Endothelial dysfunction in cerebral aneurysms

Sheinberg, Dallas; McCarthy, David; Elwardany, Omar; Bryant, Jean-Paul; Luther, Evan; Chen, Stephanie H.; Thompson, John W.; Starke, Robert M.

doi:10.3171/2019.4.focus19221

Cited by 65 publications

(38 citation statements)

References 73 publications

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“…In a mouse model of IA induced by elevated hemodynamic stress, expression of COX2 and EP2 is increased in the endothelial cell layer at early stage of IA formation. Inhibition or knockout of COX-2 or EP2 resulted in decreased NF-κB expression and a reduction of incidence of IA formation ( 71 , 72 ). The induction of COX-2/PGE2/EP2 signaling activates NF-κB, thus creating a self-amplified feedback loop that prevents the resolution of this initial process and contributes to generate the chronic inflammation in the cerebral arterial wall enabling for IA formation and progression.…”

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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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: 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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“…The gene product Nephronectin (NPNT) is a member of the epidermal growth factor (EGF) repeat superfamily of proteins and has been reported to contribute to endothelial cell activity and angiogenesis [ 35 ]. Since impaired endothelial cell function is thought to play a major role in the pathogenesis of aneurysm formation [ 36 ], re-sequencing of the entire coding region of NPNT was added to 95 familial IA probands. A nonsense variant, c.1364C>A (p.Ser455Ter), was identified in a female patient with aneurysmal SAH.…”

Section: Resultsmentioning

confidence: 99%

Whole-exome sequencing in a Japanese multiplex family identifies new susceptibility genes for intracranial aneurysms

et al. 2022

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Background Intracranial aneurysms (IAs) cause subarachnoid hemorrhage, which has high rates of mortality and morbidity when ruptured. Recently, the role of rare variants in the genetic background of complex diseases has been increasingly recognized. The aim of this study was to identify rare variants for susceptibility to IA. Methods Whole-exome sequencing was performed on seven members of a Japanese pedigree with highly aggregated IA. Candidate genes harboring co-segregating rare variants with IA were re-sequenced and tested for association with IA using additional 500 probands and 323 non-IA controls. Functional analysis of rare variants detected in the pedigree was also conducted. Results We identified two gene variants shared among all four affected participants in the pedigree. One was the splicing donor c.1515+1G>A variant in NPNT (Nephronectin), which was confirmed to cause aberrant splicing by a minigene assay. The other was the missense p.P83T variant in CBY2 (Chibby family member 2). Overexpression of p.P83T CBY2 fused with red fluorescent protein tended to aggregate in the cytoplasm. Although Nephronectin has been previously reported to be involved in endothelial angiogenic functions, CBY2 is a novel molecule in terms of vascular pathophysiology. We confirmed that CBY2 was expressed in cerebrovascular smooth muscle cells in an isoform2-specific manner. Targeted CBY2 re-sequencing in additional case-control samples identified three deleterious rare variants (p.R46H, p.P83T, and p.L183R) in seven probands, showing a significant enrichment in the overall probands (8/501) compared to the controls (0/323) (p = 0.026, Fisher’s extract test). Conclusions NPNT and CBY2 were identified as novel susceptibility genes for IA. The highly heterogeneous and polygenic architecture of IA susceptibility can be uncovered by accumulating extensive analyses that focus on each pedigree with a high incidence of IA.

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“…may reduce the number of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) in the IA wall. At the same time, in the early phase, to ght against abnormal hemodynamic stimuli, ECs and VSMCs in the wall of IAs often increase the expression of adhesion and in ammatory molecules, strengthening the cell-to-cell junction and cell-to-ECM junction [41]. On the other hand, loss of focal adhesion can lead to ECM disintegration or decrease mechanical stress on the vascular wall, resulting in IA growth and rupture [40].…”

Section: Discussionmentioning

confidence: 99%

TNFRSF19 (TROY) as a plasma biomarker for diagnosing and monitoring intracranial aneurysms progression

Zhang

Tang

et al. 2022

Preprint

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Background This study aimed to identify and validate potential blood biomarkers for intracranial aneurysms (IAs) using bioinformatics analysis. Methods GSE54083 dataset was downloaded, then differently expressed genes (DEGs) and weighted gene co-expression network analysis (WGCNA) were used to identify the consistently differential expression genes from non-IAs to rupture IAs. We then calculated the areas under the receiver operating characteristic curve (AUC) of each gene to evaluate their diagnostic capability. Moreover, the XCell algorithm was used to integrate the expression data to score the relative abundance of the vascular microenvironment. Lastly, qRT-PCR and ELISA assays were performed to validate potential biomarkers using our clinical samples. Results Six hub genes (TNFRSF19, FBXO38, SLC26A10, C11orf24, P2RX6, and RORC) were identified by AUCs greater than 0.9 in our bioinformatics analysis. From non-IAs to RIAs, the abundances of B cell types were increased while T cell types were decreased. NK T cells had the most cell abundance with a significant elevating trend. The qRT-PCR assay revealed that the expression trend of TNFRSF19, FBXO38, and RORC were consistent with the bioinformatics analysis. Eventually, the ELISA assay revealed that TNFRSF19 (TROY) was significantly elevated in patients with UIAs and RIAs. What’s more, the plasma TROY was positively correlated with CRP (r = 0.46), D-dimer (r = 0.39), and number of Neutrophil and white blood cells. Conclusions TNFRSF19 (TROY) might play a key role in the development of IAs and could be a novel blood-based biomarker for diagnosing IAs and monitoring the progression of IAs.

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Endothelial dysfunction in cerebral aneurysms

Cited by 65 publications

References 73 publications

Why Are Women Predisposed to Intracranial Aneurysm?

Why Are Women Predisposed to Intracranial Aneurysm?

Whole-exome sequencing in a Japanese multiplex family identifies new susceptibility genes for intracranial aneurysms

TNFRSF19 (TROY) as a plasma biomarker for diagnosing and monitoring intracranial aneurysms progression

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