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

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.

Download Full-text

Roles of Phytoestrogen in the Pathophysiology of Intracranial Aneurysm

Stroke ◽

10.1161/strokeaha.120.032042 ◽

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.

Download Full-text

Mast Cell Promotes the Development of Intracranial Aneurysm Rupture

Stroke ◽

10.1161/strokeaha.120.030834 ◽

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.

Download Full-text

Identification of upregulated NF-κB inhibitor alpha and IRAK3 targeting lncRNA following intracranial aneurysm rupture-induced subarachnoid hemorrhage

BMC Neurology ◽

10.1186/s12883-021-02156-1 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Wei Leng ◽

Dan Fan ◽

Zhong Ren ◽

Qiaoying Li

Keyword(s):

Subarachnoid Hemorrhage ◽

Intracranial Aneurysm ◽

Signaling Pathway ◽

Aneurysm Rupture ◽

Cytokine Receptor ◽

Gene Set Enrichment Analysis ◽

Receptor Interaction ◽

Regulatory Pathways ◽

Ruptured Intracranial Aneurysm ◽

Neurotrophin Signaling

Abstract Background This study was performed to identify genes and lncRNAs involved in the pathogenesis of subarachnoid hemorrhage (SAH) from ruptured intracranial aneurysm (RIA). Methods Microarray GSE36791 was downloaded from Gene Expression Omnibus (GEO) database followed by the identification of significantly different expressed RNAs (DERs, including lncRNA and mRNA) between patients with SAH and healthy individuals. Then, the functional analyses of DEmRNAs were conducted and weighted gene co-expression network analysis (WGCNA) was also performed to extract the modules associated with SAH. Following, the lncRNA-mRNA co-expression network was constructed and the gene set enrichment analysis (GSEA) was performed to screen key RNA biomarkers involved in the pathogenesis of SAH from RIA. We also verified the results in a bigger dataset GSE7337. Results Totally, 561 DERs, including 25 DElncRNAs and 536 DEmRNAs, were identified. Functional analysis revealed that the DEmRNAs were mainly associated with immune response-associated GO-BP terms and KEGG pathways. Moreover, there were 6 modules significantly positive-correlated with SAH. The lncRNA-mRNA co-expression network contained 2 lncRNAs (LINC00265 and LINC00937) and 169 mRNAs. The GSEA analysis showed that these two lncRNAs were associated with three pathways (cytokine-cytokine receptor interaction, neurotrophin signaling pathway, and apoptosis). Additionally, IRAK3 and NFKBIA involved in the neurotrophin signaling pathway and apoptosis while IL1R2, IL18RAP and IL18R1 was associated with cytokine-cytokine receptor interaction pathway. The expression levels of these genes have the same trend in GSE36791 and GSE7337. Conclusion LINC00265 and LINC00937 may be implicated with the pathogenesis of SAH from RIA. They were involved in three important regulatory pathways. 5 mRNAs played important roles in the three pathways.

Download Full-text

Abstract 147: Role of Nicotine in the Development of Intracranial Aneurysm Rupture

Stroke ◽

10.1161/str.48.suppl_1.147 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Yoshinobu Kamio ◽

Hajime Furukawa ◽

Kimihiko Yokosuka ◽

Masaaki Korai ◽

Kazuha Mitsui ◽

...

Keyword(s):

Intracranial Aneurysm ◽

Tobacco Smoke ◽

Intracranial Aneurysms ◽

Aneurysm Rupture ◽

Alpha7 Nicotinic Acetylcholine Receptor ◽

Acetate Salt ◽

Nicotine Receptors ◽

Aneurysm Wall ◽

Salt Hypertension

Background: Nicotine is one of main chemicals of tobacco smoke and promotes atherosclerosis and stroke. Tobacco smoke is considered an independent risk factor for intracranial aneurysm formation, growth, and rupture. There are mainly 5 subtypes of nicotine receptors. Roles of alpha7 nicotinic acetylcholine receptor (α7nAChR) in inflammation and vascular remodeling are diverse and context-dependent. Notably, endothelial α7nAChR is considered to mediate nicotine-induced inflammation. Activation of endothelial α7nAChR by nicotine may promote aneurysm rupture by increasing the aneurysm wall inflammation. Using a mouse model of intracranial aneurysm, we examined effects of nicotine in aneurysm rupture. Moreover we investigated potential roles of α7nAChR stimulation by nicotine in the pathophysiology of intracranial aneurysms. Methods: Intracranial aneurysms were induced by a combination of elastase injection into the cerebrospinal fluid and deoxycorticosteron acetate-salt (DOCA-salt) hypertension in male mice. Mice were treated with (1) nicotine (5 mg/kg/day, n=25); (2) saline sc (n=22) for three weeks after aneurysm induction. To investigate the effect of α7nAChR, mice were treated with (1) saline sc + saline ip (n=11); (2) saline sc + α7nAChR antagonist (Methyllycaconitine, MLA 5mg/kg/day) ip (n=13); (3) nicotine (5 mg/kg/day, sc, 28 days) + saline ip (n=18); (4) nicotine sc + MLA ip (n=18). Results: Nicotine alone significantly increased aneurysmal rupture compared with saline treatment (89% vs 46%, p=0.009). While α7nAChR antagonist did not affect the incidence of aneurysm or rupture rates, the α7nAChR antagonist significantly reduced the deleterious effect of nicotine as indicated by the reduction of the rupture rates (41% vs 100%: nicotine sc + MLA ip group vs nicotine sc + saline ip group, p=0.027). Conclusion: Our data indicate the promotion of aneurysm rupture by nicotine may be mediated by its stimulation of alpha7nAChR.

Download Full-text

Substitution of chromosome 1 ameliorates l-NAME hypertension and renal disease in the fawn-hooded hypertensive rat

AJP Renal Physiology ◽

10.1152/ajprenal.00374.2004 ◽

2005 ◽

Vol 288 (5) ◽

pp. F1015-F1022 ◽

Cited By ~ 26

Author(s):

David L. Mattson ◽

Mary Pat Kunert ◽

Richard J. Roman ◽

Howard J. Jacob ◽

Allen W. Cowley

Keyword(s):

Renal Disease ◽

Genetic Background ◽

Female Rats ◽

Chromosome 1 ◽

Brown Norway ◽

Male And Female ◽

Arterial Blood ◽

Male And Female Rats ◽

Induced Hypertension ◽

Excretion Rates

Linkage analysis studies previously identified genetic loci associated with proteinuria and hypertension on chromosome 1 of fawn-hooded hypertensive (FHH) rats. The present studies were performed on conscious male and female rats to evaluate the influence of transfer of chromosome 1 from the Brown Norway (BN) rat to the FHH genetic background (FHH-1BN). Rats were maintained for 2 wk on 8.0% NaCl chow with NG-nitro-l-arginine methyl ester (l-NAME) in the drinking water (12.5 mg/l) to induce hypertension and accelerate the onset of renal disease. Mean arterial blood pressure (MAP) was significantly higher in the male FHH (188 ± 3 mmHg, n = 13) compared with the BN (121 ± 3 mmHg, n = 8); MAP in the FHH-1BN was midway between the two parental strains (167 ± 5 mmHg, n = 9). Urinary protein and albumin excretion rates in the male FHH-1BN (Uprot = 189 ± 36 mg/day, Ualb = 69 ± 16 mg/day, n = 10) were also midway between levels observed in the FHH (Uprot = 485 ± 54 mg/day; Ualb = 206 ± 25 mg/day, n = 13) and the BN (Uprot = 32 ± 5 mg/day, Ualb = 5 ± 1 mg/day, n = 8). Creatinine clearance was elevated, and the degree of glomerular damage was significantly reduced in the FHH-1BN compared with the FHH. Qualitatively similar results were obtained from female FHH, FHH-1BN, and BN rats. The present results indicate that genes contributing to l-NAME-induced hypertension and renal disease are found on chromosome 1 of the FHH rat.

Download Full-text

The safety of vasopressor-induced hypertension in subarachnoid hemorrhage patients with coexisting unruptured, unprotected intracranial aneurysms

Journal of Neurosurgery ◽

10.3171/2014.12.jns141201 ◽

2015 ◽

Vol 123 (4) ◽

pp. 862-871 ◽

Cited By ~ 12

Author(s):

Matthew R. Reynolds ◽

Robert T. Buckley ◽

Santoshi S. Indrakanti ◽

Ali H. Turkmani ◽

Gerald Oh ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Intracranial Aneurysms ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Patient Characteristics ◽

Aneurysm Rupture ◽

Unruptured Aneurysms ◽

Size Number ◽

Days Of Therapy ◽

Induced Hypertension

OBJECT Vasopressor-induced hypertension (VIH) is an established treatment for patients with aneurysmal subarachnoid hemorrhage (SAH) who develop vasospasm and delayed cerebral ischemia (DCI). However, the safety of VIH in patients with coincident, unruptured, unprotected intracranial aneurysms is uncertain. METHODS This retrospective multiinstitutional study identified 1) patients with aneurysmal SAH and 1 or more unruptured, unprotected aneurysms who required VIH therapy (VIH group), and 2) patients with aneurysmal SAH and 1 or more unruptured, unprotected aneurysms who did not require VIH therapy (non-VIH group). All patients had previously undergone surgical or endovascular treatment for the presumed ruptured aneurysm. Comparisons between the VIH and non-VIH patients were made in terms of the patient characteristics, clinical and radiographic severity of SAH, total number of aneurysms, number of ruptured/unruptured aneurysms, aneurysm location/size, number of unruptured and unprotected aneurysms during VIH, severity of vasospasm, degree of hypervolemia, and degree and duration of VIH therapy. RESULTS For the VIH group (n = 176), 484 aneurysms were diagnosed, 231 aneurysms were treated, and 253 unruptured aneurysms were left unprotected during 1293 total days of VIH therapy (5.12 total years of VIH therapy for unruptured, unprotected aneurysms). For the non-VIH group (n = 73), 207 aneurysms were diagnosed, 93 aneurysms were treated, and 114 unruptured aneurysms were left unprotected. For the VIH and non-VIH groups, the mean sizes of the ruptured (7.2 ± 0.3 vs 7.8 ± 0.6 mm, respectively; p = 0.27) and unruptured (3.4 ± 0.2 vs 3.2 ± 0.2 mm, respectively; p = 0.40) aneurysms did not differ. The authors observed 1 new SAH from a previously unruptured, unprotected aneurysm in each group (1 of 176 vs 1 of 73 patients; p = 0.50). Baseline patient characteristics and comorbidities were similar between groups. While the degree of hypervolemia was similar between the VIH and non-VIH patients (fluid balance over the first 10 days of therapy: 3146.2 ± 296.4 vs 2910.5 ± 450.7 ml, respectively; p = 0.67), VIH resulted in a significant increase in mean arterial pressure (mean increase over the first 10 days of therapy relative to baseline: 125.1% ± 1.0% vs 98.2% ± 1.2%, respectively; p < 0.01) and systolic blood pressure (125.6% ± 1.1% vs. 104.1% ± 5.2%, respectively; p < 0.01). CONCLUSIONS For small, unruptured, unprotected intracranial aneurysms in SAH patients, the frequency of aneurysm rupture during VIH therapy is rare. The authors do not recommend withholding VIH therapy from these patients.

Download Full-text

Vascular Macrophages as Therapeutic Targets to Treat Intracranial Aneurysms

Frontiers in Immunology ◽

10.3389/fimmu.2021.630381 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sajjad Muhammad ◽

Shafqat Rasul Chaudhry ◽

Gergana Dobreva ◽

Michael T. Lawton ◽

Mika Niemelä ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Intracranial Aneurysms ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Therapeutic Targets ◽

Aneurysm Rupture ◽

Macrophage Infiltration ◽

Aneurysm Wall ◽

M1 Phenotype ◽

M2 Phenotype ◽

Alternatively Activated

Aneurysmal subarachnoid hemorrhage (aSAH) is a highly fatal and morbid type of hemorrhagic strokes. Intracranial aneurysms (ICAs) rupture cause subarachnoid hemorrhage. ICAs formation, growth and rupture involves cellular and molecular inflammation. Macrophages orchestrate inflammation in the wall of ICAs. Macrophages generally polarize either into classical inflammatory (M1) or alternatively-activated anti-inflammatory (M2)-phenotype. Macrophage infiltration and polarization toward M1-phenotype increases the risk of aneurysm rupture. Strategies that deplete, inhibit infiltration, ameliorate macrophage inflammation or polarize to M2-type protect against ICAs rupture. However, clinical translational data is still lacking. This review summarizes the contribution of macrophage led inflammation in the aneurysm wall and discuss pharmacological strategies to modulate the macrophageal response during ICAs formation and rupture.

Download Full-text

EVALUATING IMAGING FEATURE ON CTA AND DSA OF RUPTURED CEREBRAL ANEURYSMS

Journal of Medicine and Pharmacy ◽

10.34071/jmp.2017.4.2 ◽

2017 ◽

pp. 14-20

Author(s):

Thanh Vu Huynh ◽

Van Ngoc Cuong Le

Keyword(s):

Subarachnoid Hemorrhage ◽

Intracranial Aneurysms ◽

Cerebral Aneurysms ◽

Aneurysm Rupture ◽

Imaging Feature ◽

Key Words Aneurysm ◽

Diagnostic Efficacy ◽

Imaging Characteristics ◽

The Difference ◽

Ruptured Intracranial Aneurysms

Objective: To compare the imaging feature of ruptured intracranial aneurysms on CTA and DSA. Material and Methods: From April 2016 to June 2017, 33 cases with SAH was performed CTA and DSA to all cases. The results of the CTA were compared with the DSAresults to determine the diagnostic efficacy of CTA in evaluating characterizations of ruptured cerebral aneurysms. Results: The difference is not statistically significant between CTA and DSA in evaluating of aneurysm size, location, rupture status, and other imaging characteristics. Conclusion: CTA is invaluable in evaluatingruptured cerebral aneurysms that guide clinicians to make planning the treatment. Key words: aneurysm, rupture, subarachnoid, hemorrhage

Download Full-text

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.30 ◽

2015 ◽

Vol 35 (7) ◽

pp. 1163-1168 ◽

Cited By ~ 23

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.

Download Full-text

Underlying mechanism of hemodynamics and intracranial aneurysm

Chinese Neurosurgical Journal ◽

10.1186/s41016-021-00260-2 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Haishuang Tang ◽

Qingsong Wang ◽

Fengfeng Xu ◽

Xiaoxi Zhang ◽

Zhangwei Zeng ◽

...

Keyword(s):

Blood Flow ◽

Intracranial Aneurysm ◽

Blood Vessels ◽

Intracranial Aneurysms ◽

Physiological Condition ◽

Modern Society ◽

Underlying Mechanism ◽

Aneurysm Rupture ◽

New Perspective ◽

The Relationship

AbstractIn modern society, subarachnoid hemorrhage, mostly caused by intracranial aneurysm rupture, is accompanied by high disability and mortality rate, which has become a major threat to human health. Till now, the etiology of intracranial aneurysm has not been entirely clarified. In recent years, more and more studies focus on the relationship between hemodynamics and intracranial aneurysm. Under the physiological condition, the mechanical force produced by the stable blood flow in the blood vessels keeps balance with the structure of the blood vessels. When the blood vessels are stimulated by the continuous abnormal blood flow, the functional structure of the blood vessels changes, which becomes the pathophysiological basis of the inflammation and atherosclerosis of the blood vessels and further promotes the occurrence and development of the intracranial aneurysm. This review will focus on the relationship between hemodynamics and intracranial aneurysms, will discuss the mechanism of occurrence and development of intracranial aneurysms, and will provide a new perspective for the research and treatment of intracranial aneurysms.

Download Full-text