Development Of Aortic Aneurysm Research Articles

The presence of activating IgG Fc receptors in macrophages aggravates the development of experimental abdominal aortic aneurysm

IntroductionAbdominal aortic aneurysm (AAA) is a multifactorial, degenerative disease characterized by progressive aortic dilation and chronic activation of inflammation, proteolytic activity, and oxidative stress in the aortic wall. The immune response triggered by antibodies against antigens present in the vascular wall participates in the formation and progression of AAA through mechanisms not completely understood. This work analyses the function of specific IgG receptors (FcγR), especially those expressed by monocytes/macrophages, in the development of experimental AAA. MethodsIn the elastase-induced AAA model, the abdominal aortas from wildtype and FcγR deficient mice with/without macrophage adoptive transfer were analysed by histology and quantitative PCR. In vitro, RAW 264.7 macrophages were transfected with RNA interference of FcγRIV/CD16.2 or treated with Syk kinase inhibitor before stimulation with IgG immune complexes. ResultsMacrophage adoptive transfer in FcγR deficient mice increased the susceptibility to AAA development. Mice receiving macrophages with functional FcγR exhibited higher aortic diameter increase, higher content of macrophages and B lymphocytes, and upregulated expression of chemokine CCL2, cytokines (TNFα and IL-17), metalloproteinase MMP2, prooxidant enzyme NADPH oxidase-2, and the isoforms FcγRIII/CD16 and FcγRIV/CD16.2. In vitro, both FcγRIV/CD16.2 gene silencing and Syk inhibition reduced cytokines and reactive oxygen species production induced by IC in macrophages. ConclusionsActivation of macrophage FcγR contributes to AAA development by inducing mediators of inflammation, proteolysis, and oxidative stress. Modulation of FcγR or effector molecules may represent a potential target for AAA treatment.

The Histone Methyltransferase SETDB2 Modulates Tissue Inhibitors of Metalloproteinase-Matrix Metalloproteinase Activity During Abdominal Aortic Aneurysm Development.

To determine macrophage-specific alterations in epigenetic enzyme function contributing to the development of abdominal aortic aneurysms (AAAs). AAA is a life-threatening disease, characterized by pathologic vascular remodeling driven by an imbalance of matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs). Identifying mechanisms regulating macrophage-mediated extracellular matrix degradation is of critical importance to developing novel therapies. The role of SET Domain Bifurcated Histone Lysine Methyltransferase 2 (SETDB2) in AAA formation was examined in human aortic tissue samples by single-cell RNA sequencing and in a myeloid-specific SETDB2 deficient murine model induced by challenging mice with a combination of a high-fat diet and angiotensin II. Single-cell RNA sequencing of human AAA tissues identified SETDB2 was upregulated in aortic monocyte/macrophages and murine AAA models compared with controls. Mechanistically, interferon-β regulates SETDB2 expression through Janus kinase/signal transducer and activator of transcription signaling, which trimethylates histone 3 lysine 9 on the TIMP1-3 gene promoters thereby suppressing TIMP1-3 transcription and leading to unregulated matrix metalloproteinase activity. Macrophage-specific knockout of SETDB2 ( Setdb2f/fLyz2Cre+ ) protected mice from AAA formation with suppression of vascular inflammation, macrophage infiltration, and elastin fragmentation. Genetic depletion of SETDB2 prevented AAA development due to the removal of the repressive histone 3 lysine 9 trimethylation mark on the TIMP1-3 gene promoter resulting in increased TIMP expression, decreased protease activity, and preserved aortic architecture. Lastly, inhibition of the Janus kinase/signal transducer and activator of the transcription pathway with an FDA-approved inhibitor, Tofacitinib, limited SETDB2 expression in aortic macrophages. These findings identify SETDB2 as a critical regulator of macrophage-mediated protease activity in AAAs and identify SETDB2 as a mechanistic target for the management of AAAs.

Dysfunctions of the C-type natriuretic peptide signaling pathway involved in the development of thoracic aortic aneurysm in Marfan patients

Marfan Syndrome (MFS) is an autosomal dominant inherited connective tissue disorder affecting the cardio-vascular system. Development of thoracic aortic aneurysms (TAA) leading to dissections and ruptures is the primary cause of morbidity and mortality in these patients. No treatment really cures Marfan patients. Interestingly, in humans, mutations in the gene coding for the C-type natriuretic peptide (CNP) or its receptors lead to a “Marfan-like syndrome”. CNP is a local regulator of skeletal growth and of vascular homeostasis, remodeling and angiogenesis. CNP binds to NPR-B or NPR-C receptors, both expressed on endothelial and vascular smooth muscle cells (vSMCs) and modulates the intracellular cGMP and cAMP levels. The aim of this project is to determine whether altered CNP signaling pathway contributes to TAA development and progression to rupture in Marfan patients. Plasma and aorta biopsies were taken from Marfan patients and from Fbn1C1039G/+ mice. The CNP, TGF-beta, cAMP and cGMP concentrations were measured in the plasma. mRNA and protein levels evaluated by qRT-PCR, and Western blot analysis in aortic tissue. Male and female mice studied and alterations of the aorta structure analyzed by ultrasound imaging. Plasma proCNP level in Marfan patients depends on the age and the TAA development. Increased levels found in young patients presenting no or reduced TAA and decreased levels in patients with TAA compared to age and sex-matched non-Marfan patients. CNP and NPR-C decreased at the mRNA and protein levels in the aorta of Marfan patients when compared to the same aorta in non-Marfan patients. In Fbn1+/- mice, aortic structure alterations are detected from 10 weeks in males and 34 weeks in females. CNP and NPR-C mRNA and protein levels drastically decreased in the thoracic aorta in 2–7 week-old male mice and in 34 week-old female mice. In 52-week old Fbn1+/- mice, the plasma cAMP level is increased in males and not in females, whereas the plasma cGMP protein level is increased in females but not in males. CNP injections in 3-week old Fbn1+/- male mice partially prevented the aorta structure alterations. A deficit in CNP protein level or in the expression of the NPR-C receptor contributes to the development and progression of TAA.

Abstract 110: The Histone Methyltransferase Setdb2 Modulates Macrophage TIMP-MMP Activity During Abdominal Aortic Aneurysm Development

Introduction: Abdominal aortic aneurysms (AAA) are characterized by aortic wall degradation leading to the fatal consequence of aortic rupture. Aortic remodeling is driven by an inflammatory macrophage (MΦ) phenotype and imbalance of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs). The epigenetic enzyme, SETDB2, plays a critical role in establishing MΦ phenotype and regulating gene expression. We examine the impact of SETDB2 on AAA development and establish SETDB2 as a novel target in the treatment AAAs. Methods: Single-cell sequencing was conducted on human AAA and control tissue samples. For our murine model, C57BL/6 mice were injected with an AAV encoding a PCSK9 gain-of-function mutation and then fed a saturated fat-enriched diet and infused with AngII (1 μg/kg/min) or saline. AAA maximum diameters were quantified and MΦs were sorted. Setdb and Timp1-3 gene expression was examined. Chromatin immunoprecipitation (ChIP) was used to evaluate histone 3 lysine 9 trimethylation (H3K9me3). Results: Using single-cell RNA sequencing, we identified SETDB2 was profoundly upregulated in human aortic MΦs and two murine AAA models. Mechanistically, interferon-β regulates Setdb2 expression via JAK/STAT signaling which trimethylates histone 3 lysine 9 (H3K9) at NF-κB binding sites on the TIMP1-3 gene promoters thereby suppressing Timp1-3 transcription and leading to unregulated MMP activity. In vivo MΦ-specific knockout of SETDB2 ( Setdb2 f/f Lyz2 Cre+ ) inhibited AAA formation with significant suppression of vascular inflammation, MΦ infiltration, and elastin fragmentation. Gene expression and ChIP analysis demonstrated genetic depletion of SETDB2 prevented AAA development with removal of the repressive H3K9 trimethylation epigenetic mark on the Timp1-3 promoter resulting in increased Timp expression and preserved aortic architecture. Lastly, pharmacological inhibition of the JAK/STAT pathway with a FDA approved inhibitor, Tofacitinib, limited Setdb2 expression and inhibited AAA development. Conclusions: Taken together, our results identify SETDB2 as a critical regulator of MΦ-mediated inflammation and protease production in AAAs and suggest SETDB2 as a mechanistic target for the management of AAAs.

Role of mitochondrial dynamics in abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is an asymptomatic pathology representing 75% of aortic aneurysms and occurring mainly in men over 65 years old, with a high mortality rate (80%) due to aortic rupture. Currently, only surgical management are used, and no pharmacological treatment exists. A potential therapeutic track would be the regulation of mitochondrial functions, already involved in neurological, ophthalmic, and cardiac pathologies. However, mitochondrial dynamics regulation, especially important within smooth muscle cells, is still untapped in abdominal aortic aneurysm. Our aim is to understand the role of mitochondrial dynamics in abdominal aortic aneurysm. We used a murine model of 6 months old of hypertensive Ldlr-/- male mice (angiotensin II, 1 mg/kg/day) associated with an hypercholesterolemic diet (HCD) for 28 days. Moreover, 6 months old Opa1+/- hypertensive male mice were used to study aortic remodeling. Aortic samples were studied by histomorphometric analyzes, RT-qPCR and Western blot. Ldlr-/- mice suffering from an abdominal aortic aneurysm showed a significant increase in mitochondrial fission (FIS1, DRP1) and mitophagy (PARKIN, PINK1). In addition, our results demonstrated strong pathological adventitial remodeling in supra-renal abdominal aorta in Opa1+/- hypertensive mice with a significant increase of Mmp2/Timp2 ratio in gene expression involved in aneurysm remodeling. Those results were associated with a significant decrease in smooth muscle cell contraction gene expression, inducing phenotypic cell switch, and pathological arterial remodeling. Mitochondrial dynamics dysfunction associated with hypertensive stress are involved in abdominal aortic aneurysm development.

Purinergic receptor P2X7 contributes to abdominal aortic aneurysm development via modulating macrophage pyroptosis and inflammation

The purinergic receptor P2X7 has been established as an important mediator of inflammation and participates in a variety of cardiovascular diseases including atherosclerosis, however, its role in abdominal aortic aneurysms (AAA) remains unclear. In this study, we demonstrate that P2X7 plays essential roles in AAA development via modulating macrophage pyroptosis and inflammation. P2X7 is highly expressed in human AAA specimen, as well as in experimental murine AAA lesions (both CaCl2- and Angiotensin II-induced AAA models), and it mainly confines in macrophages. Furthermore, P2X7 deficiency or pharmacological inhibition with its antagonist could significantly attenuate aneurysm formation in experimental murine AAA models, while P2X7 agonist could promote AAA development. The caspase-1 activity, matrix metalloproteinase (MMP) activity, reactive oxygen species (ROS) production and pro-inflammatory gene expression were significantly reduced in experimental AAA lesions in mice with P2X7 deficiency or inhibition. Mechanistically, macrophage P2X7 can mediate the activation of NLRP3 inflammasome and activate its downstream caspase-1 to initiate the pyroptosis pathway. After caspase-1 activation, it further cleaves pro-interleukin (IL)-1β and gasdermin D (GSDMD). Consequently, the N-terminal fragment of GSDMD forms pores on the cell membrane, leading to macrophage pyroptosis and release of the pro-inflammatory factor IL-1β. The resulting vascular inflammation further leads to the upregulation of MMP and ROS, thereby promoting AAA development. In summary, these data identify P2X7-mediated macrophage pyroptosis signaling pathway as a novel contributory mechanism of AAA formation.

Gut dysbiosis is associated with aortic aneurysm formation and progression in Takayasu arteritis

BackgroundTakayasu arteritis (TAK) is an autoimmune large vessel vasculitis that affects the aorta and its major branches, eventually leading to the development of aortic aneurysm and vascular stenosis or occlusion. This retrospective and prospective study aimed to investigate whether the gut dysbiosis exists in patients with TAK and to identify specific gut microorganisms related to aortic aneurysm formation/progression in TAK.MethodsWe analysed the faecal microbiome of 76 patients with TAK and 56 healthy controls (HCs) using 16S ribosomal RNA sequencing. We examined the relationship between the composition of the gut microbiota and clinical parameters.ResultsThe patients with TAK showed an altered gut microbiota with a higher abundance of oral-derived bacteria, such as Streptococcus and Campylobacter, regardless of the disease activity, than HCs. This increase was significantly associated with the administration of a proton pump inhibitor used for preventing gastric ulcers in patients treated with aspirin and glucocorticoids. Among patients taking a proton pump inhibitor, Campylobacter was more frequently detected in those who underwent vascular surgeries and endovascular therapy for aortic dilatation than in those who did not. Among the genus of Campylobacter, Campylobacter gracilis in the gut microbiome was significantly associated with clinical events related to aortic aneurysm formation/worsening in patients with TAK. In a prospective analysis, patients with a gut microbiome positive for Campylobacter were significantly more likely to require interventions for aortic dilatation than those who were negative for Campylobacter. Furthermore, patients with TAK who were positive for C. gracilis by polymerase chain reaction showed a tendency to have severe aortic aneurysms.ConclusionsA specific increase in oral-derived Campylobacter in the gut may be a novel predictor of aortic aneurysm formation/progression in patients with TAK.

The association between diabetes and abdominal aortic aneurysms in men: results of two Danish screening studies, a systematic review, and a meta-analysis of population-based screening studies

BackgroundA paradoxical protective effect of diabetes on the development and progression of abdominal aortic aneurysms (AAA) has been known for years. This study aimed to investigate whether the protective role of diabetes on AAAs has evolved over the years.MethodsA cross-sectional study, a systematic review and meta-analysis. This study was based on two large, population-based, randomised screening trials of men aged 65–74; VIVA (2008–2011) and DANCAVAS (2014–2018), including measurement of the abdominal aorta by ultrasound or CT, respectively. Analyses were performed using multiple logistic regressions to estimate the odds ratios (ORs) for AAAs in men with diabetes compared to those not having diabetes. Moreover, a systematic review and meta-analysis of population-based screening studies of AAAs to visualise a potential change of the association between diabetes and AAAs. Studies reporting only on women or Asian populations were excluded.ResultsIn VIVA, the prevalence of AAA was 3.3%, crude OR for AAA in men with diabetes 1.04 (95% confidence interval, CI, 0.80-1.34), and adjusted OR 0.64 (CI 0.48-0.84). In DANCAVAS, the prevalence of AAA was 4.2%, crude OR 1.44 (CI 1.11-1.87), and adjusted OR 0.78 (CI 0.59-1.04). Twenty-three studies were identified for the meta-analysis (N = 224 766). The overall crude OR was 0.90 (CI 0.77-1.05) before 2000 and 1.16 (CI 1.03-1.30) after 1999. The overall adjusted OR was 0.63 (CI 0.59-0.69) before 2000 and 0.69 (CI 0.57-0.84) after 1999.ConclusionBoth the crude and adjusted OR showed a statistically non-significant trend towards an increased risk of AAA by the presence of diabetes. If this represents an actual trend, it could be due to a change in the diabetes population.Trial registrationDANCAVAS: Current Controlled Trials: ISRCTN12157806. VIVA: ClinicalTrials.gov NCT00662480.

A study on the role of inflammatory process of the aorta wall in the development, prognosis, and management of aortic aneurysms

Objective: Abdominal Aortic aneurysms (AAA) are pathological aortic dilations that can rupture and result in up to 90% overall mortality. These lesions have a strong inflammatory substrate since atherosclerosis, which is undoubtedly related to inflammation, also predisposes patients to develop abdominal aorta aneurysms. The primary purpose of the research was to examine the role that inflammation in the aortic wall plays in the development, prognosis, and management of aortic aneurysms. Material and methods: This prospective, non-randomized investigation analyzed the cytosolic levels of interleukin-1b, interleukin-6, and tumor necrosis factor α (TNFα) in the walls of 57 individuals with aneurysms. Study group 1 consisted of patients with ruptured aneurysms (n=11), whereas study group 2 included patients with no symptoms from their aneurysms (n=32). There were 14 kidney recipients in the control group. Result: The walls of rupture aneurysms were shown to have larger and more pronounced inflammatory processes as well as higher levels of the cytokines cytokine IL6(P

The role of aldehyde dehydrogenase 2 in cardiovascular disease.

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme involved in the detoxification of alcohol-derived acetaldehyde and endogenous aldehydes. The inactivating ALDH2 rs671 polymorphism, present in up to 8% of the global population and in up to 50% of the East Asian population, is associated with increased risk of cardiovascular conditions such as coronary artery disease, alcohol-induced cardiac dysfunction, pulmonary arterial hypertension, heart failure and drug-induced cardiotoxicity. Although numerous studies have attributed an accumulation of aldehydes (secondary to alcohol consumption, ischaemia or elevated oxidative stress) to an increased risk of cardiovascular disease (CVD), this accumulation alone does not explain the emerging protective role of ALDH2 rs671 against ageing-related cardiac dysfunction and the development of aortic aneurysm or dissection. ALDH2 can also modulate risk factors associated with atherosclerosis, such as cholesterol biosynthesis and HDL biogenesis in hepatocytes and foam cell formation and efferocytosis in macrophages, via non-enzymatic pathways. In this Review, we summarize the basic biology and the clinical relevance of the enzymatic and non-enzymatic, tissue-specific roles of ALDH2 in CVD, and discuss the future directions in the research and development of therapeutic strategies targeting ALDH2. A thorough understanding of the complex roles of ALDH2 in CVD will improve the diagnosis, management and prognosis of patients with CVD whoharbour the ALDH2 rs671 polymorphism.

Abstract TMP16: Mechanoreceptor Dysregulation Found In Human Intracerebral Aneurysms

Introduction: About 500,000 people worldwide die annually from ruptured intracranial aneurysms (IA). The pathophysiology of aneurysm formation is largely unknown. Piezo1 mechanoreceptors are expressed in endothelial and smooth muscle cells of developing blood vessels. In addition to hemodynamic forces, Piezo1 has been shown to play an inflammatory role, as stiffness-sensing macrophages lacking Piezo1 exhibit reduced inflammation and enhanced wound healing responses. Malfunction of Piezo1 mechanoreceptors has been implicated in abdominal aortic aneurysm (AAA) development. With the increasing evidence of relationship between AAA and IAs, it is important to study Piezo1 dysregulation as a potential cause of IA development and/or rupture. Methods: During craniotomy for aneurysm clipping of ruptured and unruptured IAs, we excised and collected the aneurysm dome in four patients. Immunohistochemistry (IHC) was performed for Piezo1 and with CD31 to co-localize Piezo1 in the endothelial cells, and a-SMA to co-localize in smooth muscle cells on all aneurysm domes. Additional specimen was saved for genomic analyses. Results: Piezo1 mechanoreceptor overexpression was found in the smooth muscle layer of IAs, but not in superficial temporal artery (STA) controls, in all four human cerebral aneurysm domes. Additionally, there was significant dysregulation of Piezo1 mechanoreceptors in the IA compared with the regular appearance seen in the control human STA (Figure 1). Overexpression was not seen in human arteriovenous malformation specimens. Conclusions: Our data is the first demonstration of overexpression of Piezo1 mechanoreceptors in a disorganized manner in the walls of human IAs, which may represent a therapeutic target. We hypothesize that vascular shear stress leads to Piezo1-mediated disorganization in arterial smooth muscle cells and pro-inflammatory activation, which may lead to IA development and rupture.

Cardiovascular Involvement in Tuberculosis: From Pathophysiology to Diagnosis and Complications-A Narrative Review.

Although primarily a lung disease, extra-pulmonary tuberculosis (TB) can affect any organ or system. Of these, cardiovascular complications associated with disease or drug toxicity significantly worsen the prognosis. Approximately 60% of patients with TB have a cardiovascular disease, the most common associated pathological entities being pericarditis, myocarditis, and coronary artery disease. We searched the electronic databases PubMed, MEDLINE, and EMBASE for studies that evaluated the impact of TB on the cardiovascular system, from pathophysiological mechanisms to clinical and paraclinical diagnosis of cardiovascular involvement as well as the management of cardiotoxicity associated with antituberculosis medication. The occurrence of pericarditis in all its forms and the possibility of developing constrictive pericarditis, the association of concomitant myocarditis with severe systolic dysfunction and complication with acute heart failure phenomena, and the long-term development of aortic aneurysms with risk of complications, as well as drug-induced toxicity, pose complex additional problems in the management of patients with TB. In the era of multidisciplinarity and polymedication, evidence-based medicine provides various tools that facilitate an integrative management that allows early diagnosis and treatment of cardiac pathologies associated with TB.

ADAR1 Non-Editing Function in Macrophage Activation and Abdominal Aortic Aneurysm.

Macrophage activation plays a critical role in abdominal aortic aneurysm (AAA) development. However, molecular mechanisms controlling macrophage activation and vascular inflammation in AAA remain largely unknown. The objective of the study was to identify novel mechanisms underlying adenosine deaminase acting on RNA (ADAR1) function in macrophage activation and AAA formation. Aortic transplantation was conducted to determine the importance of nonvascular ADAR1 in AAA development/dissection. Ang II (Angiotensin II) infusion of ApoE-/- mouse model combined with macrophage-specific knockout of ADAR1 was used to study ADAR1 macrophage-specific role in AAA formation/dissection. The relevance of macrophage ADAR1 to human AAA was examined using human aneurysm specimens. Moreover, a novel humanized AAA model was established to test the role of human macrophages in aneurysm formation in human arteries. Allograft transplantation of wild-type abdominal aortas to ADAR1+/- recipient mice significantly attenuated AAA formation, suggesting that nonvascular ADAR1 is essential for AAA development. ADAR1 deficiency in hematopoietic cells decreased the prevalence and severity of AAA while inhibited macrophage infiltration and aorta wall inflammation. ADAR1 deletion blocked the classic macrophage activation, diminished NF-κB (nuclear factor kappa B) signaling, and enhanced the expression of a number of anti-inflammatory microRNAs. Mechanistically, ADAR1 interacted with Drosha to promote its degradation, which attenuated Drosha-DGCR8 (DiGeorge syndrome critical region 8) interaction, and consequently inhibited pri- to pre-microRNA processing of microRNAs targeting IKKβ, resulting in an increased IKKβ (inhibitor of nuclear factor kappa-B) expression and enhanced NF-κB signaling. Significantly, ADAR1 was induced in macrophages and interacted with Drosha in human AAA lesions. Reconstitution of ADAR1-deficient, but not the wild type, human monocytes to immunodeficient mice blocked the aneurysm formation in transplanted human arteries. Macrophage ADAR1 promotes aneurysm formation in both mouse and human arteries through a novel mechanism, that is, Drosha protein degradation, which inhibits the processing of microRNAs targeting NF-kB signaling and thus elicits macrophage-mediated vascular inflammation in AAA.

Insulin Dependence Is Associated With Poor Long-term Outcomes But Equivalent Perioperative Outcomes Following AAA Repair

While diabetes is often a risk factor for vascular disease, its protective effects on abdominal aortic aneurysm (AAA) development have been well documented. Much less is known about the impact of diabetes-and in particular insulin dependence-on long-term outcomes following AAA repair. We aim to evaluate the role of diabetes on perioperative outcomes, mortality, and reintervention following both endovascular and open AAA repair.

Differences between inflammatory cells infiltrated into tunica intima, media, and adventitia of ascending aortic aneurysms within diabetic and hypertensive patients.

The risk factors that are the most significant for the development of most cardiovascular diseases are arterial hypertension (AH), type 2 diabetes (DM), and inflammation. However, for the development of aortic aneurysms, DM is not one of them. Our study aimed to evaluate the difference between inflammatory infiltration in three individual layers of the ascending aortic aneurysm within diabetic and hypertensive patients. Forty-five patients aged 36 to 80 were divided into a group with diabetic patients without AH (group DM, N=8) and hypertensive patients without DM (group AH, N=37). For the histological analysis, aortic aneurysms were stained with hematoxylin eosin and Movat. We used immunochemical methods to detect pro- (M1), anti-inflammatory (M2) macrophages, T-helper, T-killer cells, B cells, and plasma cells. Statistical analysis was done by independent-samples Kruskal-Wallis test adjusted by Bonferroni correction for multiple tests (P<0.05). We found no difference in the volume density of collagen, elastin, vascular smooth muscle cells (VSMC), and ground substance between groups. In the DM group, there were significantly fewer M2, T-helpers, and T-killers in the media than in the intima and the adventitia (P<0.05). There were no significant differences in the number of M1, B, and plasma cells between all three vascular layers (P<0.05). In the AH group, there were significantly fewer B and plasma cells, T-helper, T-killer cells, M1, and M2 in the media than in the intima and adventitia (P<0.05). Our results conclude that the tunica media in the aneurismal wall of the AH group retained immune privilege. In contrast, in the DM group, all three layers were immune-privileged.

Differences between inflammatory cells infiltrated into tunica intima, media, and adventitia of ascending aortic aneurysms within diabetic and hypertensive patients.

The risk factors that are the most significant for the development of most cardiovascular diseases are arterial hypertension (AH), type 2 diabetes (DM), and inflammation. However, for the development of aortic aneurysms, DM is not one of them. Our study aimed to evaluate the difference between inflammatory infiltration in three individual layers of the ascending aortic aneurysm within diabetic and hypertensive patients. Forty-five patients aged 36 to 80 were divided into a group with diabetic patients without AH (group DM, N=8) and hypertensive patients without DM (group AH, N=37). For the histological analysis, aortic aneurysms were stained with hematoxylin eosin and Movat. We used immunochemical methods to detect pro- (M1), anti-inflammatory (M2) macrophages, T-helper, T-killer cells, B cells, and plasma cells. Statistical analysis was done by independent-samples Kruskal-Wallis test adjusted by Bonferroni correction for multiple tests (P<0.05). We found no difference in the volume density of collagen, elastin, vascular smooth muscle cells (VSMC), and ground substance between groups. In the DM group, there were significantly fewer M2, T-helpers, and T-killers in the media than in the intima and the adventitia (P<0.05). There were no significant differences in the number of M1, B, and plasma cells between all three vascular layers (P<0.05). In the AH group, there were significantly fewer B and plasma cells, T-helper, T-killer cells, M1, and M2 in the media than in the intima and adventitia (P<0.05). Our results conclude that the tunica media in the aneurismal wall of the AH group retained immune privilege. In contrast, in the DM group, all three layers were immune-privileged.

Nicotinamide Mononucleotide Alleviates Angiotensin II-Induced Human Aortic Smooth Muscle Cell Senescence in a Microphysiological Model.

The occurrence and development of aortic aneurysms are accompanied by senescence of human aortic smooth muscle cells (HASMCs). Because the mechanism of HASMC senescence has not been fully elucidated, the efficacy of various antisenescence treatments varies. Decreased nicotinamide adenine dinucleotide (NAD + ) levels are one of the mechanisms of cell senescence, and there is a lack of evidence on whether increasing NAD + levels could alleviate HASMC senescence and further retard the progression of aortic aneurysms.We constructed an HASMC-based organ-on-a-chip microphysiological model. RNA sequencing was performed on cell samples from the vehicle control and angiotensin II groups to explore biological differences. We detected cellular senescence markers and NAD + levels in HASMC-based organ-on-a-chip. Subsequently, we pretreated HASMC using the synthetic precursor of NAD + , nicotinamide mononucleotide, and angiotensin II treatment, and used rhythmic stretching to investigate whether nicotinamide mononucleotide could delay HASMC senescence.The HASMC-based organ-on-a-chip model can simulate the biomechanical microenvironment of HASMCs in vivo, and the use of angiotensin II in the model replicated senescence in HASMCs. The senescence of HASMCs was accompanied by downregulation of the expression level of nicotinamide phosphoribosyltransferase and NAD + . Pretreatment with nicotinamide mononucleotide significantly increased the NAD + level and alleviated the senescence of HASMCs, but did not change the expression level of nicotinamide phosphoribosyltransferase.Our study provides a complementary research platform between traditional cell culture and animal experiments to explore HASMC senescence in aortic aneurysms. Furthermore, it provides evidence for NAD + boosting therapy in the clinical treatment of aortic aneurysms.

Molecular and Cellular Mechanisms Involved in Aortic Wall Aneurysm Development.

Aortic aneurysms represent a very common pathology that can affect any segment of the aorta. These types of aneurysms can be localized on the thoracic segment or on the abdominal portion, with the latter being more frequent. Though there are similarities between thoracic and abdominal aortic aneurysms, these pathologies are distinct entities. In this article, we undertook a review regarding the different mechanisms that can lead to the development of aortic aneurysm, and we tried to identify the different manners of treatment. For a long time, aortic wall aneurysms may evolve in an asymptomatic manner, but this progressive dilatation of the aneurysm can lead to a potentially fatal complication consisting in aortic rupture. Because there are limited therapies that may delay or prevent the development of acute aortic syndromes, surgical management remains the most common manner of treatment. Even though, surgical management has improved much in the last years, thus becoming less invasive and sophisticated, the morbi-mortality linked to these therapies remains increased. The identification of the cellular and molecular networks triggering the formation of aneurysm would permit the discovery of modern therapeutic targets. Molecular and cellular mechanisms are gaining a bigger importance in the complex pathogenesis of aortic aneurysms. Future studies must be developed to compare the findings seen in human tissue and animal models of aortic aneurysm, so that clinically relevant conclusions about the aortic aneurysm formation and the pharmacological possibility of pathogenic pathways blockage can be drawn.

Mechanosignals in abdominal aortic aneurysms.

Cumulative evidence has shown that mechanical and frictional forces exert distinct effects in the multi-cellular aortic layers and play a significant role in the development of abdominal aortic aneurysms (AAA). These mechanical cues collectively trigger signaling cascades relying on mechanosensory cellular hubs that regulate vascular remodeling programs leading to the exaggerated degradation of the extracellular matrix (ECM), culminating in lethal aortic rupture. In this review, we provide an update and summarize the current understanding of the mechanotransduction networks in different cell types during AAA development. We focus on different mechanosensors and stressors that accumulate in the AAA sac and the mechanotransduction cascades that contribute to inflammation, oxidative stress, remodeling, and ECM degradation. We provide perspectives on manipulating this mechano-machinery as a new direction for future research in AAA.

Group 2 Innate Lymphoid Cells Protect Mice from Abdominal Aortic Aneurysm Formation via IL5 and Eosinophils.

Development of abdominal aortic aneurysms (AAA) enhances lesion group-2 innate lymphoid cell (ILC2) accumulation and blood IL5. ILC2 deficiency in Rorafl/fl Il7rCre/+ mice or induced ILC2 depletion in Icosfl-DTR-fl/+ Cd4Cre/+ mice expedites AAA growth, increases lesion inflammation, but leads to systemic IL5 and eosinophil (EOS) deficiency. Mechanistic studies show that ILC2 protect mice from AAA formation via IL5 and EOS. IL5 or ILC2 from wild-type (WT) mice, but not ILC2 from Il5-/- mice induces EOS differentiation in bone-marrow cells from Rorafl/fl Il7rCre/+ mice. IL5, IL13, and EOS or ILC2 from WT mice, but not ILC2 from Il5-/- and Il13-/- mice block SMC apoptosis and promote SMC proliferation. EOS but not ILC2 from WT or Il5-/- mice block endothelial cell (EC) adhesion molecule expression, angiogenesis, dendritic cell differentiation, and Ly6Chi monocyte polarization. Reconstitution of WT EOS and ILC2 but not Il5-/- ILC2 slows AAA growth in Rorafl/fl Il7rCre/+ mice by increasing systemic EOS. Besides regulating SMC pathobiology, ILC2 play an indirect role in AAA protection via the IL5 and EOS mechanism.