The role of vascular smooth muscle cells in the development of aortic aneurysms and dissections

European Journal of Clinical Investigation, Год журнала: 2021, Номер 52(4)

Опубликована: Окт. 26, 2021

Aortic aneurysms (AA) are pathological dilations of the aorta, associated with an overall mortality rate up to 90% in case rupture. In addition dilation, aortic layers can separate by a tear within layers, defined as dissections (AD). Vascular smooth muscle cells (vSMC) predominant cell type wall and dysregulation vSMC functions contributes AA AD development progression. However, since exact underlying mechanism is poorly understood, finding potential therapeutic targets for challenging surgery remains only treatment option.In this review, we summarize current knowledge about give overview how altered pathogenesis, organized per anatomical location (abdominal or thoracic aorta).Important healthy diseased conditions apoptosis, phenotypic switch, extracellular matrix regeneration degradation, proliferation contractility. Stressors wall, including inflammatory infiltration (epi)genetic changes, modulate cause disturbance processes vSMC, such changes TGF-β signalling regulatory RNA expression.This review underscores central role dysfunction abdominal Further research focused on necessary find noninvasive options.

Язык: Английский

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Vascular Smooth Muscle Cells Phenotypic Switching in Cardiovascular Diseases

Cells, Год журнала: 2022, Номер 11(24), С. 4060 - 4060

Опубликована: Дек. 15, 2022

Vascular smooth muscle cells (VSMCs), the major cell type in arterial vessel wall, have a contractile phenotype that maintains normal structure and function under physiological conditions. In response to stress or vascular injury, VSMCs can switch less differentiated state (synthetic phenotype) acquire proliferative, migratory, synthetic capabilities for tissue reparation. Imbalances phenotypic switching result variety of cardiovascular diseases, including atherosclerosis, in-stent restenosis, aortic aneurysms, calcification. It is very important identify molecular mechanisms regulating prevent treat diseases with high morbidity mortality. However, key signaling pathways participating still not been fully elucidated despite long-term efforts by researchers. this review, we provide an updated summary recent studies systematic knowledge calcification, which may help guide future research novel insights into prevention treatment related diseases.

Язык: Английский

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PHB2 Maintains the Contractile Phenotype of VSMCs by Counteracting PKM2 Splicing

Circulation Research, Год журнала: 2022, Номер 131(10), С. 807 - 824

Опубликована: Окт. 6, 2022

Phenotypic transition of vascular smooth muscle cells (VSMCs) accounts for the pathogenesis a variety diseases during early stage. Recent studies indicate metabolic reprogramming may be involved in VSMC phenotypic transition. However, definite molecules that link energy metabolism to distinct phenotype remain elusive.A carotid artery injury model was used study postinjury neointima formation as well vivo. RNA-seq analysis, cell migration assay, collagen gel contraction wire myography immunoblotting, protein interactome co-immunoprecipitation, and mammalian 2-hybrid assay were performed clarify elucidate molecular mechanisms.We collected energy-regulating genes by using Gene Ontology annotation applied RNA-Seq analysis transforming growth factor-β or platelet-derived factor BB stimulated VSMCs. Six candidate overlapped from metabolism-related reciprocally upregulated downregulated BB. Among them, prohibitin 2 has been reported regulate mitochondrial oxidative phosphorylation. Indeed, 2-deficient VSMCs lost contractile evidenced reduced proteins. Consistently, Phb2SMCKO mice more susceptible proliferation compared with Phb2flox/flox mice. Further revealed 2, through its C-terminus, directly interacts hnRNPA1, key modulator pyruvate kinase M1/2 (PKM) mRNA splicing promotes PKM2 expression glycolysis. Prohibitin deficiency facilitated PKM1/2 reversion PKM1 PKM2, enhanced glycolysis Blocking 2-hnRNPA1 interaction resulted increased expression, glycolysis, repressed marker VSMCs, aggravated vivo.Prohibitin maintains interacting hnRNPA1 counteract hnRNPA1-mediated PKM alternative glucose reprogramming.

Язык: Английский

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Mechanical stress induced mitochondrial dysfunction in cardiovascular diseases: Novel mechanisms and therapeutic targets

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 174, С. 116545 - 116545

Опубликована: Апрель 10, 2024

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Others and our studies have shown that mechanical stresses (forces) including shear stress cyclic stretch, occur in various pathological conditions, play significant roles development progression CVDs. Mitochondria regulate physiological processes cardiac vascular cells mainly through adenosine triphosphate (ATP) production, calcium flux redox control while promote cell death electron transport complex (ETC) related cellular response. Mounting evidence reveal stress-induced mitochondrial dysfunction plays a vital role pathogenesis many CVDs heart failure atherosclerosis. This review summarized functions cardiovascular system under (graphical abstract). The study can further understanding underlying mechanisms, identify potential therapeutic targets, aid novel treatments

Язык: Английский

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Cellular, Molecular and Clinical Aspects of Aortic Aneurysm—Vascular Physiology and Pathophysiology

Cells, Год журнала: 2024, Номер 13(3), С. 274 - 274

Опубликована: Фев. 1, 2024

A disturbance of the structure aortic wall results in formation aneurysm, which is characterized by a significant bulge on vessel surface that may have consequences, such as distention and finally rupture. Abdominal aneurysm (AAA) major pathological condition because it affects approximately 8% elderly men 1.5% women. The pathogenesis AAA involves multiple interlocking mechanisms, including inflammation, immune cell activation, protein degradation cellular malalignments. expression inflammatory factors, cytokines chemokines, induce infiltration cells into aorta, macrophages, natural killer (NK cells) T B lymphocytes. Protein occurs with high not only matrix metalloproteinases (MMPs) but also neutrophil gelatinase-associated lipocalin (NGAL), interferon gamma (IFN-γ) chymases. loss extracellular (ECM) due to apoptosis phenotype switching reduces tissue density contribute AAA. It important consider key mechanisms initiating promoting achieve better preventative therapeutic outcomes.

Язык: Английский

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Genetic testing in cardiovascular disease

The Medical Journal of Australia, Год журнала: 2024, Номер 220(8), С. 428 - 434

Опубликована: Апрель 4, 2024

Summary Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally responsible for an estimated one‐third deaths as well significant health care utilisation. Technological bioinformatic advances have facilitated discovery pathogenic germline variants some specific CVDs, including familial hypercholesterolaemia, cardiomyopathies arrhythmic syndromes. Use these genetic tests earlier identification increasing due, in part, to decreasing costs, Medicare rebates, consumer comfort with testing. However, CVDs that occur more commonly, coronary artery atrial fibrillation, do not display monogenic inheritance patterns. Genetically, diseases generally been associated many each a small effect size. This complexity can be expressed mathematically polygenic risk score. Genetic testing kits provide scoring are becoming increasingly available directly private‐paying consumers outside traditional clinical setting. An improved understanding evidence genetics CVD will offer clinicians new opportunities individualised prediction preventive therapy.

Язык: Английский

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Unveiling cellular and molecular aspects of ascending thoracic aortic aneurysms and dissections

Basic Research in Cardiology, Год журнала: 2024, Номер 119(3), С. 371 - 395

Опубликована: Май 3, 2024

Ascending thoracic aortic aneurysm (ATAA) remains a significant medical concern, with its asymptomatic nature posing diagnostic and monitoring challenges, thereby increasing the risk of wall dissection rupture. Current management repair relies on an diameter threshold. However, this approach underestimates complexity disease due to important knowledge gaps in understanding underlying pathologic mechanisms.Since traditional factors cannot explain initiation progression ATAA leading dissection, local vascular such as extracellular matrix (ECM) smooth muscle cells (VSMCs) might harbor targets for early diagnosis intervention. Derived from diverse embryonic lineages, VSMCs exhibit varied responses genetic abnormalities that regulate their contractility. The transition into different phenotypes is adaptive response stress stimuli hemodynamic changes resulting cardiovascular disease, aging, lifestyle, predisposition. Upon longer exposure stimuli, VSMC phenotypic switching can instigate remodeling contributes pathogenesis ATAA.This review aims illuminate current cellular molecular characteristics associated emphasizing need more nuanced comprehension impaired ECM-VSMC network.

Язык: Английский

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Exosome miR-199a-5p modulated vascular remodeling and inflammatory infiltration of Takayasu’s arteritis

Arthritis Research & Therapy, Год журнала: 2025, Номер 27(1)

Опубликована: Янв. 20, 2025

Advances in treatment have swiftly alleviated systemic inflammation of Takayasu's arteritis (TAK), while subclinical vascular and the ensuing arterial remodeling continue to present unresolved challenges TAK. The phenotypic switching smooth muscle cells (VSMC) is regarded as first step pathology contributes remodeling. Exosomes facilitate transfer exchange proteins specific nucleic acids, thereby playing a significant role intercellular communication. Little known about modulatory serum exosomes VSMC Serum isolated from TAK patients were co-cultured with identify exosomes. transfected miR-199a-5p mimic inhibitor. CCK8 assays EdU performed measure proliferative ability. migration was evaluated by scratch transwell assays. flow cytometry employed apoptosis VSMC. Dual-luciferase reporter assay, RNA immunoprecipitation assay fluorescence situ hybridization utilized validate target gene miR-199a-5p. correlational analysis conducted among exosome miRNA, MMP2, TIMP2 clinical parameters patients. coculture mediated dedifferentiation Through gain- loss-of-function approaches, over-expression significantly increased expression marker genes inhibited proliferation migration, whilst opposite effect observed when endogenous knocked down. overexpression suppressed apoptosis. Further, MMP2 serves functional correlation analyses revealed an inverse between Vasculitis Damage Index level or which requires validation larger cohort. Our study indicated that miR-199a-5p/MMP2 pathway played inhibiting decreased secretion may potentially prompt intimal infiltration inflammatory within wall, offering novel therapeutic opportunity tackling both responses neointimal overgrowth associated damage. Moreover, derived possess potential future biomarkers for injury.

Язык: Английский

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TRPM7 channel activity promotes the pathogenesis of abdominal aortic aneurysms

Nature Cardiovascular Research, Год журнала: 2025, Номер 4(2), С. 197 - 215

Опубликована: Фев. 14, 2025

Язык: Английский

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From inflammation to remodelling: A novel BASP1+ monocyte subset as a catalyst for acute aortic dissection

Journal of Advanced Research, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Monocytes comprise heterogeneous cell populations. However, beyond traditionally considered as precursors of tissue macrophages, heterogeneity and detailed effects monocytes in acute aortic dissection (AAD) are largely unknown. To investigate the role brain soluble acid protein 1 positive (BASP1+) monocyte subset promoting AAD development well underlying mechanism. Monocyte/macrophage both human peripheral blood tissues were assayed by scRNA-seq. Monocyte trafficking lineage tracing detected immunofluorescence using BASP1-CreER/Lyz2-DreER-tdT reporter mice with AAD. The mechanism investigated laser speckle image, ultrasound imaging, Co-IP, ChIP-sequencing. Conditional knockout BASP1 on siRNA used to observe BASP1+ subset-targeted intervention. "PIP2-SP1-ACTN1/VAV3" "ITGB1-Rac1-GSN" signalling mediated first line immune cells infiltrating induction partial them transformed macrophages amplify inflammation. Meanwhile, induced an inflammatory phenotype vascular smooth muscle (VSMC) a ROS-enriched endothelial (EC) accompanied apoptosis normal VSMC EC, contributing remodelling dampening myo-endothelial gap junction. Selective deletion interference expression inhibited mice. Interpretation its regulatory network provides deep insight into pathogenesis novel potential target for early intervention formation.

Язык: Английский

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