Development Of Aneurysms Research Articles

Gut Microbiota Alterations in Patients With Kawasaki Disease.

The intestinal microbiota influences many host biological processes, including metabolism, intestinal barrier functions, and immune responses in the gut and distant organs. Alterations in its composition have been associated with the development of inflammatory disorders and cardiovascular diseases, including Kawasaki disease (KD). KD is an acute pediatric vasculitis of unknown etiology and the leading cause of acquired heart disease in children in the United States. The presence of gastrointestinal symptoms in the acute phase of KD has been associated with an increased risk of treatment resistance and the development of coronary artery aneurysms. Studies report alterations in fecal bacterial communities of patients with KD, characterized by the blooming of pathogenic bacteria and decreased relative abundance of short-chain fatty acid-producing bacteria. However, causality and functionality cannot be established from these observational patient cohorts of KD. This highlights the need for more advanced and rigorous studies to establish causality and functionality in both experimental models of KD vasculitis and patient cohorts. Here, we review the evidence linking an altered gut microbiota composition to the development of KD, assess the potential mechanisms involved in this process, and discuss the potential therapeutic value of these observations.

Mitochondrial NAD+ deficiency in vascular smooth muscle impairs collagen III turnover to trigger thoracic and abdominal aortic aneurysm.

Thoracic and abdominal aortic aneurysm poses a substantial mortality risk in adults, yet many of its underlying factors remain unidentified. Here, we identify mitochondrial nicotinamide adenine dinucleotide (NAD)⁺ deficiency as a causal factor for the development of aortic aneurysm. Multiomics analysis of 150 surgical aortic specimens indicated impaired NAD+ salvage and mitochondrial transport in human thoracic aortic aneurysm, with expression of the NAD+ transporter SLC25A51 inversely correlating with disease severity and postoperative progression. Genome-wide gene-based association analysis further linked low SLC25A51 expression to risk of aortic aneurysm and dissection. In mouse models, smooth muscle-specific knockout of Nampt, Nmnat1, Nmnat3, Slc25a51, Nadk2 and Aldh18a1, genes involved in NAD+ salvage and transport, induced aortic aneurysm, with Slc25a51 deletion producing the most severe effects. Using these models, we suggest a mechanism that may explain the disease pathogenesis: the production of type III procollagen during aortic medial matrix turnover imposes a high demand for proline, an essential amino acid component of collagen. Deficiency in the mitochondrial NAD⁺ pool, regulated by NAD⁺ salvage and transport, hinders proline biosynthesis in mitochondria, contributing to thoracic and abdominal aortic aneurysm.

Fibrillin-1 deficiency perturbs aortic cholinergic relaxation and adrenergic contraction in a mouse model of early onset progressively severe Marfan syndrome.

The pathogenic role of nitric oxide (NO) signaling during development of thoracic aortic aneurysm (TAA) in Marfan syndrome (MFS) is currently unclear. We characterized vasomotor function and its relationship to the activity of the NO-generating enzymes in mice with early onset progressively severe MFS. Wire myography, immunoblotting, measurements of aortic NO and superoxide levels were used to compare vasomotor function, contractile-protein levels, and the activity of endothelial and inducible NO synthase (eNOS and iNOS, respectively) in ascending thoracic aortas of Fbn1mgR/mgR mice relative to wild type (WT) littermates. Isometric force measurements of aortic rings from 16-day-old male Fbn1mgR/mgR mice revealed a significant reduction in acetylcholine (ACh)-induced relaxation and increased phenylephrine (PE)-promoted contractility, associated with abnormally low eNOSSer1177 phosphorylation, decreased NO production and augmented superoxide levels. Greater aortic contractility was associated with α1-adrenoceptor upregulation and normal levels of contractile proteins. While iNOS inhibition had no effect on vasomotor functions, mutant aortic rings pre-incubated with a non-specific NOS inhibitor yielded a greater PE response, implying a significant contribution of endothelial dysfunction to aortic hypercontractility. Impaired eNOS signaling disrupts aortic cholinergic relaxation and adrenergic contraction in MFS mice with dissecting TAA.

Impact of A1 segment asymmetry on hemodynamic conditions around the circle of Willis and anterior communicating artery aneurysm formation.

This study aims to investigate how A1 segment asymmetry-also known as A1 dominancy-influences the development of the anterior communicating artery aneurysm (AcomA) as it affects hemodynamic conditions within the circle of Willis (COW). Using time-of-flight magnetic resonance angiography (TOF-MRA), the research introduces a novel approach to assessing shear stress in A1 segments to uncover the hemodynamic factors contributing to AcomA formation. An observational study was conducted over 6 years at a tertiary university hospital's outpatient clinic. Recruited patients who underwent TOF-MRA imaging were divided into AcomA and non-AcomA groups. MRA images were analyzed using semi-automatic software (VINT, Mediimg, Inc.) to calculate the signal intensity gradient (SIG), which reflects wall shear stress. The comparison metrics included general demographics, anatomical characteristics, and hemodynamic attributes of the COW, mainly focusing on A1 segment asymmetry. Among the 700 subjects, 106 were categorized into the AcomA group, while 594 were placed in the non-AcomA group. The AcomA group showed a more significant difference in the bilateral A1 diameter (49.0% vs. 20.8%, p < 0.001) and a greater prevalence of unilateral A1 aplasia (32.1% vs. 6.7%, p < 0.001) compared to the non-AcomA group. Increased bilateral A1 asymmetry in the AcomA group corresponded with notable variations in A1 SIG, indicating increased wall shear stress. The occurrence of AcomA is associated with both anatomical factors of the circle of Willis, represented by the bilateral A1 diameter ratio, and hemodynamic factors, represented by the bilateral A1 SIG ratio, suggesting that both factors are almost equally significant. Our findings suggest that A1 segment asymmetry influences hemodynamic changes within the COW, contributing to AcomA formation. Hemodynamic factors provide an intuitive understanding of how anatomical characteristics within the COW can lead to aneurysm development.

Computational Analysis of Flow and Transport Suggests Reduced Oxygen Levels Within Intracranial Aneurysms, Especially in Individuals With Sickle-Cell Disease.

Sickle cell disease (SCD) is a genetic condition characterized by an abundance of sickle hemoglobin in red blood cells. SCD patients are more prone to intracranial aneurysms (ICA) compared to the general population, with distinctive features such as multiple intracranial aneurysms: 66% of SCD patients with ICAs have multiples ICAs, compared to 20% in nonsickle patients. The exact mechanism behind these associations is not fully understood, but there is a hypothesized link between hypoxic conditions in blood vessels and impaired synthesis of extracellular matrix, which may weaken the vessel walls, favoring aneurysm formation and rupture. SCD patients experience reduced oxygen levels in their blood, potentially exacerbating hypoxia in intracranial aneurysms, and potentially creating a feedback loop that could contribute to aneurysm development and early onset in these patients. In this work, we performed a series of computational studies (Fluent) using idealized geometries to investigate the key differences in the oxygen transport and blood flow dynamics inside an aneurysm formation for sickle and nonsickle cases. We found that using sickle cell disease parameters resulted in a 14% to 68% reduction in blood flow and a 37% to 70% reduction in oxygen availability within the aneurysm, depending on the vessel curvature and the aneurysm throat diameter, due to factors including oxygen-dependent viscosity and alteration in the oxygen transport. The results indicate that depending on geometry and flow characteristics, some degree of hypoxia maybe present in aneurysm bulb and would be more severe in sickle-cell disease patients. This study hopes to bring into attention the potential presence of hypoxic environment in the aneurysm bulb.

Interpretation of intra-operative strain differences in ascending thoracic aortic repair patients

Local biaxial deformation plays a pivotal role in evaluating the tissue state of the ascending aorta and in driving intramural cell-mediated tissue remodeling. Unfortunately, the absence of anatomical markers on the ascending aorta presents challenges in capturing deformation. Utilizing our established intra-operative biaxial strain measurement method, we delineated local biaxial deformation characteristics in patients undergoing aortic valve replacement and coronary artery bypass graft surgery recipients (n = 20), and Aortic Repair surgery patients (n = 47). Expectedly, mean circumferential strains positively correlated with pulse pressure and negatively correlated with age and diameter. A new observation was that the mean axial strains exhibited the same trend as the mean circumferential strains when correlated with pulse pressure, age and diameter. Interestingly, on analyzing local biaxial strains, our findings revealed higher circumferential strains (by 1 %) proximal to the heart compared to distal regions across the cohorts and within each patient cohort. Furthermore, no discernible regional strain distinctions were noted between the medial and lateral sides of the ascending aorta for the entire patient population and individual cohorts. Patients undergoing Aortic Repair surgery indicated lower strains (ranging from 1 to 3 %) as compared to the other cohort. Our approach holds the potential to establish a foundational framework for the integrated examination of the mechanical and biological conditions and their role in ascending aortic aneurysm development.

Intervention effect of regulating GABA-A receptor activity on the formation of experimental abdominal aortic aneurysm in rats

Abdominal aortic aneurysm is a potentially fatal vascular inflammatory disease characterized by infiltration of various inflammatory cells.The GABA-A receptor is expressed in many inflammatory cells such as macrophages and T cells and has anti-inflammatory and antioxidant effects. Therefore, the GABA-A receptor may become a potential therapeutic target for abdominal aortic aneurysms. The purpose of this study was to investigate the effect of regulating the activity of the GABA-A receptor on the formation of experimental abdominal aortic aneurysm in rats. In this study, the abdominal aortic aneurysm model of rats was established by aorta intracavitary perfusion of elastase combined with aorta extracavitary infiltration of calcium chloride. GABA-A receptor agonist (topiramate) and antagonist (bicuculline) were used to treating the abdominal aortic aneurysm model rats, which were divided into sham operation group, model group, topiramate group, and bicuculline group(n = 10). Histopathology, immunohistochemistry, fluorescence quantitative PCR, Western blotting, ELISA and Gelatine zymogram were used to study. Regulation of GABA-A receptor activity can interfere with the development and severity of abdominal aortic aneurysms in rats. The GABA-A receptor agonist topiramate reduces the infiltration of inflammatory cells, particularly T cells, into the abdominal aortic wall, while also modulating the balance of Th1/Th2 cytokines in peripheral blood, leading to a significant reduction in inflammatory responses. Additionally, topiramate decreases the secretion of matrix metalloproteinases MMP2 and MMP9, thereby inhibiting extracellular matrix degradation and slowing the progression of aneurysms. In contrast, the GABA-A receptor antagonist bicuculline exacerbates inflammation and promotes aneurysm development. At the molecular level, the mechanisms of action of the GABA-A receptor agonist topiramate and the antagonist bicuculline may involve inhibition or activation of the p38 MAPK signaling pathway. Regulation of GABA-A receptor activity can effectively intervene in the occurrence and development of abdominal aortic aneurysms in rats.

Deficiency of ATF3 facilitates both angiotensin II-induced and spontaneously formed aortic aneurysm and dissection development by activating cGAS-STING pathway.

Sporadic aortic aneurysm and dissection (AAD) is a critical condition characterised by the progressive loss of vascular smooth muscle cells (VSMCs) and the breakdown of the extracellular matrix. However, the molecular mechanisms responsible for the phenotypic switch and loss of VSMCs in AAD are not fully understood. In this study, we employed a discovery-driven, unbiased approach. This approach encourages us to explore the unknown functions of activating transcription factor 3 (ATF3) rather than merely confirming existing hypotheses, while no assumptions were made about ATF3 prior to the experiments. We ensured the unbiased nature of our assessment by conducting morphological evaluations with two independent observers in a blinded manner. We identified elevated expression of ATF3 in both human sporadic AAD tissues and mouse AAD models. VSMC-specific ATF3 conditional knockout (Atf3 cKO) mice showed notable enlargement, dissection and rupture in both thoracic and abdominal aortic regions after exposure to Ang II. Interestingly, older Atf3 cKO mice exhibited spontaneous aortic dissections and senescence of the aortic wall. Mechanistically, ATF3 deficiency led to the degradation of P21 through ubiquitination. Impaired DNA repair in VSMCs resulted in micronuclei formation in the cytoplasm, activating the cyclicGMP-AMP synthase- stimulator of interferon genes (cGAS-STING) pathway and inducing VSMC phenotypic switching and apoptosis. Finally, both pharmacological complementation of P21 function and knockdown of STING expression alleviated ATF3 deficiency-induced AAD. Our study indicates that ATF3 is essential for genomic DNA stability in VSMCs through the P21-cGAS-STING pathway, suggesting that enhancing ATF3 expression in VSMCs could help prevent sporadic AAD. ATF3 deficiency led to degradation of P21 through ubiquitination, which abolished the G1 phase arrest. VSMCs had no time window to repair the damaged DNA, leading to generation of micronuclei in cytoplasm. Cytoplasmic micronuclei facilitating the activation of cGAS-STING pathway, thus inducing the phenotypic switch and apoptosis of VSMCs.

Predictors of Left Ventricular Ejection Fraction Decrease in Patients With ST-Segment Elevation Myocardial Infarction.

To identify predictors and construct a model for predicting left ventricular (LV) ejection fraction (EF) in patients with ST-segment elevation myocardial infarction (STEMI). This was a prospective registry study of patients with STEMI admitted within the first 24 hours of the disease onset. Patients were evaluated and treated according to the current clinical guidelines. On the first day of STEMI, concentrations of growth stimulating factor, proprotein convertase subtilisin-kexin type 9 (PCSK9), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin I and C-reactive protein were measured. Echocardiography was performed on the first day and on day 10-12 of admission; LVEF was calculated by the Simpson method. The study included 138 patients; 3 patients were excluded from this part of the study due to death before repeat echocardiography. Based on the LVEF value on day 10-12 of STEMI, the patients were divided into the groups with preserved LVEF (pLVEF) ≥50% (n=34), reduced LVEF (rLVEF) ≤40% (n=21), and moderately reduced LVEF (mrLVEF) 41-49% (n=80). The ordinal regression analysis showed that the factors influencing LVEF in STEMI patients included a history of chronic heart failure, Killip class II-IV acute heart failure at the index hospitalization, the development of LV dilation and postinfarction aneurysm, and an increase in NTproBNP. Based on the obtained estimates of the regression parameters, a prognostic model was constructed that showed the highest sensitivity of the model for predicting rLVEF, 94.4%, mrLVEF, 92.9%, and a lower sensitivity for predicting pLVEF, 62.5%. In the presence of a history of chronic heart failure, Killip class II-IV acute heart failure, developed LV dilation and postinfarction aneurism, and elevated NTproBNP, patients with STEMI are expected to have lower LVEF values.

LncRNA PVT1 Promotes Intracranial Aneurysm Development via USP10/KLF4/NLRP3 Axis‐Mediated Pyroptosis in Human Cerebral Smooth Muscle Cells

ABSTRACTOur previous research identified that lncRNA PVT1 is upregulated in patients with IA. However, the precise functions of PVT1 in IA remain unclear. We compared the levels of PVT1, caspase‐3, caspase‐1, and NLRP3 in normal and IA patients. The GEO database was utilized to evaluate the expression of KLF4 and NLRP3 in IA. In vitro, we constructed transfected plasmids for silencing (si) and overexpression (oe) of PVT1 and USP10. We assessed cell apoptosis and measured the levels of IL‐18, IL‐1β, NLRP3, ASC, GSDMD‐N, cleaved‐caspase‐3, and cleaved‐caspase‐1. CHX chase, immunoprecipitation assays, and bioinformatics tools were employed to evaluate the interactions among PVT1, USP10, and KLF4. Significant differences were observed in the levels of PVT1, KLF4, NLRP3, caspase‐3, caspase‐1, and histological examinations between normal and IA patients. Compared to the oe‐NC group, the levels of IL‐18, IL‐1β, NLRP3, ASC, GSDMD‐N, cleaved‐caspase‐3, and cleaved‐caspase‐1 were significantly increased in the oe‐PVT1 and oe‐USP10 groups. The effect of oe‐USP10 was completely inhibited in the oe‐USP10+si‐PVT1 group. The RIPseq database demonstrated that PVT1 interacts with both USP10 and KLF4. The CHX chase assay showed that KLF4 interacts with both USP10 and PVT1. The RIP assay confirmed the interaction between PVT1 and USP10. The Co‐IP assay and UbiBrowser indicated that KLF4 interacts with USP10. The ChIP assay demonstrated that KLF4 interacts with NLRP3. PVT1 may play a role in the pathophysiology of IA by regulating the USP10/KLF4/NLRP3 axis‐mediated pyroptosis of HCSMCs.

Cancer-type somatic mutations in saccular cerebral aneurysms.

Intracranial aneurysms (IAs) are a major cause of subarachnoidal hemorrhage (SAH) which can have a significant morbidity and mortality. The processes underlying the aneurysm development remains unclear. We performed whole exome sequencing of DNA derived from 20 saccular cerebral aneurysms of 20 patients, followed by somatic variant calling. Eleven (55%) of the 20 patients had detectable nonsynonymous somatic mutations and in total, 48 mutations were detected in the aneurysm samples. The mutations were highly enriched in cancer-related genes and 77% were predictably deleterious. A p.Tyr562Asp somatic mutation was detected in the PDGFRB gene; somatic mutations at the same codon have been reported in fusiform cerebral aneurysms. These results widen the concept on the role of somatic mutations in cerebral aneurysms, indicating their possible role in the more common saccular aneurysm, similarly to the rarer fusiform aneurysm.

Aneurysm Formation at the Internal Carotid Artery Bifurcation Is Related to the Vascular Geometry of the Bifurcation.

In this study, we aimed to comparatively evaluate the morphology of internal carotid artery (ICA) bifurcations with and without aneurysms and identify risk factors for aneurysm development that are associated with the bifurcation geometry. In this two-center study, the computerized tomography angiography data of 1512 patients were evaluated. The study included 64 (4.2%) patients with ICA bifurcation aneurysms (ICAbifAn) and patients with anterior circulation aneurysms (non-ICAbifAn). ICA (P1) was defined as the parent artery, and the middle (M1) and anterior (A1) cerebral artery segments were defined as daughter arteries. We measured the diameters of the P1, M1, and A1 and their ratios (BifSR) to identify the risk factors. In addition, we calculated the bifurcation angle in two ways by measuring all angles between the P1 and daughter arteries and compared these two methods. The first method was the angle between the M1 and A1 (α), and the second was the sum of the angles between the P1 and daughter arteries (BifA). A total of 163 patients who met the inclusion criteria were included in this study: 58 patients in the ICAbifAn group and 105 patients in the non-ICAbifAn group. A univariate logistic regression analysis revealed that the P1, BifSR, α, and BifA measurements were significant predictors of aneurysm formation. However, after a multivariate analysis, only the BifA angle retained its significance (OR, 0.911 (0.877-0.946), p < 0.001). In the ROC curve, the optimal BifA threshold for accurately differentiating between an ICAbifAn and non-aneurysmal bifurcation was 210° (area under the curve (AUC), 0.81; sensitivity, 69%; and specificity, 87%). The α angle had an AUC of 0.68. These results suggest that bifurcation geometry plays a significant role in the likelihood of aneurysm formation. We also showed that the BifA was more predictive of aneurysm formation than the α angle.

Coordination among cytoskeletal organization, cell contraction, and extracellular matrix development is dependent on LOX for aneurysm prevention.

Distinct and seemingly independent cellular pathways affecting intracellular machinery or extracellular matrix (ECM) deposition and organization have been implicated in aneurysm formation. One of the key genes associated with this pathology in both humans and mice is lysyl oxidase (LOX), a secreted ECM-modifying enzyme, highly expressed in medial vascular smooth muscle cells. To dissect the mechanisms leading to aneurysm development, we conditionally deleted Lox in smooth muscle cells. We find that cytoskeletal organization is lost following Lox deletion. Cell culture assays and in vivo analyses demonstrate a cell-autonomous role for LOX affecting myosin light-chain phosphorylation and cytoskeletal assembly resulting in irregular smooth muscle contraction. These results not only highlight new intracellular roles for LOX, but notably, they provide a link between multiple processes leading to aneurysm formation, suggesting LOX coordinates ECM development, cytoskeletal organization, and cell contraction required for media development and function.

Association between high-density lipoprotein cholesterol and risk of abdominal aortic aneurysm among males and females aged 60years and over.

Whether high-density lipoprotein cholesterol (HDL-C) has a protective role against abdominal aortic aneurysm (AAA) development in both older males and females remains uncertain. This study aims to assess the sex-specific association between HDL-C and incident AAA in older adults from the UK Biobank. This cohort study included 86,184 males and 95,682 females aged ≥60years from the UK biobank. Baseline HDL-C was modelled either as a continuous or categorical variable. The primary outcome was incident AAA. Cox proportional hazard models were used for sex-stratified analysis, adjusting for baseline confounders. Restricted cubic splines were plotted to visualize any nonlinear relationship. Harrell's C-index was calculated to assess the added value of HDL-C to the discrimination of model including age and smoking. Over a mean follow-up of 14.4years, 1549 and 328 incident AAA were observed in males and females, respectively. Adjusted hazard ratios for AAA with a 1-mmol/L HDL-C increase was 0.26 (95% confidence interval, 0.21- 0.32) and 0.31 (95% confidence interval, 0.21-0.46) in males and females, respectively (both P< .001). Consistent with the results from Cox model modelling HDL-C as a categorical variable showing an inverse and dose-dependent relationship between HDL-C and incident AAA in both sexes, restricted cubic splines confirmed the monotonic, inverse associations. Adding HDL-C to a model including age and smoking significantly improve the model discrimination for AAA in both sexes (C-index+2.1% in males and+1.5% in females; both P< .05). This study revealed a significant association between low HDL-C levels and a high risk of incident AAA in both older males and females, suggesting the potential clinical usefulness of HDL-C for AAA risk stratification. Our study was limited by its observational design and the presence of possible residual confounding. Studies using real-world data are warranted to evaluate the practical implications of incorporating HDL-C into AAA screening guidelines and its impact on patient outcomes.

Glucose transporter 1 in vascular smooth muscle cells is dispensable for abdominal aortic aneurysm induced by angiotensin II

Treatment with an inhibitor of glucose utilization via glucose transporters (GLUT) has been shown to attenuate experimental abdominal aortic aneurysm (AAA) development in mice. Vascular smooth muscle cell signaling appears essential for angiotensin II-induced AAA in mice. Accordingly, we have tested a hypothesis that VSMC silencing of the major GLUT, GLUT1, prevents AAA development and rupture in mice treated with angiotensin II plus β-aminopropionitrile. A mouse model of inducible VSMC GLUT1 deletion was created and aortic GLUT1 silencing was confirmed. Without angiotensin II plus β-aminopropionitrile treatment, no difference was observed regarding the external aortic diameter (control 1.06±0.18 mm vs deletion 0.97±0.26 mm) or systolic blood pressure (control 102±9 mmHg vs deletion 107±11 mmHg) between control or GLUT1 silenced mice. With treatment, control mice as well as vascular smooth muscle cell GLUT1 silenced mice equally developed AAA (control 2.37±0.75 mm vs deletion 2.41±0.93 mm) whereas a tendency toward lower blood pressure was observed in GLUT1 silenced mice (control 150±9 mmHg vs deletion 135±22 mmHg). No significant difference was observed regarding the rate of rupture-dependent mortality. We concluded that vascular smooth muscle cell GLUT1 is dispensable for AAA development induced by angiotensin II in mice.

Exercise, Sports, and Cardiac Rehabilitation Recommendations in Patients with Aortic Aneurysms and Post-Aortic Repair: A Review of the Literature.

Balancing the well-documented benefits of regular exercise, particularly its positive impact on cardiovascular risk factors like hypertension, with the potential risks for patients with aortic aneurysms presents a significant challenge. This narrative review aims to summarize the current evidence and guidelines to assist clinicians in making informed exercise and sports recommendations for patients with aortic aneurysms or post-aortic repair. Nine clinical trials on the effect of exercise on abdominal aortic aneurysms (AAAs) were identified, including one study on cardiopulmonary exercise testing (CPET) in AAA patients. As no clinical trials on exercise in thoracic aortic aneurysms (TAAs) were found, we extrapolated data from other studies on exercise in aortic diseases, including data from patients who have had an aortic dissection, as well as three studies on cardiac rehabilitation (CR) and one study on CPET after proximal aortic repair. Review articles and guidelines were also incorporated to ensure a comprehensive overview of the topic. Currently, no clear correlation exists between intense sports activities and the development of aortic aneurysms or dissections. Light to moderate physical activity appears safe and beneficial for patients with aortic aneurysms and post-aortic repair. Given the lack of evidence linking athletic activity to aortic complications, caution is warranted in restricting such activities for athletes, underscoring the importance of shared decision-making. Regular follow-up and optimal management of cardiovascular risk factors are essential.

High wall shear stress-dependent podosome formation in a novel murine model of intracranial aneurysm

High wall shear stress (HWSS) contributes to intracranial aneurysm (IA) development. However, the underlying molecular mechanisms remain unclear, in part due to the lack of robust animal models that develop IAs in a HWSS-dependent manner. The current study established a new experimental IA model in mice that was utilized to determine HWSS-triggered downstream mechanisms. By a strategic combination of HWSS and low dose elastase, IAs were induced with a high penetrance in hypertensive mice. In contrast, no IAs were observed in control groups where HWSS was absent, suggesting that our new IA model is HWSS-dependent. IA outcomes were assessed by neuroscores that correlate with IA rupture events. Pathological analyses confirmed these experimental IAs resemble those found in humans. Interestingly, HWSS alone promotes the turnover of collagen IV, a major basement membrane component underneath the endothelium, and the formation of endothelial podosomes, subcellular organelles that are known to degrade extracellular matrix proteins. These induced podosomes are functional as they degrade collagen-based substrates locally in the endothelium. These data suggest that this new murine model develops IAs in a HWSS-dependent manner and highlights the contribution of endothelial cells to the early phase of IA. With this model, podosome formation and function was identified as a novel endothelial phenotype triggered by HWSS, which provides new insight into IA pathogenesis.

Genetic Manipulation of Caveolin-1 in a Transgenic Mouse Model of Aortic Root Aneurysm: Sex-Dependent Effects on Endothelial and Smooth Muscle Function.

Marfan syndrome (MFS) is a systemic connective tissue disorder stemming from mutations in the gene encoding Fibrillin-1 (Fbn1), a key extracellular matrix glycoprotein. This condition manifests with various clinical features, the most critical of which is the formation of aortic root aneurysms. Reduced nitric oxide (NO) production due to diminished endothelial nitric oxide synthase (eNOS) activity has been linked to MFS aortic aneurysm pathology. Caveolin-1 (Cav1), a structural protein of plasma membrane caveolae, is known to inhibit eNOS activity, suggesting its involvement in MFS aneurysm progression by modulating NO levels. In this study, we examined the role of Cav1 in aortic smooth muscle and endothelial function, aortic wall elasticity, and wall strength in male and female MFS mice (FBN1+/Cys1041Gly) by generating developing Cav1-deficient MFS mice (MFS/Cav1KO). Our findings reveal that Cav1 ablation leads to a pronounced reduction in aortic smooth muscle contraction in response to phenylephrine, attributable to an increase in NO production in the aortic wall. Furthermore, we observed enhanced aortic relaxation responses to acetylcholine in MFS/Cav1KO mice, further underscoring Cav1's inhibitory impact on NO synthesis within the aorta. Notably, van Gieson staining and chamber myography analyses showed improved elastin fiber structure and wall strength in male MFS/Cav1KO mice, whereas these effects were absent in female counterparts. Cav1's regulatory influence on aortic root aneurysm development in MFS through NO-mediated modulation of smooth muscle and endothelial function, with notable sex-dependent variations.

PIEZO1 attenuates Marfan syndrome aneurysm development through TGF-β signaling pathway inhibition via TGFBR2.

Marfan syndrome (MFS) is a hereditary disorder primarily caused by mutations in the FBN1 gene. Its critical cardiovascular manifestation is thoracic aortic aneurysm (TAA), which poses life-threatening risks. Owing to the lack of effective pharmacological therapies, surgical intervention continues to be the current definitive treatment. In this study, the role of Piezo-type mechanosensitive ion channel component 1 (Piezo1) in MFS was investigated and the activation of PIEZO1 was identified as a potential treatment for MFS. PIEZO1 expression was detected in MFS mice (Fbn1C1041G/+) and patients. Piezo1 conditional knockout mice in vascular smooth muscle cells of MFS mice (MFS × CKO) was generated, and bioinformatics analysis and experiments in vitro and in vivo were performed to investigate the role of Piezo1 in MFS. PIEZO1 expression decreased in the aortas of MFS mice; MFS × CKO mice showed aggravated TAA, inflammation, extracellular matrix remodelling, and TGF-β pathway activation compared to MFS mice. Mechanistically, PIEZO1 knockout exacerbated the activation of the TGF-β signalling pathway by inhibiting the endocytosis and autophagy of TGF-β receptor 2 mediated by Rab GTPase 3C. Additionally, the pharmacological activation PIEZO1 through Yoda1 prevented TGF-β signalling pathway activation and reversed TAA in MFS mice. Piezo1 deficiency aggravates MFS aneurysms by promoting TGF-β signalling pathway activation via TGF-β receptor 2 endocytosis and a decrease in autophagy. These data suggest that PIEZO1 may be a potential therapeutic target for MFS treatment.

Computational hemodynamic pathophysiology of internal carotid artery blister aneurysms

ObjectiveBlister aneurysms of the internal carotid artery (ICA) are rare and are primarily documented in the literature through small series and case reports. The intraoperative observation of a hemorrhage in the artery wall proximal to the aneurysmal bulge led to the hypothesis that some of these aneurysms might develop in a retrograde manner.MethodsWe developed software to reconstruct the ICA with and without Type I and II blister aneurysms using patients’ imagery as input to simulate hemodynamic conditions before and after their formation. Kinematic blood flow data before and after aneurysm formation were obtained using a finite volume solver. We compared the wall shear stress (WSS) distribution of the arterial wall prior to aneurysm formation.ResultsIn two out of four cases, WSS was significantly elevated on the dorsal wall of the supraclinoid segment of the ICA at the distal part of the future site of the aneurysm sac, suggesting that the aneurysm sac may ultimately develop in a retrograde fashion. Once the structural changes have been initiated, WSS gradient (WSSG) was significantly elevated at the proximal and distal boundaries of the bulging aneurysmal pouch. Low WSS and high WSSG at the proximal part of the aneurysm sac seem to contribute to the extension of the proximal intramural hematoma observed during blister aneurysm surgery.ConclusionsBy enabling assessment of the impact of elevated WSS and its gradient, our computational pipeline supports the hypothesis that the development of blister aneurysms may occur either in a retrograde or anterograde fashion.