Interleukin-6 Promotes Murine Estrogen Deficiency-Associated Cerebral Aneurysm Rupture

Wajima, Daisuke; Hourani, Siham; Dodd, William; Patel, Devan; Jones, Chad H; Motwani, Kartik; Fazal, Hanain; Hosaka, Koji; Hoh, Brian L.

doi:10.1093/neuros/nyz220

Cited by 20 publications

(16 citation statements)

References 33 publications

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“…The mechanisms linking high wall shear stress to the activation of proinflammatory signaling pathway at arterial bifurcation are not fully elucidated, but the transcription factor nuclear factor kappa B (NF-κB) is shown to play a critical role in IA formation and rupture (Figure 3). Its activation leads to an increase in the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein-1 (MCP-1), which are responsible for the recruitment and adhesion of inflammatory cells to the endothelium where they produce proinflammatory cytokines such as tumor necrotizing factor alpha (TNFα), interleukin (IL)-1β, and IL-6 (56,(64)(65)(66)(67). These cytokines then perpetuate local inflammation and neutrophil and macrophage infiltration in the cerebral artery wall, which produced damaging matrix metalloproteinases (MMP-2/9), and reactive oxygen species (ROS) (55).…”

Section: Estrogen Effect On Cerebral Artery Inflammationmentioning

confidence: 99%

“…Recently, a bioactive phytoestrogen daidzein, which reverses the increased IA incidence in ovariectomized mice via ERβ, was shown to decrease IL-6 mRNA level in cerebral arteries and, to a lesser extent, IL-1β and TNFα mRNAs ( 68 ). IL-6 level in the serum is increased and involved in the formation and rupture of IA in estrogen-deficient mice but not in control mice, which suggests that estrogen-induced repression of IL-6 expression participates to the beneficial effect of estrogen on IA ( 67 ).…”

Section: Molecular Mechanisms Of Estrogen Protection To Ia Formationmentioning

confidence: 99%

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Why Are Women Predisposed to Intracranial Aneurysm?

Fréneau

Baron-Menguy

Vion

et al. 2022

Front. Cardiovasc. Med.

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Intracranial aneurysm (IA) is a frequent and generally asymptomatic cerebrovascular abnormality characterized as a localized dilation and wall thinning of intracranial arteries that preferentially arises at the arterial bifurcations of the circle of Willis. The devastating complication of IA is its rupture, which results in subarachnoid hemorrhage that can lead to severe disability and death. IA affects about 3% of the general population with an average age for detection of rupture around 50 years. IAs, whether ruptured or unruptured, are more common in women than in men by about 60% overall, and more especially after the menopause where the risk is double-compared to men. Although these data support a protective role of estrogen, differences in the location and number of IAs observed in women and men under the age of 50 suggest that other underlying mechanisms participate to the greater IA prevalence in women. The aim of this review is to provide a comprehensive overview of the current data from both clinical and basic research and a synthesis of the proposed mechanisms that may explain why women are more prone to develop IA.

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Section: Estrogen Effect On Cerebral Artery Inflammationmentioning

confidence: 99%

Section: Molecular Mechanisms Of Estrogen Protection To Ia Formationmentioning

confidence: 99%

Why Are Women Predisposed to Intracranial Aneurysm?

Fréneau

Baron-Menguy

Vion

et al. 2022

Front. Cardiovasc. Med.

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“…We then examined expressions of pro-inflammatory factors, TNF-α [3,56,60], CCL2 (MCP-1) 19,20 , PTGS2 (COX-2) 8,21 and IL-6 22,23 as a marker of chronic inflammatory responses in lesions, in immunohistochemistry, because chronic inflammation plays a pivotal role in the pathogenesis 8,12,[24][25][26] . Expression of all these pro-inflammatory factors was detected at the adventitia and also at the intimal hyperplasia lied beneath the disrupted IEL (Fig.…”

Section: Potential Of Dedifferentiated Smcs As a Regulator Of Chronicmentioning

confidence: 99%

Dedifferentiation of smooth muscle cells in intracranial aneurysms and its potential contribution to the pathogenesis

Oka

Shimo²,

Ohno

et al. 2020

Sci Rep

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Smooth muscle cells (SMCs) are the major type of cells constituting arterial walls and play a role to maintain stiffness via producing extracellular matrix. Here, the loss and degenerative changes of SMCs become the major histopathological features of an intracranial aneurysm (IA), a major cause of subarachnoid hemorrhage. Considering the important role of SMCs and the loss of this type of cells in IA lesions, we in the present study subjected rats to IA models and examined how SMCs behave during disease progression. We found that, at the neck portion of IAs, SMCs accumulated underneath the internal elastic lamina according to disease progression and formed the intimal hyperplasia. As these SMCs were positive for a dedifferentiation marker, myosin heavy chain 10, and contained abundant mitochondria and rough endoplasmic reticulum, SMCs at the intimal hyperplasia were dedifferentiated and activated. Furthermore, dedifferentiated SMCs expressed some pro-inflammatory factors, suggesting the role in the formation of inflammatory microenvironment to promote the disease. Intriguingly, some SMCs at the intimal hyperplasia were positive for CD68 and contained lipid depositions, indicating similarity with atherosclerosis. We next examined a potential factor mediating dedifferentiation and recruitment of SMCs. Platelet derived growth factor (PDGF)-BB was expressed in endothelial cells at the neck portion of lesions where high wall shear stress (WSS) was loaded. PDGF-BB facilitated migration of SMCs across matrigel-coated pores in a transwell system, promoted dedifferentiation of SMCs and induced expression of pro-inflammatory genes in these cells in vitro. Because, in a stenosis model of rats, PDGF-BB expression was expressed in endothelial cells loaded in high WSS regions, and SMCs present nearby were dedifferentiated, hence a correlation existed between high WSS, PDGFB and dedifferentiation in vivo. In conclusion, dedifferentiated SMCs presumably by

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“…We previously reported a murine model of aneurysm formation and rupture using elastase, hemodynamic changes, and hypertension [5]. While this model has been used to uncover novel mechanisms and therapeutic targets, we sought to modify the model to be simpler [15,[17][18][19].…”

Section: Discussionmentioning

confidence: 99%

A Modification to a Murine Model for Intracranial Aneurysm Formation and Rupture

Patel¹,

Dodd²,

Motwani³

et al. 2021

Cureus

Self Cite

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Between 3.6% and 6.0% of the population has an intracranial aneurysm. The mechanisms underlying intracranial aneurysm formation and rupture are not fully known. Several rodent models have been developed to better understand intracranial aneurysm pathophysiology. Hypertension, hemodynamic changes, and vessel injury are all necessary for aneurysm induction; however, multiple invasive procedures may disrupt an animal's physiology. Therefore, we hypothesized that our method for inducing hypertension could be modified to create a simpler model. We previously developed a highly reproducible murine model of intracranial aneurysm formation and rupture that involves hemodynamic changes through ligation of the left common carotid artery, vessel wall degradation using elastase and a lysyl oxidase inhibitor, and hypertension through a high-salt diet, continuous angiotensin II infusion, and right renal artery ligation. In order to create a simpler model, we sought to eliminate renal artery ligation. We assessed aneurysm formation, aneurysm rupture, and blood pressure in two separate cohorts of C57BL/6 mice: one cohort underwent our model as above, while another cohort did not receive right renal artery ligation. Our results demonstrate that intracranial aneurysm formation and rupture rates did not differ between each group. Further, the blood pressures between cohorts did not differ at various timepoints in the model. Both cohorts, however, did have a significant increase in blood pressure from baseline, suggesting that renal artery ligation is not needed for inducing hypertension. These findings demonstrate that our murine model can be modified to eliminate right renal artery ligation. Thus, we propose this modification to our murine model for studying intracranial aneurysm pathophysiology.

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Interleukin-6 Promotes Murine Estrogen Deficiency-Associated Cerebral Aneurysm Rupture

Cited by 20 publications

References 33 publications

Why Are Women Predisposed to Intracranial Aneurysm?

Why Are Women Predisposed to Intracranial Aneurysm?

Dedifferentiation of smooth muscle cells in intracranial aneurysms and its potential contribution to the pathogenesis

A Modification to a Murine Model for Intracranial Aneurysm Formation and Rupture

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