scholarly journals Roles of Phytoestrogen in the Pathophysiology of Intracranial Aneurysm

Stroke ◽  
2021 ◽  
Author(s):  
Kimihiko Yokosuka ◽  
Caleb Rutledge ◽  
Yoshinobu Kamio ◽  
Atsushi Kuwabara ◽  
Hiroki Sato ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Subarachnoid Hemorrhage ◽  
Intracranial Aneurysm ◽  
Protective Effect ◽  
Postmenopausal Women ◽  
Intracranial Aneurysms ◽  
Estrogen Receptor Β ◽  
Systemic Hypertension ◽  
Female Mice ◽  
Aneurysm Formation

Background and Purpose: The incidences of intracranial aneurysm and aneurysmal subarachnoid hemorrhage are high in postmenopausal women. Although population-based studies suggest that hormone replacement therapy is beneficial for postmenopausal women with intracranial aneurysms, estrogen replacement may no longer be recommended for the prevention of chronic diseases given its association with adverse outcomes, such as cancer and ischemic stroke. The isoflavone daidzein and its intestinal metabolite equol are bioactive phytoestrogens and potent agonists of estrogen receptors. Given their estrogenic properties, we investigated whether the isoflavones daidzein and equol are protective against the formation and rupture of intracranial aneurysms in a mouse model of the postmenopausal state. Methods: We induced intracranial aneurysms in ovariectomized adult female mice using a combination of induced systemic hypertension and a single injection of elastase into the cerebrospinal fluid. We fed the mice with an isoflavone-free diet with/without daidzein supplementation, or in a combination of intraperitoneal equol, or oral vancomycin treatment. We also used estrogen receptor beta knockout mice. Results: Both dietary daidzein and supplementation with its metabolite, equol, were protective against aneurysm formation in ovariectomized mice. The protective effects of daidzein and equol required estrogen receptor-β. The disruption of the intestinal microbial conversion of daidzein to equol abolished daidzein’s protective effect against aneurysm formation. Mice treated with equol had lower inflammatory cytokines in the cerebral arteries, suggesting that phytoestrogens modulate inflammatory processes important to intracranial aneurysm pathogenesis. Conclusions: Our study establishes that both dietary daidzein and its metabolite, equol, protect against aneurysm formation in ovariectomized female mice through the activation of estrogen receptor-β and subsequent suppression of inflammation. Dietary daidzein’s protective effect required the intestinal conversion to equol. Our results indicate the potential therapeutic value of dietary daidzein and its metabolite, equol, for the prevention of the formation of intracranial aneurysms and related subarachnoid hemorrhage.

scholarly journals Mast Cell Promotes the Development of Intracranial Aneurysm Rupture

Stroke ◽  
2020 ◽  
Vol 51 (11) ◽  
pp. 3332-3339
Author(s):  
Hajime Furukawa ◽  
Kosuke Wada ◽  
Yoshiteru Tada ◽  
Atsushi Kuwabara ◽  
Hiroki Sato ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Intracranial Aneurysm ◽  
Intracranial Aneurysms ◽  
Critical Role ◽  
Aneurysm Rupture ◽  
Systemic Hypertension ◽  
Rupture Rate ◽  
Aneurysm Formation ◽  
Adult Mice

Background and Purpose: Inflammation has emerged as a key component of the pathophysiology of intracranial aneurysms. Mast cells have been detected in human intracranial aneurysm tissues, and their presence was associated with intramural microhemorrhage and wall degeneration. We hypothesized that mast cells play a critical role in the development of aneurysmal rupture, and that mast cells can be used as a therapeutic target for the prevention of aneurysm rupture. Methods: Intracranial aneurysms were induced in adult mice using a combination of induced systemic hypertension and a single injection of elastase into the cerebrospinal fluid. Aneurysm formation and rupture were assessed over 3 weeks. Roles of mast cells were assessed using a mast cell stabilizer (cromolyn), a mast cell activator (C48/80), and mice that are genetically lacking mature mast cells (Kit W-sh/W-sh mice). Results: Pharmacological stabilization of mast cells with cromolyn markedly decreased the rupture rate of aneurysms (80% versus 19%, n=10 versus n =16) without affecting the aneurysm formation. The activation of mast cells with C48/80 significantly increased the rupture rate of aneurysms (25% versus 100%, n=4 versus n=5) without affecting the overall rate of aneurysm formation. Furthermore, the genetic deficiency of mast cells significantly prevented aneurysm rupture (80% versus 25%, n=10 versus n=8, wild-type versus Kit W-sh/W-sh mice). Conclusions: These results suggest that mast cells play a key role in promoting aneurysm rupture but not formation. Stabilizers of mast cells may have a potential therapeutic value in preventing intracranial aneurysm rupture in patients.

scholarly journals Sex and Genetic Background Effects on the Outcome of Experimental Intracranial Aneurysms

Stroke ◽  
2020 ◽  
Vol 51 (10) ◽  
pp. 3083-3094
Author(s):  
Takeshi Yanagisawa ◽  
Hua Zhang ◽  
Tomoaki Suzuki ◽  
Yoshinobu Kamio ◽  
Tsubasa Takizawa ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Intracranial Aneurysm ◽  
Genetic Background ◽  
Intracranial Aneurysms ◽  
Aneurysm Rupture ◽  
Circle Of Willis ◽  
Male And Female ◽  
Aneurysm Formation ◽  
Proinflammatory Mediators ◽  
Arterial Blood

Background and Purpose: Intracranial aneurysm formation and rupture risk are, in part, determined by genetic factors and sex. To examine their role, we compared 3 mouse strains commonly used in cerebrovascular studies in a model of intracranial aneurysm formation and rupture. Methods: Intracranial aneurysms were induced in male CD1 (Crl:CD1[ICR]), male and female C57 (C57BL/6NCrl), and male 129Sv (129S2/SvPasCrl or 129S1/SvImJ) mice by stereotaxic injection of elastase at the skull base, combined with systemic deoxycorticosterone acetate–salt hypertension. Neurological deficits and mortality were recorded. Aneurysms and subarachnoid hemorrhage grades were quantified postmortem, either after spontaneous mortality or at 7 to 21 days if the animals survived. In separate cohorts, we examined proinflammatory mediators by quantitative reverse transcriptase–polymerase chain reaction, arterial blood pressure via the femoral artery, and the circle of Willis by intravascular latex casting. Results: We found striking differences in aneurysm formation, rupture, and postrupture survival rates among the groups. 129Sv mice showed the highest rates of aneurysm rupture (80%), followed by C57 female (36%), C57 male (27%), and CD1 (21%). The risk of aneurysm rupture and the presence of unruptured aneurysms significantly differed among all 3 strains, as well as between male and female C57. The same hierarchy was observed upon Kaplan-Meier analysis of both overall survival and deficit-free survival. Subarachnoid hemorrhage grades were also more severe in 129Sv. CD1 mice showed the highest resistance to aneurysm rupture and the mildest outcomes. Higher mean blood pressures and the major phenotypic difference in the circle of Willis anatomy in 129Sv provided an explanation for the higher incidence of and more severe aneurysm ruptures. TNFα (tumor necrosis factor-alpha), IL-1β (interleukin-1-beta), and CCL2 (chemokine C-C motif ligand 2) expressions did not differ among the groups. Conclusions: The outcome of elastase-induced intracranial aneurysm formation and rupture in mice depends on genetic background and shows sexual dimorphism.

scholarly journals Estrogen Receptor β Controls Muscle Growth and Regeneration in Young Female Mice

2020 ◽  
Vol 15 (3) ◽  
pp. 577-586 ◽  
Author(s):  
Daiki Seko ◽  
Ryo Fujita ◽  
Yuriko Kitajima ◽  
Kodai Nakamura ◽  
Yuuki Imai ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Muscle Growth ◽  
Young Female ◽  
Estrogen Receptor Β ◽  
Female Mice

scholarly journals Vasa Vasorum Formation is Associated With Rupture of Intracranial Aneurysms

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Haruka Miyata ◽  
Hirokazu Koseki ◽  
Kampei Shimizu ◽  
Yu Abekura ◽  
Mieko Oka ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Intracranial Aneurysms ◽  
Histopathological Examination ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Vasa Vasorum ◽  
Systemic Hypertension ◽  
External Carotid ◽  
Anterior Communicating Artery ◽  
Sprague Dawley ◽  
The Right

Abstract INTRODUCTION Subarachnoid hemorrhage has a poor outcome despite a modern advancement in medical care. The development of a novel therapeutic strategy to prevent rupture of intracranial aneurysms (IAs) or a novel diagnostic marker to predict rupture-prone lesions is thus mandatory. Therefore, in the present study, we established a rat model in which IAs spontaneously rupture and examined this model to clarify histopathological features associated with rupture of lesions. METHODS In detail, female Sprague-Dawley rats were subjected to the bilateral ovariectomy, the ligation of the left common carotid, the right external carotid, and the right pterygopalatine arteries, the induced systemic hypertension, and the administration of a lysyl oxidase inhibitor. RESULTS Aneurysmal subarachnoid hemorrhage occurred one-thirds of manipulated animals and locations of ruptured IAs were exclusively at a posterior or an anterior communicating artery. Histopathological examination using ruptured IAs, rupture-prone ones induced at a posterior or an anterior communicating artery, ones induced at an anterior cerebral artery-olfactory artery bifurcation that never rupture revealed the formation of vasa vasorum as an event associated with rupture of IAs. CONCLUSION We thus proposed the contribution of a structural change in an adventitia, vasa vasorum formation, to rupture of IAs. Findings from this study provide important insights about the pathogenesis of IAs.

scholarly journals Expression of Estrogen Receptor β Is Developmentally Regulated in Reproductive Tissues of Male and Female Mice

2000 ◽  
Vol 62 (2) ◽  
pp. 310-317 ◽  
Author(s):  
Wendy N. Jefferson ◽  
John F. Couse ◽  
Elizabeth Padilla Banks ◽  
Kenneth S. Korach ◽  
Retha R. Newbold
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Β ◽  
Developmentally Regulated ◽  
Male And Female ◽  
Female Mice ◽  
Reproductive Tissues

scholarly journals Angiotensin-(1-7) Protects against the Development of Aneurysmal Subarachnoid Hemorrhage in Mice

2015 ◽  
Vol 35 (7) ◽  
pp. 1163-1168 ◽  
Author(s):  
Kenji Shimada ◽  
Hajime Furukawa ◽  
Kosuke Wada ◽  
Yuan Wei ◽  
Yoshiteru Tada ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Protective Effect ◽  
Receptor Antagonist ◽  
Intracranial Aneurysms ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Cerebral Arteries ◽  
Aneurysm Rupture ◽  
Dependent Manner ◽  
Aneurysmal Rupture ◽  
Mas Receptor

Angiotensin-(1-7) (Ang-(1-7)) can regulate vascular inflammation and remodeling, which are processes that have important roles in the pathophysiology of intracranial aneurysms. In this study, we assessed the effects of Ang-(1-7) in the development of intracranial aneurysm rupture using a mouse model of intracranial aneurysms in which aneurysmal rupture (i.e., aneurysmal subarachnoid hemorrhage) occurs spontaneously and causes neurologic symptoms. Treatment with Ang-(1-7) (0.5 mg/kg/day), Mas receptor antagonist (A779 0.5 mg/kg/day or 2.5 mg/kg/day), or angiotensin II type 2 receptor (AT2R) antagonist (PD 123319, 10 mg/kg/day) was started 6 days after aneurysm induction and continued for 2 weeks. Angiotensin-(1-7) significantly reduced the rupture rate of intracranial aneurysms without affecting the overall incidence of aneurysms. The protective effect of Ang-(1-7) was blocked by the AT2R antagonist, but not by the Mas receptor antagonist. In AT2R knockout mice, the protective effect of Ang-(1-7) was absent. While AT2R mRNA was abundantly expressed in the cerebral arteries and aneurysms, Mas receptor mRNA expression was very scarce in these tissues. Angiotensin-(1-7) reduced the expression of tumor necrosis factor-α and interleukin-1β in cerebral arteries. These findings indicate that Ang-(1-7) can protect against the development of aneurysmal rupture in an AT2R-dependent manner.

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