DNA methylation in intracranial aneurysm pathogenesis

DNA methylation in intracranial aneurysm pathogenesis

Epigenetic modifications, including DNA methylation, are thought to play a role in the intracranial aneurysm pathogenesis. Here’s how:

Gene Expression Regulation: DNA methylation can regulate the expression of genes involved in various aspects of vascular biology, including inflammation, vascular smooth muscle cell function, and extracellular matrix remodeling. Aberrant DNA methylation patterns in these genes may contribute to the weakening of blood vessel walls and the development of aneurysms.

Inflammation and Immune Response: Chronic inflammation and immune system activation are associated with IA development. DNA methylation can influence the expression of genes involved in the regulation of immune responses. Altered DNA methylation patterns in immune-related genes may contribute to the chronic inflammation observed in IA pathogenesis.

Vascular Smooth Muscle Cell Dysfunction: Proper functioning of vascular smooth muscle cells (VSMCs) is essential for maintaining blood vessel integrity. Dysregulated DNA methylation in genes related to VSMC contractility and function may lead to VSMC dysfunction and contribute to aneurysm formation.

Extracellular Matrix Remodeling: The extracellular matrix (ECM) provides structural support to blood vessel walls. DNA methylation can affect the expression of genes involved in ECM remodeling and integrity. Changes in DNA methylation patterns may disrupt the balance between ECM synthesis and degradation, making blood vessels more susceptible to aneurysm formation.

Risk Factors and Environmental Influences: Environmental factors, such as smoking, hypertension, and inflammation, are known risk factors for IAs. These factors can influence DNA methylation patterns in genes related to vascular health, further contributing to IA development in susceptible individuals.

Research in this area is ongoing, and studies are actively exploring the epigenetic mechanisms, including DNA methylation, that underlie IA pathogenesis. Identifying specific DNA methylation changes associated with IAs may lead to the development of novel diagnostic markers or therapeutic targets for this condition. However, it’s important to note that IA development is likely influenced by a complex interplay of genetic, epigenetic, and environmental factors, and more research is needed to fully understand the precise mechanisms involved.


Maimaiti et al. employed a comprehensive bioinformatics investigation of DNA methylation in IA, utilizing a transcriptomics-based methodology that encompassed 100 machine learning algorithms, genome-wide association study (GWAS), Mendelian randomization (MR), and summary-data-based Mendelian randomization (SMR). The sophisticated analytical strategy allowed for a systematic assessment of differentially methylated genes and their implications on the onset, progression, and rupture of IA.

They identified DNA methylation-related genes (MRGs) and associated molecular pathways, and the MR and SMR analyses provided evidence for potential causal links between the observed DNA methylation events and IA predisposition.

These insights not only augment our understanding of the molecular underpinnings of IA but also underscore potential novel biomarkers and therapeutic avenues. Although the study faces inherent limitations and hurdles, it represents a groundbreaking initiative in deciphering the intricate relationship between genetic, epigenetic, and environmental factors implicated in IA pathogenesis 1).

The IL6/JAK/STAT signaling pathway (ISP) is significant positively correlated with intracranial aneurysm onset. The biological function of the ISP is positively correlated with that of the estrogen response pathway (ERP), and is significantly associated with immune cells activities. CSF2RB, FAS, IL6, PTPN1, STAT2, TGFB1 of the ISP gene set and ALDH3A2, COX6C, IGSF1, KRT18, MICB, NPY1R of the ERP gene set were proved to be the characteristic genes. The STAT2 gene can be the potential biomarker of IA onset. The immune score of IA samples was significantly higher than the controls. The STAT2 gene expression is associated with infiltration of immune cells. The WGCNA results were consistent with our finds. Acetaminophen can be a potential therapeutic drug for IA targeting STAT2

They identified that the ISP was one of the most significant positively correlated pathways in IA onset, and it was activated in this process concordant with the ERP and immune responses. Except for beneficial effects, complex and multiple roles of estrogen may be involved in IA formation. STAT2 could be a potential biomarker and a promising therapeutic target of IA pathogenesis 2).

Saccular intracranial aneurysm rupture leads to subarachnoid hemorrhage and is preceded by chronic inflammation and atherosclerotic changes of the Saccular intracranial aneurysm wall. Increased lymphangiogenesis has been detected in atherosclerotic extracranial arteries and in abdominal aortic aneurysms, but the presence of lymphatic vessels in saccular intracranial aneurysm (sIAs) has remained unexplored. Huuska et al. studied the presence of lymphatic vessels in 36 intraoperatively resected sIAs (16 unruptured and 20 ruptured), using immunohistochemical and immunofluorescence stainings for Lymphatic endothelial cells (LEC)markers. Of these LEC-markers, both extracellular and intracellular LYVE1podoplaninVEGFR-3, and Prox1-positive stainings were detected in 83%, 94%, 100%, and 72% of the 36 sIA walls, respectively. Lymphatic vessels were identified as ring-shaped structures positive for one or more of the LEC markers. Of the sIAs, 78% contained lymphatic vessels positive for at least one LEC marker. The presence of LECs and lymphatic vessels were associated with the number of CD68+ and CD163+ cells in the sIA walls, and with the expression of inflammation indicators such as serum amyloid A, myeloperoxidase, and cyclo-oxygenase 2, with the presence of a thrombus, and with the sIA wall rupture. Large areas of VEGFR-3 and α-smooth muscle actin (αSMA) double-positive cells were detected in medial parts of the sIA walls. Also, a few podoplanin and αSMA double-positive cells were discovered. In addition, LYVE-1 and CD68 double-positive cells were detected in the sIA walls and in the thrombus revealing that certain CD68+ macrophages are capable of expressing LEC markers. This study demonstrates for the first time the presence of lymphatic vessels in human sIA walls. Further studies are needed to understand the role of lymphatic vessels in the saccular intracranial aneurysm pathogenesis 3).

Dysfunction of vascular smooth muscle cells (VSMCs) plays a critical role in the intracranial aneurysm pathogenesis (IA). Circular RNAs (circRNAs) have been implicated by reducing microRNA (miRNA) activity. Qin et al. investigated the precise roles of circRNA ADP ribosylation factor interacting protein 2 (circ-ARFIP2, circ_0021001) in VSMC dysfunction. The levels of circ-ARFIP2, miR-338-3p and kinase insert domain receptor (KDR) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. Ribonuclease (RNase) R and subcellular fractionation assays were used to assess the stability and localization of circ-ARFIP2, respectively. Cell viability was detected by Cell Counting Kit-8 (CCK-8) assay, and cell invasion was measured by transwell assay. Cell proliferation was gauged by 5-Ethynyl-2′-Deoxyuridine (EdU) assay. Cell migration was evaluated by transwell and wound-healing assays. Targeted correlations among circ-ARFIP2, miR-338-3p and KDR were validated by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Circ-ARFIP2 and KDR were underexpressed and miR-338-3p was overexpressed in the arterial wall tissues of IA patients. Overexpression of circ-ARFIP2 in human umbilical artery smooth muscle cells (HUASMCs) showed a significant promotion in cell proliferation, migration and invasion. Mechanistically, circ-ARFIP2 targeted miR-338-3p, and circ-ARFIP2 regulated cell behaviors by miR-338-3p. KDR was a direct and functional target of miR-338-3p. Moreover, KDR was a downstream effector of circ-ARFIP2 function. Circ-ARFIP2 regulated KDR expression by targeting miR-338-3p.The findings demonstrated that the increased level of circ-ARFIP2 enhanced HUASMC proliferation, migration and invasion at least in part by the miR-338-3p/KDR axis 4).

Pathogenic inflammation contributes to aneurysm formation by mediating the destruction of the endothelium and the extracellular matrix and promoting the pathogenic proliferation of smooth muscle cells. In mouse models, tolerance-inducing T regulatory (Treg) cells could significantly reduce the incidence and severity of aneurysms. Hence, it should be investigated why in human intracranial aneurysm (IA) patients, Treg cells failed to provide protection against aneurysm formation. In this study, the frequency and function of Treg cells in IA patients were examined. The frequency of Foxp3+ Treg cells was significantly lower in IA patients than in healthy controls. This downregulation was only specific to the Treg subset of CD4+ T cells, as the frequency of total CD4+ T cell was increased in IA patients. Subsequently, we found that the expressions of Treg-associated molecules, including Foxp3, CTLA-4, TGF-β, and IL-10, were significantly lower in Foxp3+ Treg cells from IA patients than in Foxp3+ Treg cells from healthy controls. In both healthy controls and IA patients, Foxp3+ Treg cells were distinguished into a more potent Tim-3+ subset and a less potent Tim-3- subset. The Tim-3+ subset of Foxp3+ Treg cells was significantly reduced in IA patients. Signaling via IL-2, IL-7, IL-15 and IL-21 was shown to promote Tim-3 upregulation in CD4+ and CD8+ T cells. Interestingly, we found that Tim-3 could be upregulated in Treg cells via the same mechanism, but compared to the Treg cells from healthy controls, the Treg cells from IA patients presented defects in Tim-3 upregulation upon cytokine stimulation. Together, our results demonstrated that Foxp3+ Treg cells in IA patients presented reduced function, which was associated with a defect in Tim-3 upregulation 5).

here’s a multiple-choice test based on the information provided about epigenetic modifications and their role in intracranial aneurysm (IA) pathogenesis:

What is the primary role of DNA methylation in gene expression regulation?

a) Activating gene expression b) Repressing gene expression c) Altering DNA sequences d) Enhancing protein translation

In the context of IA pathogenesis, what role does DNA methylation play in vascular biology?

a) Promoting blood vessel dilation b) Reducing inflammation c) Regulating immune responses d) Weakening blood vessel walls

Which of the following is NOT a component of the extracellular matrix (ECM)?

a) Collagen b) Elastin c) Fibronectin d) Lymphocytes

How do matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) contribute to ECM remodeling?

a) MMPs inhibit ECM degradation, while TIMPs promote it. b) Both MMPs and TIMPs promote ECM degradation. c) MMPs promote ECM degradation, while TIMPs inhibit it. d) MMPs and TIMPs have no role in ECM remodeling.

What type of cells are responsible for synthesizing and secreting ECM components?

a) Neurons b) Vascular smooth muscle cells c) Red blood cells d) Epithelial cells

How does DNA methylation relate to the risk factors and environmental influences associated with IA development?

a) It decreases the risk of IA. b) It has no impact on IA risk factors. c) It can be influenced by environmental factors and may contribute to IA development. d) It is solely determined by genetic factors.

What is the primary role of circular RNAs (circRNAs) in the context of vascular smooth muscle cell (VSMC) dysfunction in IA?

a) Promoting VSMC proliferation b) Suppressing VSMC migration c) Inhibiting DNA methylation d) Regulating immune responses

What is the significance of the IL6/JAK/STAT signaling pathway in IA onset?

a) It has no relevance to IA. b) It negatively regulates immune responses. c) It is positively correlated with IA onset and influences immune cell activities. d) It directly causes IA formation.

What is the main function of T regulatory (Treg) cells in the context of IA?

a) Promoting inflammation b) Reducing the severity of IA c) Causing aneurysm formation d) Increasing the frequency of IA

How do Tim-3+ subsets of Foxp3+ Treg cells differ between IA patients and healthy controls?

a) They are more potent in IA patients. b) They are less potent in IA patients. c) They are equally potent in both groups. d) They have no impact on IA.

Answers:

b) Repressing gene expression d) Weakening blood vessel walls d) Lymphocytes c) MMPs promote ECM degradation, while TIMPs inhibit it. b) Vascular smooth muscle cells c) It can be influenced by environmental factors and may contribute to IA development. a) Promoting VSMC proliferation c) It is positively correlated with IA onset and influences immune cell activities. b) Reducing the severity of IA b) They are less potent in IA patients


1)

Maimaiti A, Turhon M, Abulaiti A, Dilixiati Y, Zhang F, Axieer A, Kadeer K, Zhang Y, Maimaitili A, Yang X. DNA methylation regulator-mediated modification patterns and risk of intracranial aneurysm: a multi-omics and epigenome-wide association study integrating machine learning, Mendelian randomization, eQTL and mQTL data. J Transl Med. 2023 Sep 23;21(1):660. doi: 10.1186/s12967-023-04512-w. PMID: 37742034.
2)

Wu A, Zhao C, Mou S, Li S, Cui X, Zhang R. Integrated analysis identifies the IL6/JAK/STAT signaling pathway and the estrogen response pathway associated with the pathogenesis of intracranial aneurysms. Front Immunol. 2022 Nov 14;13:1046765. doi: 10.3389/fimmu.2022.1046765. PMID: 36451838; PMCID: PMC9702531.
3)

Huuska N, Netti E, Lehti S, Kovanen PT, Niemelä M, Tulamo R. Lymphatic vessels are present in human saccular intracranial aneurysms. Acta Neuropathol Commun. 2022 Sep 5;10(1):130. doi: 10.1186/s40478-022-01430-8. PMID: 36064651.
4)

Qin K, Tian G, Zhou D, Chen G. Circular RNA circ-ARFIP2 regulates proliferation, migration and invasion in human vascular smooth muscle cells via miR-338-3p-dependent modulation of KDR. Metab Brain Dis. 2021 Apr 10. doi: 10.1007/s11011-021-00726-3. Epub ahead of print. PMID: 33837886.
5)

Zhang HF, Liang GB, Zhao MG, Zhao GF, Luo YH. Patients with intracranial aneurysms presented defects in regulatory T cells, which were associated with impairment in Tim-3 upregulation. Int Immunopharmacol. 2018 Sep 19;64:350-355. doi: 10.1016/j.intimp.2018.09.020. [Epub ahead of print] PubMed PMID: 30243071.

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