JNK2-MMP-9 axis facilitates the progression of intracranial aneurysms.

Intracranial aneurysm (IA) can cause subarachnoid hemorrhage or some other hemorrhagic stroke after rupture. Because of the poor outcome in spite of the intensive medical care after the onset of hemorrhage, the development of a novel therapeutic strategy like medical therapy to prevent the progression of the disease becomes a social need. As the reduction of arterial stiffness due to the degeneration of the extracellular matrix via Matrix Metalloproteinases (MMPs) becomes one of the central machineries leading to the progression of IAs through a series of studies, factors regulating the expression or the activity of MMPs could be a therapeutic target. In the present study, specimens from human IA lesions and the animal model of IAs were used to examine the expression of c-Jun N-terminal kinase (JNK) which might exacerbate expressions of MMPs in the lesions to weaken arterial walls resulting in the progression of the disease. In some human IA lesions examined, the expression of p-JNK, the activated form of JNK, could be detected mostly in the medial smooth muscle cells. In IA lesions induced in rats, the activation of JNK was induced during the progression of the disease and accompanied with the activation of downstream transcriptional factor c-Jun and importantly with the expression of MMP-2 or -9. The genetic deletion of Jnk2, not Jnk1, in mice significantly prevented the incidence of IAs with the suppression of the expression of MMP-2 or MMP-9. These results combined together have suggested the crucial role of JNK in the progression of IAs through regulating the expression of MMPs. The results from the present study provides the novel insights about the pathogenesis of IA progression and also about the therapeutic target.

Hemodynamic differences determining rupture and non-rupture in middle cerebral aneurysms after growth.

BACKGROUND AND PURPOSE: Intracranial aneurysm growth is a significant risk factor for rupture; however, a few aneurysms remain unruptured for long periods, even after growth. Here, we identified hemodynamic features associated with aneurysmal rupture after growth. MATERIALS AND METHODS: We analyzed nine middle cerebral artery aneurysms that grew during the follow-up period using computational fluid dynamics analysis. Growth patterns of the middle cerebral artery aneurysms were divided into homothetic growth (Type 1), de novo bleb formation (Type 2), and bleb enlargement (Type 3). Hemodynamic parameters of the four ruptured aneurysms after growth were compared with those of the five unruptured aneurysms. RESULTS: Among nine aneurysms (78%), seven were Type 1, one was Type 2, and one was Type 3. Three (43%) Type 1 aneurysms ruptured after growth. Maximum oscillatory shear index after aneurysmal growth was significantly higher in ruptured Type 1 cases than in unruptured Type 1 cases (ruptured vs. unruptured: 0.455 ± 0.007 vs. 0.319 ± 0.042, p = 0.003). In Type 1 cases, a newly emerged high-oscillatory shear index area was frequently associated with rupture, indicating a rupture point. Aneurysm growth was observed in the direction of the high-pressure difference area before enlargement. In Types 2 and 3 aneurysms, the maximum oscillatory shear index decreased slightly, however, the pressure difference values remain unchanged. In Type 3 aneruysm, the maximum OSI and PD values remained unchanged. CONCLUSIONS: This study suggests that hemodynamic variations and growth pattern changes are crucial in rupture risk determination using computational fluid dynamics analysis. High-pressure difference areas may predict aneurysm enlargement direction. Additionally, high maximum oscillatory shear index values after enlargement in cases with homothetic growth patterns were potential rupture risk factors.

Phoenixin-14 maintains the contractile type of vascular smooth muscle cells in cerebral aneurysms rats.

The rupture of intracranial aneurysm (IA) is the primary reason contributing to the occurrence of life-threatening subarachnoid hemorrhages. The oxidative stress-induced phenotypic transformation from the contractile phenotype to the synthetic phenotype of vascular smooth muscle cells (VSMCs) plays a pivotal role in IA formation and rupture. Our study aimed to figure out the role of phoenixin-14 in VSMC phenotypic switching during the pathogenesis of IA by using both cellular and animal models. Primary rat VSMCs were isolated from the Willis circle of male Sprague-Dawley rats. VSMCs were stimulated by hydrogen peroxide (H2O2) to establish a cell oxidative damage model. After pretreatment with phoenixin-14 and exposure to H2O2, VSMC viability, migration, and invasion were examined through cell counting kit-8 (CCK-8), wound healing, and Transwell assays. Intracellular reactive oxygen species (ROS) production in VSMCs was evaluated by using 2',7'-Dichlorofluorescin diacetate (DCFH-DA) fluorescence probes and flow cytometry. Rat IA models were established by ligation of the left common carotid arteries and posterior branches of both renal arteries. The histopathological changes of rat intracranial blood vessels were observed through hematoxylin and eosin staining. The levels of contractile phenotype markers (alpha-smooth muscle actin [α-SMA] and smooth muscle 22 alpha [SM22α]) in VSMCs and rat arterial rings were determined through real-time quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. Our results showed that H2O2 stimulated the production of intracellular ROS and induced oxidative stress in VSMCs, while phoenixin-14 pretreatment attenuated intracellular ROS levels in H2O2-exposed VSMCs. H2O2 exposure promoted VSMC migration and invasion, which, however, was reversed by phoenixin-14 pretreatment. Besides, phoenixin-14 administration inhibited IA formation and rupture in rat models. The decrease in α-SMA and SM22α levels in H2O2-exposed VSMCs and IA rat models was antagonized by phoenixin-14. Collectively, phoenixin-14 ameliorates the progression of IA through preventing the loss of the contractile phenotype of VSMCs.

The Role of Long Noncoding RNAs in Vascular Smooth Muscle Cell Phenotype and the Pathogenesis of Cardiovascular and Cerebrovascular Aneurysms.

ABSTRACT: Aneurysms are localized dilations of blood vessels, which can expand to 50% of the original diameter. They are more common in cardiovascular and cerebrovascular vessels. Rupture is one of the most dangerous complications. The pathophysiology of aneurysms is complex and diverse, often associated with progressive vessel wall dysfunction resulting from vascular smooth muscle cell death and abnormal extracellular matrix synthesis and degradation. Multiple studies have shown that long noncoding RNAs (lncRNAs) play a significant role in the progression of cardiovascular and cerebrovascular diseases. Therefore, it is necessary to find and summarize them. LncRNAs control gene expression and disease progression by regulating target mRNA or miRNA and are biomarkers for the diagnosis and prognosis of aneurysmal cardiovascular and cerebrovascular diseases. This review explores the role, mechanism, and clinical value of lncRNAs in aneurysms, providing new insights for a deeper understanding of the pathogenesis of cardiovascular and cerebrovascular aneurysms.

Assessing accuracy and consistency in intracranial aneurysm sizing: human expertise vs. artificial intelligence.

Intracranial aneurysms (IAs) are a common vascular pathology and are associated with a risk of rupture, which is often fatal. Aneurysm growth of more than 1 mm is considered a surrogate of rupture risk, therefore, this study presents a comprehensive analysis of intracranial aneurysm measurements utilizing a dataset comprising 358 IA from 248 computed tomography angiography (CTA) scans measured by four junior raters and one senior rater. The study explores the variability in sizing assessments by employing both human raters and an Artificial Intelligence (AI) system. Our findings reveal substantial inter- and intra-rater variability among junior raters, contrasting with the lower intra-rater variability observed in the senior rater. Standard deviations of all raters were above the threshold for IA growth (1 mm). Additionally, the study identifies a systemic bias, indicating a tendency for human experts to measure aneurysms smaller than the AI system. Our findings emphasize the challenges in human assessment while also showcasing the capacity of AI technology to improve the precision and reliability of intracranial aneurysm assessments, especially beneficial for junior raters. The potential of AI was particularly evident in the task of monitoring IA at various intervals, where the AI-based approach surpassed junior raters and achieved performance comparable to senior raters.

Rupture risk of intracranial aneurysms: Comparison between small ruptured intracranial aneurysms and large unruptured intracranial aneurysms.

To compare the differences in clinical and morphological features between small ruptured intracranial aneurysms and large unruptured intracranial aneurysms to evaluate the risk factors for the rupture of IAs. The clinical data of 189 consecutive patients with 193 IAs were reviewed. The patients and IAs were divided into ruptured (<5 mm) and unruptured groups (>10 mm). The characteristics of the patients and the intracranial aneurysms (IAs) were compared between the 2 groups, and the risk factors for rupture of IAs were assessed using multiple logistic regression. Patient age (odds ratio [OR], 0.955), IA located at the internal carotid artery (ICA, OR, 0.202), irregular shape (OR, 0.083) and parent vessel diameter (OR, 0.426) were negatively correlated with the risk of IA rupture. IAs located at bifurcations (OR, 6.766) were positively correlated with the risk of IA rupture. In addition to the size of the IAs, regardless of IAs shape, other factors, such as younger age (<63.5 years), location at a bifurcation, IAs located at the ICA and a small parent vessel diameter (<3.25 mm), can influence the risk of IA rupture.

A comprehensive investigation of morphological features responsible for cerebral aneurysm rupture using machine learning.

Cerebral aneurysms are a silent yet prevalent condition that affects a significant global population. Their development can be attributed to various factors, presentations, and treatment approaches. The importance of selecting the appropriate treatment becomes evident upon diagnosis, as the severity of the disease guides the course of action. Cerebral aneurysms are particularly vulnerable in the circle of Willis and pose a significant concern due to the potential for rupture, which can lead to irreversible consequences, including fatality. The primary objective of this study is to predict the rupture status of cerebral aneurysms. To achieve this, we leverage a comprehensive dataset that incorporates clinical and morphological data extracted from 3D real geometries of previous patients. The aim of this research is to provide valuable insights that can help make informed decisions during the treatment process and potentially save the lives of future patients. Diagnosing and predicting aneurysm rupture based solely on brain scans is a significant challenge with limited reliability, even for experienced physicians. However, by employing statistical methods and machine learning techniques, we can assist physicians in making more confident predictions regarding rupture likelihood and selecting appropriate treatment strategies. To achieve this, we used 5 classification machine learning algorithms and trained them on a substantial database comprising 708 cerebral aneurysms. The dataset comprised 3 clinical features and 35 morphological parameters, including 8 novel morphological features introduced for the first time in this study. Our models demonstrated exceptional performance in predicting cerebral aneurysm rupture, with accuracy ranging from 0.76 to 0.82 and precision score from 0.79 to 0.83 for the test dataset. As the data are sensitive and the condition is critical, recall is prioritized as the more crucial parameter over accuracy and precision, and our models achieved outstanding recall score ranging from 0.85 to 0.92. Overall, the best model was Support Vector Machin with an accuracy and precision of 0.82, recall of 0.92 for the testing dataset and the area under curve of 0.84. The ellipticity index, size ratio, and shape irregularity are pivotal features in predicting aneurysm rupture, respectively, contributing significantly to our understanding of this complex condition. Among the multitude of parameters under investigation, these are particularly important. In this study, the ideal roundness parameter was introduced as a novel consideration and ranked fifth among all 38 parameters. Neck circumference and outlet numbers from the new parameters were also deemed significant contributors.

Circ_0008571 modulates the phenotype of vascular smooth muscle cells by targeting miR-145-5p in intracranial aneurysms.

BACKGROUND: The dysfunction of human vascular smooth cells (hVSMCs) is significantly connected to the development of intracranial aneurysms (IAs). By suppressing the activity of microRNAs (miRNAs), circular RNAs (circRNAs) participate in IA pathogenesis. Nevertheless, the role of hsa_circ_0008571 in IAs remains unclear. METHODS: circRNA sequencing was used to identify circRNAs from human IA tissues. To determine the function of circ_0008571, Transwell, wound healing, and cell proliferation assays were conducted. To identify the target of circ_0008571, the analyses of CircInteractome and TargetScan, as well as the luciferase assay were carried out. Furthermore, circ_0008571 knockdown and over-expression were performed to investigate its functions in IA development and the underlying molecular mechanisms. RESULTS: Both hsa_circ_0008571 and Integrin beta 8 (ITGB8) were downregulated, while miR-145-5p transcription was elevated in the aneurysm wall of IAs patients compared to superficial temporal artery tissues. In vitro, cell migration and growth were dramatically suppressed after hsa_circ_0008571 overexpression. Mechanistically, has_circ_0008571 could suppress miR-145-5p activity by direct sponging. Moreover, we found that ITGB8 expression and the activation of the TGF-ß-mediated signaling pathway were significantly enhanced. CONCLUSION: The hsa_circ_0008571-miR-145-5p-ITGB8 axis plays an essential role in IA progression.

[Analysis of intracranial saccular aneurysm wall: neuroimaging and histopathological correlates]. / Issledovanie stenki intrakranial'nykh meshotchatykh anevrizm: neirovizualizatsionnye i gistopatologicheskie korrelyaty.

BACKGROUND: Contrast enhancement of intracranial aneurysm wall during MRI with targeted visualization of vascular wall correlates with previous aneurysm rupture and, according to some data, may be a predictor of further rupture of unruptured aneurysms. OBJECTIVE: To analyze possible causes of aneurysm contrast enhancement considering morphological data of aneurysm walls. MATERIAL AND METHODS: The study included 44 patients with intracranial aneurysms who underwent preoperative MRI between November 2020 and September 2022. Each aneurysm was assessed regarding contrast enhancement pattern. Microsurgical treatment of aneurysm was accompanied by resection of its wall for subsequent histological and immunohistochemical analysis regarding thrombosis, inflammation and neovascularization. Specimens were subjected to histological and immunochemical analysis. Immunohistochemical analysis was valuable to estimate inflammatory markers CD68 and CD3, as well as neurovascularization marker SD31. RESULTS: Aneurysms with contrast-enhanced walls were characterized by higher number of CD3+, CD68+, CD31+ cells and parietal clots. Intensity of contrast enhancement correlated with aneurysm wall abnormalities. CONCLUSION: Contrast enhancement of aneurysm wall can characterize various morphological abnormalities.

Intracranial aneurysm circulating exosome-derived LncRNA ATP1A1-AS1 promotes smooth muscle cells phenotype switching and apoptosis.

Exosomal long non-coding RNAs (LncRNAs) play a crucial role in the pathogenesis of cerebrovascular diseases. However, the expression profiles and functional significance of exosomal LncRNAs in intracranial aneurysms (IAs) remain poorly understood. Through high-throughput sequencing, we identified 1303 differentially expressed LncRNAs in the plasma exosomes of patients with IAs and healthy controls. Quantitative real-time polymerase chain reaction (qRT-PCR) verification confirmed the differential expression of LncRNAs, the majority of which aligned with the sequencing results. ATP1A1-AS1 showed the most significant upregulation in the disease group. Importantly, subsequent in vitro experiments validated that ATP1A1-AS1 overexpression induced a phenotype switching in vascular smooth muscle cells, along with promoting apoptosis and upregulating MMP-9 expression, potentially contributing to IAs formation. Furthermore, expanded-sample validation affirmed the high diagnostic value of ATP1A1-AS1. These findings suggest that ATP1A1-AS1 is a potential therapeutic target for inhibiting IAs progression and serves as a valuable clinical diagnostic marker.

Internal carotid artery bulb width: a novel potential parameter for the prediction of cerebral vascular diseases.

OBJECTIVE: To investigate the relationship between the width of the internal carotid artery (ICA) bulb and cerebral vascular diseases including stroke and intracranial aneurysms. MATERIAL AND METHODS: In total 300 patients who had supra-aortic computed tomography angiography (CTA) were enrolled in this study from 2015 to 2021. The study groups consisted of 100 ischemic stroke patients, 100 patients with intracranial aneurysms, and 100 control subjects. The intracranial aneurysm patient group was divided into two subgroups according to the presence of subarachnoid hemorrhage (SAH). The largest diameters of the ICA C1 (cervical) and C2 (petrous) segments in all individuals were measured bilaterally on CTA images. The ICA diameter ratios of the cases were measured using the formula C1-C2C1. The relationship between the age and ICA vessel analysis was evaluated as well. RESULTS: The mean ICA bulb width values in the ischemic stroke patient group and the intracranial aneurysm patient group were significantly higher than the control group (p < 0.001). The ICA C1 and C2 segment diameter values and ICA diameter ratio were smaller in the intracranial aneurysm patients with SAH than those who had not (p = 0.7). There was a statistically significant but weak relationship between the age and ICA diameter ratios in all study groups (R-squared value of 0.26, p = 0.03). CONCLUSION: ICA bulb width is a parameter that can be easily evaluated with neuroimaging modalities and is a successful method that may be used for predicting the risk of ischemic stroke or the presence of an intracranial aneurysm.

Effects of regulatory B cells on intracranial aneurysms by mediating IL-1ß/IL-1R pathways.

The purpose of this study was to explore the effects of regulatory B-cells (Breg) on intracranial aneurysms by mediating IL-1ß/IL-1R pathways.  The study involved 60 patients undergoing angiography in a hospital from January to June 2022, divided into two groups: 30 with intracranial aneurysms (observation group) and 30 without (control group). Researchers extracted peripheral blood mononuclear cells (PBMC) to analyze the proportion of CD19+CD24hiCD38hiB cells using flow cytometry. These cells, along with T-cells and regulatory T-cells (Treg), were isolated through magnetic bead cell sorting. Following co-culture, the proliferation of T-cells and their related secretory factors were assessed. Additionally, Breg cells, treated with an IL-1R receptor blocker or IL-1R expression adenovirus, were studied to evaluate the levels of IL-10 and TGF-ß. In the study, the observation group showed lower levels of CD19+CD24hiCD38hiB cells, IL-10, and TGF-ß in PBMC than the control group (P<0.05). T-cell proportions were similar in both groups pre and post co-culture (P>0.05). Post co-culture, IFN-γ decreased while IL-4 increased in both groups. The observation group had higher IFN-γ and lower IL-4 than the control group (P<0.05). TNF-α in CD8+T cells, and granzyme B and perforin mRNA levels decreased post co-culture but were higher in the observation group (P<0.05). IL-10 and TGF-ß in Treg cells increased in both groups post co-culture but were lower in the observation group (P<0.05). The observation group also had fewer CD19+IL-1R+IL-10+B cells (P<0.05). After IL-1R blocker addition, IL-10 and TGF-ß in the supernatant decreased in the observation group (P<0.05). Following transfection, IL-1 and TGF-ß levels increased compared to the blank group (P<0.05). The function of peripheral blood CD19+CD24hiCD38hiB cells is impaired in patients with intracranial aneurysms, which may be related to IL-1ß/IL-1R pathways disorder.

Preliminary Study on Application of Combined Monitoring of Neuroelectrophysiology-Intracranial Pressure-Cerebral Perfusion Pressure in Craniotomy for Intracranial Aneurysm Clipping: An Anatomical and Clinical Study

SUMMARY: Intracranial aneurysm is a common cerebrovascular disease with high mortality. Neurosurgical clipping for the treatment of intracranial aneurysms can easily lead to serious postoperative complications. Studies have shown that intraoperative monitoring of the degree of cerebral ischemia is extremely important to ensure the safety of operation and improve the prognosis of patients. Aim of this study was to probe the application value of combined monitoring of intraoperative neurophysiological monitoring (IONM)-intracranial pressure (ICP)-cerebral perfusion pressure (CPP) in craniotomy clipping of intracranial aneurysms. From January 2020 to December 2022, 126 patients in our hospital with intracranial aneurysms who underwent neurosurgical clipping were randomly divided into two groups. One group received IONM monitoring during neurosurgical clipping (control group, n=63), and the other group received IONM-ICP-CPP monitoring during neurosurgical clipping (monitoring group, n=63). The aneurysm clipping and new neurological deficits at 1 day after operation were compared between the two groups. Glasgow coma scale (GCS) score and national institutes of health stroke scale (NIHSS) score were compared before operation, at 1 day and 3 months after operation. Glasgow outcome scale (GOS) and modified Rankin scale (mRS) were compared at 3 months after operation. All aneurysms were clipped completely. Rate of new neurological deficit at 1 day after operation in monitoring group was 3.17 % (2/63), which was markedly lower than that in control group of 11.11 % (7/30) (P0.05). Combined monitoring of IONM-ICP-CPP can monitor the cerebral blood flow of patients in real time during neurosurgical clipping, according to the monitoring results, timely intervention measures can improve the consciousness state of patients in early postoperative period and reduce the occurrence of early postoperative neurological deficits.

El aneurisma intracraneal es una enfermedad cerebrovascular común con alta mortalidad. El clipaje neuroquirúrgico para el tratamiento de aneurismas intracraneales puede provocar complicaciones posoperatorias graves. Los estudios han demostrado que la monitorización intraoperatoria del grado de isquemia cerebral es extremadamente importante para garantizar la seguridad de la operación y mejorar el pronóstico de los pacientes. El objetivo de este estudio fue probar el valor de la aplicación de la monitorización combinada de la monitorización neurofisiológica intraoperatoria (IONM), la presión intracraneal (PIC) y la presión de perfusión cerebral (CPP) en el clipaje de craneotomía de aneurismas intracraneales. Desde enero de 2020 hasta diciembre de 2022, 126 pacientes de nuestro hospital con aneurismas intracraneales que se sometieron a clipaje neuroquirúrgico se dividieron aleatoriamente en dos grupos. Un grupo recibió monitorización IONM durante el clipaje neuroquirúrgico (grupo de control, n=63) y el otro grupo recibió monitorización IONM-ICP-CPP durante el clipaje neuroquirúrgico (grupo de monitorización, n=63). Se compararon entre los dos grupos el recorte del aneurisma y los nuevos déficits neurológicos un día después de la operación. La puntuación de la escala de coma de Glasgow (GCS) y la puntuación de la escala de accidentes cerebrovasculares de los institutos nacionales de salud (NIHSS) se compararon antes de la operación, 1 día y 3 meses después de la operación. La escala de resultados de Glasgow (GOS) y la escala de Rankin modificada (mRS) se compararon 3 meses después de la operación. Todos los aneurismas fueron cortados por completo. La tasa de nuevo déficit neurológico 1 día después de la operación en el grupo de seguimiento fue del 3,17 % (2/63), que fue notablemente inferior a la del grupo de control del 11,11 % (7/30) (P 0,05). La monitorización combinada de IONM-ICP-CPP puede controlar el flujo sanguíneo cerebral de los pacientes en tiempo real durante el corte neuroquirúrgico; de acuerdo con los resultados de la monitorización, las medidas de intervención oportunas pueden mejorar el estado de conciencia de los pacientes en el período postoperatorio temprano y reducir la aparición de problemas postoperatorios tempranos y déficits neurológicos.

A Systematic Review and Meta-Analysis of the Pathology Underlying Aneurysm Enhancement on Vessel Wall Imaging.

Intracranial aneurysms are common, but only a minority rupture and cause subarachnoid haemorrhage, presenting a dilemma regarding which to treat. Vessel wall imaging (VWI) is a contrast-enhanced magnetic resonance imaging (MRI) technique used to identify unstable aneurysms. The pathological basis of MR enhancement of aneurysms is the subject of debate. This review synthesises the literature to determine the pathological basis of VWI enhancement. PubMed and Embase searches were performed for studies reporting VWI of intracranial aneurysms and their correlated histological analysis. The risk of bias was assessed. Calculations of interdependence, univariate and multivariate analysis were performed. Of 228 publications identified, 7 met the eligibility criteria. Individual aneurysm data were extracted for 72 out of a total of 81 aneurysms. Univariate analysis showed macrophage markers (CD68 and MPO, p = 0.001 and p = 0.002), endothelial cell markers (CD34 and CD31, p = 0.007 and p = 0.003), glycans (Alcian blue, p = 0.003) and wall thickness (p = 0.030) were positively associated with enhancement. Aneurysm enhancement therefore appears to be associated with inflammatory infiltrate and neovascularisation. However, all these markers are correlated with each other, and the literature is limited in terms of the numbers of aneurysms analysed and the parameters considered. The data are therefore insufficient to determine if these associations are independent of each other or of aneurysm size, wall thickness and rupture status. Thus, the cause of aneurysm-wall enhancement currently remains unknown.

CNS-associated macrophages contribute to intracerebral aneurysm pathophysiology.

Intracerebral aneurysms (IAs) are pathological dilatations of cerebral arteries whose rupture leads to subarachnoid hemorrhage, a significant cause of disability and death. Inflammation is recognized as a critical contributor to the formation, growth, and rupture of IAs; however, its precise actors have not yet been fully elucidated. Here, we report CNS-associated macrophages (CAMs), also known as border-associated macrophages, as one of the key players in IA pathogenesis, acting as critical mediators of inflammatory processes related to IA ruptures. Using a new mouse model of middle cerebral artery (MCA) aneurysms we show that CAMs accumulate in the IA walls. This finding was confirmed in a human MCA aneurysm obtained after surgical clipping, together with other pathological characteristics found in the experimental model including morphological changes and inflammatory cell infiltration. In addition, in vivo longitudinal molecular MRI studies revealed vascular inflammation strongly associated with the aneurysm area, i.e., high expression of VCAM-1 and P-selectin adhesion molecules, which precedes and predicts the bleeding extent in the case of IA rupture. Specific CAM depletion by intracerebroventricular injection of clodronate liposomes prior to IA induction reduced IA formation and rupture rate. Moreover, the absence of CAMs ameliorated the outcome severity of IA ruptures resulting in smaller hemorrhages, accompanied by reduced neutrophil infiltration. Our data shed light on the unexplored role of CAMs as main actors orchestrating the progression of IAs towards a rupture-prone state.

Balloon neck-plasty to create a wide-necked aneurysm in the elastase-induced rabbit model.

PURPOSE: The elastase-induced aneurysm (EIA) model in rabbits has been proposed for translational research; however, the adjustment of aneurysm neck size remains challenging. In this study, the technical feasibility and safety of balloon neck-plasty to create a wide-necked aneurysm in rabbit EIA model were investigated. METHODS: Male New Zealand White rabbits (N = 15) were randomly assigned to three groups: group A, EIA creation without neck-plasty; group B, neck-plasty immediately after EIA creation; group C, neck-plasty 4 weeks after EIA creation. The diameter of balloon used for neck-plasty was determined 1 mm larger than origin carotid artery diameter. All rabbits were euthanized 4 weeks after their final surgery. Aneurysm neck, height, dome-to-neck (D/N) ratio, and histologic parameters were compared among the groups. RESULTS: Aneurysm creation was technically successful in 14 out of 15 rabbits (93.3%), with one rabbit experiencing mortality due to an adverse anesthetic event during the surgery. Saccular and wide-necked aneurysms were successfully created in all rabbits. Aneurysm neck was significantly greater in groups B and C compared to group A (all P < .05). D/N ratio was significantly lower in groups B and C compared to group A (all P < .05). Additionally, tunica media thickness, vessel area, and luminal area were significantly greater in groups B and C compared to group A (all P < .05). These variables were found to be significantly greater in group B compared to group C (all P < .05). CONCLUSION: The creation of a wide-necked aneurysm using balloon neck-plasty after elastase induction in rabbits has been determined to be technically feasible and safe.

Three-dimensional wall-thickness distributions of unruptured intracranial aneurysms characterized by micro-computed tomography.

Aneurysmal rupture is associated with wall thinning, but the mechanism is poorly understood. This study aimed to characterize the three-dimensional wall-thickness distributions of unruptured intracranial aneurysms. Five aneurysmal tissues were investigated using micro-computed tomography. First, the wall thickness was related to the aneurysmal wall appearances during surgery. The median wall thicknesses of the translucent and non-translucent walls were 50.56 and 155.93 µm, respectively (p < 0.05) with significant variation in the non-translucent wall thicknesses (p < 0.05). The three-dimensional observations characterized the spatial variation of wall thicknesses. Thin walls showed a uniform thickness profile ranging from 10 to 40 µm, whereas thick walls presented a peaked thickness profile ranging from 300 to 500 µm. In transition walls, the profile undulated due to the formation of focal thin/thick spots. Overall, the aneurysmal wall thicknesses were strongly site-dependent and spatially varied by 10 to 40 times within individual cases. Aneurysmal walls are exposed to wall stress driven by blood pressure. In theory, the magnitude of wall stress is inversely proportional to wall thickness. Thus, the observed spatial variation of wall thickness may increase the spatial variation of wall stress to a similar extent. The irregular wall thickness may yield stress concentration. The observed thin walls and focal thin spots may be caused by excessive wall stresses at the range of mechanical failure inducing wall injuries, such as microscopic tears, during aneurysmal enlargement. The present results suggested that blood pressure (wall stress) may have a potential of acting as a trigger of aneurysmal wall injury.

ADORA3: A Key Player in the Pathogenesis of Intracranial Aneurysms and a Potential Diagnostic Biomarker.

BACKGROUND: The effects of genes on the development of intracranial aneurysms (IAs) remain to be elucidated, and reliable blood biomarkers for diagnosing IAs are yet to be established. This study aimed to identify genes associated with IAs pathogenesis and explore their diagnostic value by analyzing IAs datasets, conducting vascular smooth muscle cells (VSMC) experiments, and performing blood detection. METHODS: IAs datasets were collected and the differentially expressed genes were analyzed. The selected genes were validated in external datasets. Autophagy was induced in VSMC and the effect of selected genes was determined. The diagnostic value of selected gene on the IAs were explored using area under curve (AUC) analysis using IAs plasma samples. RESULTS: Analysis of 61 samples (32 controls and 29 IAs tissues) revealed a significant increase in expression of ADORA3 compared with normal tissues using empirical Bayes methods of "limma" package; this was further validated by two external datasets. Additionally, induction of autophagy in VSMC lead to upregulation of ADORA3. Conversely, silencing ADORA3 suppressed VSMC proliferation and autophagy. Furthermore, analysis of an IAs blood sample dataset and clinical plasma samples demonstrated increased ADORA3 expression in patients with IA compared with normal subjects. The diagnostic value of blood ADORA3 expression in IAs was moderate when analyzing clinical samples (AUC: 0.756). Combining ADORA3 with IL2RB or CCR7 further enhanced the diagnostic ability for IAs, with the AUC value over 0.83. CONCLUSIONS: High expression of ADORA3 is associated with IAs pathogenesis, likely through its promotion of VSMC autophagy. Furthermore, blood ADORA3 levels have the potential to serve as an auxiliary diagnostic biomarker for IAs.

Decreased PDLIM1 expression in endothelial cells contributes to the development of intracranial aneurysm.

INTRODUCTION: Intracranial aneurysm (IA) is a common vascular enlargement that occurs in the wall of cerebral vessels and frequently leads to fatal subarachnoid hemorrhage. PDZ and LIM domain protein 1 (PDLIM1) is a cytoskeletal protein that functions as a platform for multiple protein complex formation. However, whether PDLIM is involved in the pathogenesis of IA remains poorly understood. METHODS: Loss-of-function and gain-of-function strategies were employed to determine the in vitro roles of PDLIM1 in vascular endothelial cells (VECs). A rat model of IA was generated to study the role of PDLIM1 in vivo. Gene expression profiling, Western blotting, and dual luciferase reporter assays were performed to uncover the underlying cellular mechanism. Clinical IA samples were used to determine the expression of PDLIM1 and its downstream signaling molecules. RESULTS: PDLIM1 expression was reduced in the endothelial cells of IA and was regulated by Yes-associated protein 1 (YAP1). Genetic silencing of PDLIM1 inhibited the viability, migratory ability, and tube formation ability of VECs. Opposite results were obtained by ectopic expression of PDLIM1. Additionally, PDLIM1 overexpression mitigated IA in vivo. Mechanistic investigations revealed that PDLIM1 promoted the transcriptional activity of ß-catenin and induced the expression of v-myc myelocytomatosis viral oncogene homolog (MYC) and cyclin D1 (CCND1). In clinical settings, reduced expression of PDLIM1 and ß-catenin downstream target genes was observed in human IA samples. CONCLUSION: Our study indicates that YAP1-dependent expression of PDLIM1 can inhibit IA development by modulating the activity of the Wnt/ß-catenin signaling pathway and that PDLIM1 deficiency in VECs may represent a potential marker of aggressive disease.