risk of complications of the different treatments is needed in order to get the consensus.

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Roles of Estrogen in the Formation of Intracranial Aneurysms in Ovariectomized Female Mice

Cited by 56 publications

References 33 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

A higher aneurysmal subarachnoid hemorrhage incidence in women prior to menopause: a retrospective analysis of 4,895 cases from eight hospitals in China

Carotid Intern Aneurysms

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