Progression Of Aortic Aneurysms Research Articles

Early growth response 1 exacerbates thoracic aortic aneurysm and dissection of mice by inducing the phenotypic switching of vascular smooth muscle cell through the activation of Krüppel-like factor 5.

Vascular smooth muscle cell (VSMC) phenotypic switching has been reported to regulate vascular function and thoracic aortic aneurysm and dissection (TAAD) progression. Early growth response 1 (Egr1) is associated with the differentiation of VSMCs. However, the mechanisms through which Egr1 participates in the regulation of VSMCs and progression of TAAD remain unknown. This study aimed to investigate the role of Egr1 in the phenotypic switching of VSMCs and the development of TAAD. Wild-type C57BL/6 and SMC-specific Egr1-knockout mice were used as experimental subjects and fed β-aminopropionitrile for 4 weeks to construct the TAAD model. Ultrasound and aortic staining were performed to examine the pathological features in thoracic aortic tissues. Transwell, wound healing, CCK8, and immunofluorescence assays detected the migration and proliferation of synthetic VSMCs. Egr1 was directly bound to the promoter of Krüppel-like factor 5 (KLF5) and promoted the expression of KLF5, which was validated by JASPAR database and dual-luciferase reporter assay. Egr1 expression increased and was partially co-located with VSMCs in aortic tissues of mice with TAAD. SMC-specific Egr1 deficiency alleviated TAAD and inhibited the phenotypic switching of VSMC. Egr1 knockdown prevented the phenotypic switching of VSMCs and subsequently suppressed the migration and proliferation of synthetic VSMCs. The inhibitory effects of Egr1 deficiency on VSMCs were blunted once KLF5 was overexpressed. Egr1 aggravated the development of TAAD by promoting the phenotypic switching of VSMCs via enhancing the transcriptional activation of KLF5. These results suggest that inhibition of SMC-specific Egr1 expression is a promising therapy for TAAD.

Biogenesis of circRBM33 mediated by N6-methyladenosine and its function in abdominal aortic aneurysm

ABSTRACT This study aimed to explore whether m6A modification affects the biogenesis of circRBM33, which is involved in the progression of abdominal aortic aneurysm (AAA). For in vitro experiments, vascular smooth muscle cells (VSMCs) were treated with Ang II. MeRIP‒PCR was used to assess m6A modification of circRBM33. Gene expression was measured using RT‒qPCR and Western blotting. For in vivo experiments, a mouse model of AAA was established via Ang II infusion. HE, Sirius Red and TUNEL staining was performed to evaluate pathological changes and cell apoptosis in aortic vessels. The results showed that the m6A level of circRBM33 was abnormally increased in Ang II-induced VSMCs. In addition, METTL3 positively regulated circRBM33 expression. YTHDC1 deficiency decreased circRBM33 expression but had no effect on RBM33 mRNA expression. Notably, neither METTL3 nor YTHDC1 influenced the stability of circRBM33 or RBM33 mRNA. The interaction between circRBM33 and METTL3/YTHDC1 was verified by RIP analysis. Moreover, the Ang II-induced increase in circRBM33 expression was reversed by cycloleucine (an inhibitor of m6A methylation). Importantly, the m6A modification and expression of circRBM33 in the circRBM33-m6A-mut2-expressing VSMCs were not altered by METTL3 silencing. Mechanistically, METTL3/YTHDC1 modulates the biogenesis of circRBM33 in an m6A-dependent manner. In addition, circRBM33 knockdown alleviated AAA by reducing ECM degradation in the Ang II-infused mice. In conclusion, this study demonstrated that METTL3/YTHDC1-mediated m6A modification modulates the biogenesis of circRBM33 from exons of the RBM33 gene. Moreover, knockdown of circRBM33 alleviated AAA by reducing ECM degradation, which may provide a novel therapeutic strategy for treating AAA.

TRIM25 activates Wnt/β-catenin signalling by destabilising MAT2A mRNA to drive thoracic aortic aneurysm development.

This study explored the roles of methionine adenosyltransferase 2A (MAT2A) and tripartite motif containing 25 (TRIM25) in the progression of thoracic aortic aneurysm (TAA). The TAA model was established based on the β-aminopropionitrile method. The effects of MAT2A on thoracic aortic lesions and molecular levels were analyzed by several pathological staining assays (hematoxylin-eosin, Verhoeff-Van Gieson, TUNEL) and molecular biology experiments (qRT-PCR, Western blot). Angiotensin II (Ang-II) was used to induce injury in vascular smooth muscle cells (VSMCs) in vitro. The effects of MAT2A, shMAT2A, shTRIM25 and/or Wnt inhibitor (IWR-1) on the viability, apoptosis and protein expressions of VSMCs were examined by CCK-8, Annexin V-FITC/PI and Western blot assays. In TAA mice, overexpression of MAT2A alleviated thoracic aortic injury, inhibited the aberrant expressions of aortic contractile proteins and dedifferentiation markers, and blocked the activation of Wnt/β-catenin pathway. In Ang-II-induced VSMCs, up-regulation of MAT2A increased cellular activity and repressed the expression of β-catenin protein. TRIM25 knockdown promoted activity of VSMCs, inhibited apoptosis, and blocked the Wnt/β-catenin pathway activation by binding to MAT2A. IWR-1 partially counteracted the regulatory effects of shMAT2A. Collectively, TRIM25 destabilises the mRNA of MAT2A to activate Wnt/β-catenin signaling and ultimately exacerbate TAA injury.

SLC44A2-mediated phenotypic switch of vascular smooth muscle cells contributes to aortic aneurysm.

The phenotypic switch of vascular smooth cells (VSMCs) from a contractile to a synthetic state is associated with the development and progression of aortic aneurysm (AA). However, the mechanism underlying this process remains unclear. In this issue of the JCI, Song et al. identified SLC44A2 as a regulator of the phenotypic switch in VSMCs. Inhibition of SLC44A2 facilitated the switch to the synthetic state, contributing to the development of AA. Mechanistically, SLC44A2 interacted with NRP1 and ITGB3 to activate the TGF-β/SMAD signaling pathway, resulting in VSMCs with a contractile phenotype. Furthermore, VSMC-specific SLC44A2 overexpression by genetic or pharmacological manipulation reduced AA in mouse models. These findings suggest the potential of targeting the SLC44A2 signaling pathway for AA prevention and treatment.

Associated Factors in Progression of Aortic Aneurysms

Associated Factors in Progression of Aortic Aneurysms

Integrative analysis of single-Cell RNA sequencing and experimental validation in the study of abdominal aortic aneurysm progression

BackgroundAbdominal aortic aneurysm (AAA) is a complex vascular disorder characterized by the progressive dilation of the abdominal aorta, with a high risk of rupture and mortality.Understanding the cellular interactions and molecular mechanisms underlying AAA development is critical for identifying potential therapeutic targets. MethodsThis study utilized datasets GSE197748, GSE164678 and GSE183464 from the GEO database, encompassing bulk and single-cell RNA sequencing data from AAA and control samples. We performed principal component analysis, differential expression analysis, and functional enrichment analysis to identify key pathways involved in AAA. Cell-cell interactions were investigated using CellPhoneDB, focusing on fibroblasts, vascular smooth muscle cells (VSMCs), and macrophages. We further validated our findings using a mouse model of AAA induced by porcine pancreatic enzyme infusion, followed by gene expression analysis and co-immunoprecipitation experiments. ResultsOur analysis revealed significant alterations in gene expression profiles between AAA and control samples, with a pronounced immune response and cell adhesion pathways being implicated. Single-cell RNA sequencing data highlighted an increased proportion of pro-inflammatory macrophages, along with changes in the composition of fibroblasts and VSMCs in AAA. CellPhoneDB analysis identified critical ligand-receptor interactions, notably collagen type I alpha 1 chain (COL1A1)/COL1A2-CD18 and thrombospondin 1 (THBS1)-CD3, suggesting complex communication networks between fibroblasts and VSMCs. In vivo experiments confirmed the upregulation of these genes in AAA mice and demonstrated the functional interaction between COL1A1/COL1A2 and CD18. ConclusionThe interaction between fibroblasts and VSMCs, mediated by specific ligand-receptor pairs such as COL1A1/COL1A2-CD18 and THBS1-CD3, plays a pivotal role in AAA pathogenesis.

Abstract Tu019: Single-Cell RNA Sequencing Identifies IFNICs as a Cellular Target for Mitigating the Progression of Abdominal Aortic Aneurysm and Rupture Risk

Introduction: Abdominal aortic aneurysm (AAA) represents a life-threatening condition characterized by medial layer degeneration of the abdominal aorta. Nevertheless, knowledge regarding changes in regulators associated with aortic status remains incomplete. A thorough understanding of cell types and signaling pathways involved in the development and progression of AAAs is essential for the development of medical therapy. Methods and Results: We harvested specimens of the abdominal aorta with different pathological features in Angiotensin II (AngII)-infused ApoE -/- mice, conducted scRNA-seq, identified a unique population of interferon-inducible monocytes/macrophages (IFNICs), which were amply found in the abdominal aortic aneurysms (AAAs). Gene set variation analysis (GSVA) revealed that activation of the cytosolic DNA sensing cGAS-STING and JAK-STAT pathways promoted the secretion of type I interferons in monocytes/macrophages and differentiated them into IFNICs. We generated myeloid cell-specific deletion of Sting1 ( Lyz2 -Cre +/- ; Sting1 flox/flox ) mice and performed bone marrow transplantation and found that myeloid cell-specific deletion of Sting1 or Ifnar1 significantly reduced the incidence of AAA, aortic rupture rate and diameter of the abdominal aorta. Mechanistically, the activated pyroptosis- and inflammation-related signaling pathways, regulated by IRF7 in IFNICs, play critical roles in the developing AAAs. Conclusion: IFNICs is a unique monocyte/macrophage subset implicated in the development of AAAs and aortic rupture.

Exploiting the anti-fibrotic effects of statins on thoracic aortic aneurysm progression: results from a meta-analysis and experimental data.

Thoracic aortic aneurysm (TAA) that progress to acute aortic dissection is often fatal and there is no pharmacological treatment that can reduce TAA progression. We aim to evaluate statins' effects on TAA growth rate and outcomes using a meta-analysis approach. A detailed search related to the effects of statins on TAA was conducted according to PRISMA guidelines. The analyses of statins' effects on TAA growth rate were performed on 4 studies (n = 1850), while the impact on outcomes was evaluated on 3 studies (n = 2,867). Patients under statin treatment showed a reduced TAA growth rate (difference in means = -0.36cm/year; 95%CI: -0.64, -0.08; p = 0.013) when compared to controls, patients not taking statins. Regarding the outcomes (death, dissection, or rupture of the aorta, and the need for operative repair), statins exhibited a protective effect reducing the number of events (log odds ratio = -0.56; 95%CI: -1.06, -0.05; p = 0.030). In vitro, the anti-fibrotic effect of atorvastatin was tested on vascular smooth muscle cells (VMSC) isolated from patients with TAA. Our results highlighted that, in transforming growth factor beta 1 (TGF-β1) pro-fibrotic condition, VSMC expressed a significant lower amount of collagen type I alpha 1 chain (COL1A1) when treated with atorvastatin (untreated = +2.66 ± 0.23 fold-change vs. treated = +1.63 ± 0.09 fold-change; p = 0.014). Statins show a protective effect on TAA growth rate and adverse outcomes in patients with TAA, possibly via their anti-fibrotic properties on VSMC. Given the current lack of effective drug treatments for TAA, we believe our findings highlight the need for more in-depth research to explore the potential benefits of statins in this context.

A comprehensive MRI-based computational model of blood flow in compliant aorta using radial basis function interpolation

BackgroundProperly understanding the origin and progression of the thoracic aortic aneurysm (TAA) can help prevent its growth and rupture. For a better understanding of this pathogenesis, the aortic blood flow has to be studied and interpreted in great detail. We can obtain detailed aortic blood flow information using magnetic resonance imaging (MRI) based computational fluid dynamics (CFD) with a prescribed motion of the aortic wall.MethodsWe performed two different types of simulations—static (rigid wall) and dynamic (moving wall) for healthy control and a patient with a TAA. For the latter, we have developed a novel morphing approach based on the radial basis function (RBF) interpolation of the segmented 4D-flow MRI geometries at different time instants. Additionally, we have applied reconstructed 4D-flow MRI velocity profiles at the inlet with an automatic registration protocol.ResultsThe simulated RBF-based movement of the aorta matched well with the original 4D-flow MRI geometries. The wall movement was most dominant in the ascending aorta, accompanied by the highest variation of the blood flow patterns. The resulting data indicated significant differences between the dynamic and static simulations, with a relative difference for the patient of 7.47±14.18% in time-averaged wall shear stress and 15.97±43.32% in the oscillatory shear index (for the whole domain).ConclusionsIn conclusion, the RBF-based morphing approach proved to be numerically accurate and computationally efficient in capturing complex kinematics of the aorta, as validated by 4D-flow MRI. We recommend this approach for future use in MRI-based CFD simulations in broad population studies. Performing these would bring a better understanding of the onset and growth of TAA.

Circulating inflammatory proteins and abdominal aortic aneurysm: A two-sample Mendelian randomization and colocalization analyses

ObjectivesInflammatory proteins are implicated in the progression of abdominal aortic aneurysms (AAA); however, it remains debated whether they are causal or consequential. This study aimed to assess the influence of circulating inflammatory proteins on AAA via two-sample Mendelian randomization (MR) and colocalization analysis. MethodsSummary data on 91 circulating inflammatory protein levels were extracted from a comprehensive protein quantitative trait loci (pQTL) study involving 14,824 individuals. Genetic associations with AAA were derived from the FinnGen study (3,869 cases and 381,977 controls). MR analysis was conducted to assess the relationships between proteins and AAA risk. Colocalization analysis was employed to explore potential shared causal variants between identified proteins and AAA. ResultsUsing a two-sample bidirectional MR study, our findings suggested that genetically predicted elevated levels of TGFB1 (OR = 1.21, P = 0.003), SIRT2 (OR = 1.196, P = 0.031) and TNFSF14 (OR = 1.129, P = 0.034) were linked to an increased risk of AAA. Conversely, genetically predicted higher levels of CD40 (OR = 0.912, P = 0.049), IL2RB (OR = 0.839, P = 0.028) and KITLG (OR = 0.827, P = 0.008) were associated with a decreased risk of AAA. Colocalization analyses supported the association of TGFB1 and SIRT2 levels with AAA risk. ConclusionsThe proteome-wide MR and colocalization study identified TGFB1 and SIRT2 as being associated with the risk of AAA, warranting further investigation as potential therapeutic targets.

Automatic segmentation of intraluminal thrombosis of abdominal aortic aneurysms from CT angiography using a mixed-scale-driven multiview perception network (M2Net) model

Intraluminal thrombosis (ILT) plays a critical role in the progression of abdominal aortic aneurysms (AAA). Understanding the role of ILT can improve the evaluation and management of AAAs. However, compared with highly developed automatic vessel lumen segmentation methods, ILT segmentation is challenging. Angiographic contrast agents can enhance the vessel lumen but cannot improve boundary delineation of the ILT regions; the lack of intrinsic contrast in the ILT structure significantly limits the accurate segmentation of ILT. Additionally, ILT is not evenly distributed within AAAs; its sparsity and scattered distributions in the imaging data pose challenges to the learning process of neural networks. Thus, we propose a multiview fusion approach, allowing us to obtain high-quality ILT delineation from computed tomography angiography (CTA) data. Our multiview fusion network is named Mixed-scale-driven Multiview Perception Network (M2Net), and it consists of two major steps. Following image preprocessing, the 2D mixed-scale ZoomNet segments ILT from each orthogonal view (i.e., Axial, Sagittal, and Coronal views) to enhance the prior information. Then, the proposed context-aware volume integration network (CVIN) effectively fuses the multiview results.Using contrast-enhanced computed tomography angiography (CTA) data from human subjects with AAAs, we evaluated the proposed M2Net. A quantitative analysis shows that the proposed deep-learning M2Net model achieved superior performance (e.g., DICE scores of 0.88 with a sensitivity of 0.92, respectively) compared with other state-of-the-art deep-learning models. In closing, the proposed M2Net model can provide high-quality delineation of ILT in an automated fashion and has the potential to be translated into the clinical workflow.

Administration of an antibody against apoptosis inhibitor of macrophage prevents aortic aneurysm progression in mice

Apoptosis inhibitor of macrophage (AIM) is known to induce apoptosis resistance in macrophages and to exacerbate chronic inflammation, leading to arteriosclerosis. The role of AIM in aortic aneurysm (AA) remains unknown. This study examined the effects of an anti-AIM antibody in preventing AA formation and progression. In apolipoprotein E-deficient mice, AA was induced by subcutaneous angiotensin II infusion. Mice were randomly divided into two groups: (i) AIM group; weekly anti-murine AIM monoclonal antibody injection (n = 10), and (ii) IgG group; anti-murine IgG antibody injection as control (n = 14). The AIM group, compared with the IgG group, exhibited reduced AA enlargement (aortic diameter at 4 weeks: 2.1 vs. 2.7 mm, respectively, p = 0.012); decreased loss of elastic lamellae construction; reduced expression levels of IL-6, TNF-α, and MCP-1; decreased numbers of AIM-positive cells and inflammatory M1 macrophages (AIM: 1.4 vs. 8.0%, respectively, p = 0.004; M1 macrophages: 24.5 vs. 55.7%, respectively, p = 0.017); and higher expression of caspase-3 in the aortic wall (22.8 vs. 10.5%, respectively, p = 0.019). Our results suggest that administration of an anti-AIM antibody mitigated AA progression by alleviating inflammation and promoting M1 macrophage apoptosis.

Cerebral Microvascular Density, Permeability of the Blood-Brain Barrier, and Neuroinflammatory Responses Indicate Early Aging Characteristics in a Marfan Syndrome Mouse Model.

Marfan Syndrome (MFS) is a connective tissue disorder due to mutations in fibrillin-1 ( Fbn1 ), where a Fbn1 missense mutation ( Fbn1 C1039G/+ ) can result in systemic increases in the bioavailability and signaling of transforming growth factor-β (TGF-β). In a well-established mouse model of MFS ( Fbn1 C1041G/+ ), pre-mature aging of the aortic wall and the progression of aortic root aneurysm are observed by 6-months-of-age. TGF-β signaling has been implicated in cerebrovascular dysfunction, loss of blood-brain barrier (BBB) integrity, and age-related neuroinflammation. We have reported that pre-mature vascular aging in MFS mice could extend to cerebrovasculature, where peak blood flow velocity in the posterior cerebral artery (PCA) of 6-month-old (6M) MFS mice was reduced, similarly to 12-month-old (12M) control mice. Case studies of MFS patients have documented neurovascular manifestations, including intracranial aneurysms, stroke, arterial tortuosity, as well as headaches and migraines, with reported incidence of pain and chronic fatigue. Despite these significant clinical observations, investigation into cerebrovascular dysfunction and neuropathology in MFS remains limited. Using 6M-control ( C57BL/6 ) and 6M-MFS ( Fbn1 C1041G/+ ) and healthy 12M-control male and female mice, we test the hypothesis that abnormal Fbn1 protein expression is associated with altered cerebral microvascular density, BBB permeability, and neuroinflammation in the PCA-perfused hippocampus, all indicative of a pre-mature aging brain phenotype. Using Glut1 staining, 6M-MFS mice and 12M-CTRL similarly present decreased microvascular density in the dentate gyrus (DG), cornu ammonis 1 (CA1), and cornu ammonis 3 (CA3) regions of the hippocampus. 6M-MFS mice exhibit increased BBB permeability in the DG, CA1, and CA3 as evident by Immunoglobulin G (IgG) staining, which was more comparable to 12M-CTRL mice. 6M-MFS mice show a higher number of microglia in the hippocampus compared to age-matched control mice, a pattern resembling that of 12M-CTRL mice. This study represents the first known investigation into neuropathology in a mouse model of MFS and indicates that the pathophysiology underlying MFS leads to a systemic pre-mature aging phenotype. This study is crucial for identifying and understanding MFS-associated neurovascular and neurological abnormalities, underscoring the need for research aimed at improving the quality of life and managing pre-mature aging symptoms in MFS and related connective tissue disorders.

Roles and Mechanisms of miRNAs in Abdominal Aortic Aneurysm: Signaling Pathways and Clinical Insights.

Abdominal aortic aneurysm refers to a serious medical condition that can cause the irreversible expansion of the abdominal aorta, which can lead to ruptures that are associated with up to 80% mortality. Currently, surgical and interventional procedures are the only treatment options available for treating abdominal aortic aneurysm patients. In this review, we focus on the upstream and downstream molecules of the microRNA-related signaling pathways and discuss the roles, mechanisms, and targets of microRNAs in abdominal aortic aneurysm modulation to provide novel insights for precise and targeted drug therapy for the vast number of abdominal aortic aneurysm patients. Recent studies have highlighted that microRNAs, which are emerging as novel regulators of gene expression, are involved in the biological activities of regulating abdominal aortic aneurysms. Accumulating studies suggested that microRNAs modulate abdominal aortic aneurysm development through various signaling pathways that are yet to be comprehensively summarized. A total of six signaling pathways (NF-κB signaling pathway, PI3K/AKT signaling pathway, MAPK signaling pathway, TGF-β signaling pathway, Wnt signaling pathway, and P53/P21 signaling pathway), and a total of 19 miRNAs are intimately associated with the biological properties of abdominal aortic aneurysm through targeting various essential molecules. MicroRNAs modulate the formation, progression, and rupture of abdominal aortic aneurysm by regulating smooth muscle cell proliferation and phenotype change, vascular inflammation and endothelium function, and extracellular matrix remodeling. Because of the broad crosstalk among signaling pathways, a comprehensive analysis of miRNA-mediated signaling pathways is necessary to construct a well-rounded upstream and downstream regulatory network for future basic and clinical research of AAA therapy.

HDL-C mediates the causal relationship between serum urate and aortic aneurysm: a Mendelian randomization study

Background and purpose: Studies have indicated a close relationship between serum urate and an increased risk of aortic aneurysm or aortic dissection. However, the causality between them and the mediators of this association have not been identified. This study employs bidirectional and multivariable Mendelian randomization (MR) to investigate the causality between serum urate and aortic aneurysm or dissection and identify mediators of this relationship. Methods: We first investigated the causal association between serum urate and aortic aneurysm or aortic dissection using two-sample bidirectional MR, with the inverse-variance-weighted method as the principal analysis technique. Subsequently, we applied multivariable MR to determine probable mediators. Results: Genetically serum urate levels were linked to an increased risk of aortic aneurysm (odds ratio [OR]: 1.160, 95% confidence interval [95% CI]: 1.011–1.332, P = 0.034), with high-density lipoprotein cholesterol (HDL-C) mediating this causal relationship, accounting for 10.2% of the effect. No causal relationship was found between serum urate and aortic dissection. Conclusions: Serum urate is a risk factor for aortic aneurysm, and this causal relationship is mediated through HDL-C. Monitoring HDL-C levels in patients with hyperuricemia is essential to prevent and slow the progression of aortic aneurysm.

Bridging the gap: Navigating the impact of dietary supplements on abdominal aortic aneurysm progression- A systematic review.

Vitamins D, E, A, B, C, and Omega-3 play crucial roles in modulating inflammatory and oxidative stress pathways, both implicated in abdominal aortic aneurysm (AAA) development. Recent research has explored the potential impact of dietary supplements on AAA progression. The systematic review aims to assess interventional studies investigating the effects of various dietary supplements on the development and severity of abdominal aortic aneurysms. A systematic search using relevant keywords related to abdominal aortic aneurysm and dietary supplements was conducted across four databases (PubMed, Embase, Scopus, and Web of Science). Quality assessment for animal studies employed SYRCLE and the Cochrane Collaboration Risk of Bias Tool for randomized control trials. The study protocol is registered in PROSPERO under the registry code CRD42023455958. Supplementation with Omega-3, Vitamins A, C, D, E, and the Vitamin B family exhibited positive effects in AAA progression. These supplements contributed to a reduction in AAA diameter, elastin degradation, inflammatory responses, and reactive oxygen species. Additional supplements such as Zinc, methionine, and phytoestrogen also played roles in mitigating AAA progression. The findings of this study underscore the potential role of dietary supplements in the progression of AAA. Predominantly based on animal studies, the results indicate that these supplements can limit AAA progression, primarily evidenced by their ability to mitigate inflammatory processes and oxidative stress pathways.

SLC44A2 regulates vascular smooth muscle cell phenotypic switching and aortic aneurysm.

Aortic aneurysm is a life-threatening disease with limited interventions that is closely related to vascular smooth muscle cell (VSMC) phenotypic switching. SLC44A2, a member of the solute carrier series 44 (SLC44) family, remains undercharacterized in the context of cardiovascular diseases. Venn diagram analysis based on microarray and single-cell RNA sequencing identified SLC44A2 as a major regulator of VSMC phenotypic switching in aortic aneurysm. Screening for Slc44a2 among aortic cell lineages demonstrated its predominant location in VSMCs. Elevated levels of SLC44A2 were evident in the aorta of both patients with abdominal aortic aneurysm and angiotensin II-infused (Ang II-infused) Apoe-/- mice. In vitro, SLC44A2 silencing promoted VSMCs toward a synthetic phenotype, while SLC44A2 overexpression attenuated VSMC phenotypic switching. VSMC-specific SLC44A2-knockout mice were more susceptible to aortic aneurysm under Ang II infusion, while SLC44A2 overexpression showed protective effects. Mechanistically, SLC44A2's interaction with NRP1 and ITGB3 activates TGF-β/SMAD signaling, thereby promoting contractile gene expression. Elevated SLC44A2 in aortic aneurysm is associated with upregulated runt-related transcription factor 1 (RUNX1). Furthermore, low-dose lenalidomide (LEN; 20 mg/kg/day) suppressed aortic aneurysm progression by enhancing SLC44A2 expression. These findings reveal that the SLC44A2-NRP1-ITGB3 complex is a major regulator of VSMC phenotypic switching and provide a potential therapeutic approach (LEN) for aortic aneurysm treatment.

Single-cell RNA sequencing identifies IFNICs as a cellular target for mitigating the progression of abdominal aortic aneurysm and rupture risk.

Abdominal aortic aneurysm (AAA) represents a life-threatening condition characterized by medial layer degeneration of the abdominal aorta. Nevertheless, knowledge regarding changes in regulators associated with aortic status remains incomplete. A thorough understanding of cell types and signaling pathways involved in the development and progression of AAAs is essential for the development of medical therapy. We harvested specimens of the abdominal aorta with different pathological features in Angiotensin II (AngII)-infused ApoE-/- mice, conducted scRNA-seq, identified a unique population of interferon-inducible monocytes/macrophages (IFNICs), which were amply found in the abdominal aortic aneurysms (AAAs). Gene set variation analysis (GSVA) revealed that activation of the cytosolic DNA sensing cGAS-STING and JAK-STAT pathways promoted the secretion of type I interferons in monocytes/macrophages and differentiated them into IFNICs. We generated myeloid cell-specific deletion of Sting1 (Lyz2-Cre+/-; Sting1flox/flox) mice and performed bone marrow transplantation and found that myeloid cell-specific deletion of Sting1 or Ifnar1 significantly reduced the incidence of AAA, aortic rupture rate and diameter of the abdominal aorta. Mechanistically, the activated pyroptosis- and inflammation-related signaling pathways, regulated by IRF7 in IFNICs, play critical roles in the developing AAAs. IFNICs is a unique monocyte/macrophage subset implicated in the development of AAAs and aortic rupture.

A new combinatory pharmacological treatment strategy involving antioxidants to ameliorate aortic aneurysm progression in Marfan syndrome

A new combinatory pharmacological treatment strategy involving antioxidants to ameliorate aortic aneurysm progression in Marfan syndrome

Inhibition of alphaV integrins with cilengitide downregulates in vitro pro-fibrotic events in aortic smooth muscle cells and limits in vivo thoracic aortic aneurysm progression

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Italian Ministry of Health "Ricerca Finalizzata - Giovani Ricercatori" Background The ‘greatest artery’, i.e., the aorta, can be affected by either acute conditions or chronic disorders, such as the aneurysm, which is the segmental aortic dilation with at least 50% increase in the normal diameter. Aortic dilation can often lead to lethal events, such as aortic dissection and/or vessel rupture. The aneurysms occurring in the thoracic trait of the aorta (TAA) may depend on comorbidities, such as hypertension (i.e., sporadic non-syndromic TAA, sTAA), or on genetically determined conditions, such as Marfan syndrome (MFS). To date, the surgical replacement of aorta represents the most effective therapeutic approach in all TAA patients, since an etiologic pharmacological treatment is still lacking. Thus, the identification of novel disease targets is mandatory. Integrin receptors are key players in cellular mechanotransduction responses. Specifically, integrins containing αV subunit have been described as important mechanotransduction mediators and responsible for pro-fibrotic molecular events. Recently, it has been reported the effectiveness of a broad αV integrin inhibitor in limiting the TAA progression by acting on FAK/AKT/mTORC signaling pathway in a MFS in vivo model. However, the specific αV integrin subgroup directly involved in this detrimental process is yet not known. Purpose We evaluated the effectiveness of a specific αVβ3 and αVβ5 integrin inhibitor (i.e., cilengitide) in downregulating pro-fibrotic in vitro events on vascular smooth muscle cells (VSMC) isolated from TAA patients’ aortic wall, and in limiting in vivo thoracic aortic dilation on a MFS mice model. Results By comparison with healthy control (HC)-VSMC, both sTAA-VSMC and MFS-VSMC showed higher levels of αVβ3 and αVβ5 integrins as well as pro-fibrotic collagen I. The in vitro inhibition of these two αV integrins mediated by cilengitide resulted more effective in collagen I downregulation when compared with GLPG0187 (pan αV inhibitor). Noteworthy, the cilengitide-mediated αV integrin inhibition consistently tempered pro-fibrotic phenotype of sTAA- and MFS-VSMC by directly acting on both canonical (p-SMAD2/3) and non-canonical (p-ERK1/2) TGF-β downstream pathways and by downregulating mechanotransduction mediators (e.g., RhoA GTPase, ROCK1, talin-1). The 2D-echocardiographic results on MFS mice treated with cilengitide confirmed the greater effectiveness of this drug in limiting the TAA progression, in comparison not only with vehicle but also with the broad integrin inhibitor GLPG0187. Conclusion Altogether, our results improve the know-how on αV integrin inhibition, highlighting the role of cilengitide as potential target for future therapeutic approaches to limit TAA progression, both in sporadic and in MFS patients.