Sayahpour FA, Nejati M, Jolfayi AG
… +10 more, Shahrokhi Nejad S, Azimi A, Mihankhah A, Tamimi M, Gousias C, Tafazoli P, Aly M, Hosseinzade D, Rajabi S, Tayebi L
The study of angiogenesis has rapidly evolved from fundamental morphometric observations to complex, multidimensional investigations. This comprehensive review synthesizes the expanding toolkit of angiogenesis assays, en...The study of angiogenesis has rapidly evolved from fundamental morphometric observations to complex, multidimensional investigations. This comprehensive review synthesizes the expanding toolkit of angiogenesis assays, encompassing established in vitro models, ex vivo systems, and advanced in vivo platforms. Furthermore, we detail the integration of next-generation technologies, including artificial intelligence-based image analysis, spatial transcriptomics, and CRISPR-Cas9 screening, into modern vascular biology. Crucially, this review moves beyond the mere description of methodologies to provide a strategic, application-driven decision-making framework for researchers. By introducing a comprehensive decision matrix and an algorithmic selection guide, we empower investigators to navigate the complexities of assay selection. This framework carefully balances physiological fidelity and expected readouts against practical laboratory constraints and the ethical imperatives of the 3Rs principle (Replacement, Reduction, and Refinement). Ultimately, this strategic approach enables the design of highly reproducible, cost-effective, and translationally relevant experimental pipelines tailored to specific molecular, metabolic, or pharmacological research questions.
BACKGROUND: Effective pharmacological therapies for small abdominal aortic aneurysms (AAAs) have not been identified. Most preclinical work focuses on aneurysm initiation rather than established disease, reducing transla...BACKGROUND: Effective pharmacological therapies for small abdominal aortic aneurysms (AAAs) have not been identified. Most preclinical work focuses on aneurysm initiation rather than established disease, reducing translational relevance. METHODS: We conducted a systematic review and meta-analysis of murine studies evaluating pharmacological or stem cell-based interventions on established small AAAs. Forty-three studies met inclusion criteria, and 35 (n = 1163 mice) provided quantitative data. Aneurysms were induced using angiotensin II, calcium chloride, or elastase. RESULTS: Anti-inflammatory agents, protease inhibitors, stem cells, antithrombotic therapies, and renin-angiotensin system inhibitors each significantly reduced aneurysm diameter. Earlier initiation of therapy enhanced intervention efficacy (R = 10.5%; p = 0.03). Only anti-inflammatory drugs significantly reduced rupture incidence (risk ratio 0.40; 95% CI 0.18-0.89). Risk of bias was moderate-to-high across most studies, with indications of potential publication bias. CONCLUSION: Targeting inflammation, proteolysis, thrombosis, and vascular remodelling can attenuate progression of established small AAAs in mice, with anti-inflammatory therapy uniquely demonstrating protection against rupture.
Extracellular vesicles (EVs) function as the central mechanobiological orchestrators connecting vascular inflammation and hemostasis. In this review, we propose a unified mechanistic model wherein EV thrombogenicity is g...Extracellular vesicles (EVs) function as the central mechanobiological orchestrators connecting vascular inflammation and hemostasis. In this review, we propose a unified mechanistic model wherein EV thrombogenicity is governed by convergent catalytic switches: phosphatidylserine (PS) externalization, which scaffolds tenase and prothrombinase assembly, and the structural "decryption" of Tissue Factor (TF) via membrane reorganization and thiol-disulfide exchange. While these molecular drivers are universal, their pathological manifestations diverge strictly by hemodynamic context. In the high-shear arterial environment, EVs act as stress transducers; platelet-EVs leverage von Willebrand factor-GPIb interactions to drive acute occlusion. Conversely, under venous stasis, an immunothrombotic axis dominates; here, hypoxic endothelial- and leukocyte-EVs shuttle mitochondrial DAMPs to potentiate Neutrophil Extracellular Trap (NET) formation, scaffolding the fibrin-rich "red thrombus." Despite this mechanistic clarity, clinical translation is impeded by methodological constraints, particularly the confounding interference of lipoproteins (e.g., chylomicrons) in functional assays. Ultimately, harnessing EVs as "liquid biopsy" biomarkers or therapeutic vectors requires a paradigm shift from particle enumeration to functional phenotyping, alongside rigorous safety engineering to resolve the inherent thrombogenic paradox of EV-based interventions.
Thoracic aortic dissection (TAD) is a severe aortic disease with high mortality. One of its pathological hallmarks is aortic smooth muscle cell death, but the death modalities are not fully known. Recent studies suggest...Thoracic aortic dissection (TAD) is a severe aortic disease with high mortality. One of its pathological hallmarks is aortic smooth muscle cell death, but the death modalities are not fully known. Recent studies suggest an association of pyroptosis with aortic diseases, but whether it contributes to TAD remains unknown. Here, we modeled TAD by feeding 3-week-old mice with β-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, for 28 days. By means of global knockout of Caspase11 and Gsdmd in mice, two key knots in non-canonical pyroptosis pathway, we showed that neither Caspase11 nor Gsdmd influenced TAD phenotypes, including death rate, aortic lesions. This pilot study on pyroptosis yields no positive outcome, but is informative and thought-provoking. It highlights factors to consider when designing future experiments, including conditional gene knockout, multiple model validation, and extensive Caspases screening. The role of pyroptosis in TAD warrants further investigations through more precise methodologies in more animal models.
Zhu J, Darko F, Han F
… +4 more, Simeroth S, Li L, Gu H, Yu P
Vascul Pharmacol
· 2026 Jun · PMID 41932558
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The lymphatic vascular system plays essential roles in tissue fluid drainage, dietary fat absorption and transport, and immune cell trafficking. To support these physiological functions, the lymphatic vasculature forms a...The lymphatic vascular system plays essential roles in tissue fluid drainage, dietary fat absorption and transport, and immune cell trafficking. To support these physiological functions, the lymphatic vasculature forms an extensive and highly organized network throughout the body. We recently discovered that the mechanistic target of rapamycin complex 1 (mTORC1), with RAPTOR as an indispensable component, directs glycolysis and glutaminolysis in lymphatic endothelial cells (LECs) to promote lymphatic vessel formation. However, the role of mTORC1 in regulating LEC metabolism remains incompletely understood. Here, by conducting untargeted metabolomic profiling of control and RAPTOR-deficient LECs, we uncover a global impact of mTORC1 inhibition on amino acid utilization. Specifically, RAPTOR deficiency impairs the conversion of glutamine to glutamic acid, resulting in decreased levels of glutamic acid and aspartic acid, as well as reduced abundance of N-acetyl-glutamic acid and N-acetyl-aspartic acid-two metabolites unexpectedly detected in LECs. Integrated metabolomic and transcriptomic analyses further reveal that impaired glutaminolysis in RAPTOR-depleted LECs is accompanied by increased intracellular asparagine, arginine, and metabolites associated with arginine catabolism, potentially driven by upregulation of their respective transporters. In addition, RAPTOR depletion results in abnormal accumulation of branched-chain amino acids (BCAAs) and other essential amino acids primarily involved in protein synthesis. Mechanistically, our data suggest that defective BCAA catabolism and impaired translational control contribute to these metabolic alterations. Collectively, these findings reveal an important role of mTORC1 signaling in coordinating amino acid utilization and suggest that this regulation is critical for lymphatic vessel formation.
Raynaud's phenomenon (RP) is a functional vascular disorder characterized by episodic vasospasm of the digital microcirculation, resulting in transient ischemia, sensory disturbances, and pain. Despite long-standing clin...Raynaud's phenomenon (RP) is a functional vascular disorder characterized by episodic vasospasm of the digital microcirculation, resulting in transient ischemia, sensory disturbances, and pain. Despite long-standing clinical recognition, effective pharmacological management of RP remains challenging due to perfusion-limited drug delivery, short drug residence time at ischemic sites, and frequent systemic adverse effects associated with conventional vasodilator therapies. These limitations are particularly pronounced in secondary RP, where structural microvasculature damage further compromises therapeutic efficacy. Emerging nanocarrier-based drug delivery systems offer a promising strategy to address these challenges by enhancing drug stability, improving site-specific accumulation, and enabling controlled or stimuli-responsive release in affected tissues. This review examines RP from a drug-delivery-oriented perspective, highlighting how nanocarriers such as liposomes, polymeric nanoparticles, dendrimers, micelles, and nanoemulsions can overcome RP-specific vascular and cutaneous barriers. Particular emphasis is placed on aligning nanocarrier design with RP pathophysiology, including episodic ischemia, endothelial dysfunction, oxidative stress, and differences between primary and secondary disease. Route-specific delivery strategies and translational considerations, including manufacturing and regulatory challenges, are also discussed. By reframing RP as a delivery-limited disorder rather than solely a pharmacological one, this review provides a translational framework for the rational development of next-generation, personalized nanomedicine-based therapies for RP.
Sodium nitroprusside (SNP) is one of the oldest, yet most powerful intravenous vasodilators used in acute cardiovascular care. Although newer vasoactive agents have been introduced, SNP continues to play a relevant role...Sodium nitroprusside (SNP) is one of the oldest, yet most powerful intravenous vasodilators used in acute cardiovascular care. Although newer vasoactive agents have been introduced, SNP continues to play a relevant role in clinical practice, particularly when rapid and tightly controlled hemodynamic modulation is required. In this systematic review, conducted according to PRISMA recommendations, we provide a comprehensive overview of the pharmacological profile, clinical applications, and safety considerations of SNP in acute heart failure (AHF), cardiogenic shock, hypertensive emergencies, and acute aortic dissection. Through nitric oxide-mediated activation of the cGMP pathway, SNP induces balanced arterial and venous vasodilation, leading to effective preload and afterload reduction and prompt blood pressure control. Available evidence suggests meaningful hemodynamic improvement in selected patients with advanced AHF, with observational data indicating possible survival benefits. In hypertensive crises and acute aortic syndromes, SNP remains an effective option for rapid blood pressure reduction and wall stress control, consistent with current guideline recommendations. However, concerns regarding cyanide and thiocyanate toxicity, particularly during high-dose or prolonged infusions, limit its extended use. Overall, SNP remains a valuable therapeutic tool, but a more individualized approach and well-designed randomized trials are needed to better define its long-term clinical impact in contemporary vascular pharmacotherapy.
Wennersten SA, Wang H, Franklin JL
… +1 more, Nanda V
Vascul Pharmacol
· 2025 Dec · PMID 41880186
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The transition of smooth muscle cells (SMCs) from a contractile to a synthetic phenotype is a key contributor to cardiovascular disease (CVD) pathologies, such as atherosclerosis and in-stent restenosis. We previously re...The transition of smooth muscle cells (SMCs) from a contractile to a synthetic phenotype is a key contributor to cardiovascular disease (CVD) pathologies, such as atherosclerosis and in-stent restenosis. We previously reported that loss of leiomodin 1 (LMOD1), a coronary artery disease risk gene highly expressed in SMCs, promotes SMC phenotypic switching in vitro. However, the in vivo role of LMOD1 and the molecular mechanisms driving this transition remain unknown. In this study, we found that Lmod1 heterozygous mice subjected to carotid artery ligation developed larger neointimal lesions. Histopathological analyses attributed this phenotype to increased SMC proliferation. RNA sequencing studies of LMOD1-deficient SMCs revealed a significant upregulation of genes associated with increased cell proliferation, particularly those involved in the G1/S phase transition. Further analysis identified cyclin-dependent kinase 6 (CDK6) as a potential mediator of this hyperproliferative response. Notably, the knockdown of CDK6 in LMOD1-deficient cultured SMCs restored SMC proliferation to near baseline levels, indicating that the observed phenotype is reversible in vitro. Collectively, these findings indicate that LMOD1 deficiency promotes SMC proliferation by upregulating CDK6 expression and provide mechanistic insight into how reduced LMOD1 expression may contribute to increased neointimal lesion size and vascular remodeling.
Vascul Pharmacol
· 2026 Jun · PMID 41819434
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Mortality factor 4-like 1 (MORF4L1) is a highly ubiquitinated protein, initially discovered for its role in reversing cellular immortalization. It functions as a component of multi-subunit complexes, including the NuA4 (...Mortality factor 4-like 1 (MORF4L1) is a highly ubiquitinated protein, initially discovered for its role in reversing cellular immortalization. It functions as a component of multi-subunit complexes, including the NuA4 (nucleosome acetyltransferase of H4) histone acetyltransferase, SIN3B histone deacetylase complexes, and histone methyltransferase. It thereby directly influences histone acetylation, methylation, and gene expression. MORF4L1 has emerged as a key player in several biological processes, such as chromatin remodeling, DNA damage response, and cellular senescence. Recent research findings highlight its expanded role in lipid metabolism and metabolic diseases. Genome-wide association studies reveal single-nucleotide polymorphisms near the MORF4L1 locus correlating with lipid traits, type 2 diabetes, and coronary artery disease. This review provides a comprehensive overview of MORF4L1's regulation and its multifaceted roles, implicating its emerging importance in vascular homeostasis and cardiometabolic disease. We propose that MORF4L1's intricate mechanisms demand a deeper understanding. As a regulatory protein at the interface of chromatin biology, cellular senescence, and lipid metabolism, MORF4L1 holds promise as a potential therapeutic target for ameliorating vascular and metabolic dysfunction in cardiometabolic diseases.
Manzi G, Badagliacca R, D'Alto M
… +40 more, Ghio S, Palazzini M, Romeo E, Scelsi L, Airò E, Argiento P, Baldi F, Bauleo C, Bonsante E, Carignola R, Carmina MG, Cannillo M, Casu G, Confalonieri M, Corda M, Correale M, D'Angelo L, De Michele L, Fortunato F, Galié N, Galgano G, Garascia A, Giuliani L, Marra WG, Madonna R, Mercurio V, Monti S, Mulé M, Paciocco G, Papa S, Pezzuto B, Prati D, Raineri C, Romaniello A, Renon F, Stolfo D, Vatrano M, Vitulo P, Manes A, Vizza CD
BACKGROUND: The demographic shift of pulmonary arterial hypertension (PAH) patients, the expanding therapeutic armamentarium with new emerging drugs and the heterogenous experience in handling more complex therapies are...BACKGROUND: The demographic shift of pulmonary arterial hypertension (PAH) patients, the expanding therapeutic armamentarium with new emerging drugs and the heterogenous experience in handling more complex therapies are making the management of PAH increasingly challenging. This project was developed to standardize PAH management across Italian centres and ensure timely access to the optimal therapeutic strategies. METHODS: A consensus document containing 10 statements, mainly focused on the use of parenteral prostanoids, was developed by eight experts in PAH during in-person and web-based meetings. Forty-six physicians were invited online to rate each statement, indicating their agreement, neutrality or disagreement. RESULTS: Forty physicians participated to the survey. There was strong agreement that age and comorbidities significantly influence the choice of PAH-targeted therapies. Agreement was also reached on the use of parenteral prostanoids in the following clinical scenarios: a) treatment-naive patients at high risk; b) newly diagnosed patients classified as intermediate-risk, with severe right ventricular dysfunction assessed invasively and c) prevalent high-risk patients, as defined by the 4-strata risk score. The use of parenteral prostanoids in selected newly diagnosed intermediate-risk patients with severe right ventricular dysfunction assessed by imaging achieved a mild agreement. Three statements did not meet the predefined threshold for consensus. CONCLUSIONS: These consensus statements are intended to support physicians in starting parenteral prostanoids, minimizing delays that could negatively affect patient prognosis.
D'Alto M, Scelsi L, Giuliani L
… +17 more, Perna GP, Baldi F, Guerra F, Di Poi E, Vicenzi M, Badagliacca R, Corda M, Airò E, Ferrero P, Ameri P, Bux F, Agostoni P, D'Agostino C, Casu G, Biancospino M, Uglietti A, De Santis S
Benzo[a]pyrene (BaP), a pervasive environmental pollutant, has been implicated in cardiovascular injury, yet its mechanistic contribution to atherosclerosis remains unclear. Here, we combined network toxicology, RNA-seq...Benzo[a]pyrene (BaP), a pervasive environmental pollutant, has been implicated in cardiovascular injury, yet its mechanistic contribution to atherosclerosis remains unclear. Here, we combined network toxicology, RNA-seq profiling, molecular simulations, and cellular validation to elucidate BaP-driven vascular effects. Integration of BaP-associated targets with atherosclerosis gene sets identified SPP1 as a key hub. Transcriptomic analysis of aortas from BaP-treated ApoE/ mice revealed differential expression enriched in inflammatory responses, cytokine signaling, xenobiotic metabolism, and lipid-handling pathways. STRING-based protein interaction networks and Reactome analysis further supported coordinated activation of innate immunity and metabolic dysfunction. Molecular docking and 100-ns MD simulations demonstrated stable, energetically favorable binding between BaP and SPP1. In THP-1 macrophages, BaP enhanced oxLDL-induced SPP1 expression, reduced cell viability, and promoted a foam-cell-like phenotype characterized by suppressed ABCA1 and increased CD36 and PLIN2. Silencing SPP1 partially rescued BaP-induced cytotoxicity and lipid dysregulation, confirming SPP1's functional involvement. Collectively, these findings indicate that BaP aggravates atherosclerosis through SPP1-mediated macrophage inflammation and impaired lipid metabolism, highlighting SPP1 as a potential mechanistic link and therapeutic target for pollution-exacerbated vascular disease.
BACKGROUND: Atherosclerosis is a chronic inflammatory process wherein macrophages play a central role in the evolution of arterial wall plaques in extracellular matrix. Colchicine, a drug used most commonly to treat gout...BACKGROUND: Atherosclerosis is a chronic inflammatory process wherein macrophages play a central role in the evolution of arterial wall plaques in extracellular matrix. Colchicine, a drug used most commonly to treat gout, reduces immune cell motility and recruitment to inflamed joints by targeting microtubules. Colchicine also reduces cardiovascular events in patients with recent acute or chronic coronary disease, but the mechanisms are incompletely understood. AIMS: To characterise the effect of low-dose colchicine on human and mouse macrophages, focusing on the microtubule cytoskeleton and macrophage function. METHODS: Human monocytes were isolated from buffy coats and differentiated into macrophages (huMDM) in culture medium. Mouse bone marrow-derived macrophages (msBMM) were extracted from C57BL/6 mice and grown in culture medium to produce mature adherent macrophages. RESULTS: HuMDM treated with 10 nM colchicine showed marked morphological and functional changes associated with disruption of the microtubule cytoskeleton. Colchicine reduced the footprint area of huMDM by almost 50% and matrix degradation by 20%. In contrast, colchicine minimally affected the morphology of msBMM. However, it reduced the density of the microtubule cytoskeleton at the leading edge of msBMM with detectable disruption of microtubules, resulting in a significant decrease in motility. CONCLUSIONS: While msBMM appeared less susceptible to low-dose colchicine than huMDM, there was a measurable effect on their microtubules that resulted in reduced motility. Inhibition of huMDM matrix degradative capacity may contribute to colchicine's effect in reducing cardiovascular events.
Vascul Pharmacol
· 2026 Mar · PMID 41702467
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Cardiomyopathy is a disorder of the myocardium characterized by structural and functional abnormalities that result in impaired cardiac mechanical and/or electrical function. Aging induces a natural, gradual decline in c...Cardiomyopathy is a disorder of the myocardium characterized by structural and functional abnormalities that result in impaired cardiac mechanical and/or electrical function. Aging induces a natural, gradual decline in cardiac structure and function (cardiac aging) that increases susceptibility to cardiomyopathy and exacerbates pre-existing cardiomyopathy. Despite ongoing research, the complex, multifactorial nature of this process substantially increases the risk of heart failure and remains a significant clinical and scientific challenge. With rising global life expectancy, effective pharmacological strategies are urgently needed. Here, we discuss chronic inflammation as a key driver of cardiomyopathy in older adults and explore perspectives on anti-inflammatory interventions that may slow disease progression and improve outcomes for the older population.
D'Alto M, Scelsi L, Giuliani L
… +17 more, Perna GP, Baldi F, Guerra F, Di Poi E, Vicenzi M, Badagliacca R, Corda M, Airò E, Ferrero P, Ameri P, Bux F, Agostoni P, D'Agostino C, Casu G, Biancospino M, Uglietti A, De Santis S
BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease associated with significant morbidity and mortality. Combination therapy targeting multiple pathways has been shown to improve clinical outcomes....BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease associated with significant morbidity and mortality. Combination therapy targeting multiple pathways has been shown to improve clinical outcomes. METHODS: The INSPECTIO study was a prospective, multicenter, observational study conducted across 29 Italian centers specializing in PAH management. The study sought to explore the impact of combination therapy on disease progression and quality of life, by assessing non-invasive risk parameters, echocardiographic and hemodynamic conditions, and patient-reported outcomes (PROs). Patients with PAH at low or intermediate mortality risk, treated with macitentan and/or selexipag (as monotherapy or in combination), were enrolled. Data on non-invasive low-risk criteria (WHO Functional Class, 6-min walk distance [6MWD], and NT-proBNP), REVEAL risk scores, echocardiographic and hemodynamic parameters, and patient-reported outcomes (emPHasis-10) were collected at baseline and 12 months. A Narrative Medicine analysis complemented quantitative findings by exploring patients' experiences. RESULTS: Among 176 patients with follow-up data, the number of non-invasive low-risk criteria increased by an average of 0.15 at 12 months (p = 0.0167). REVEAL 2.0 and REVEAL Lite 2 scores showed significant reductions (mean changes: -1.0, p = 0.0142; -0.8, p = 0.0111, respectively). Modest changes were observed in echocardiographic and hemodynamic parameters. Narrative analysis highlighted strengthened patient-provider relationships and improved coping strategies. Safety outcomes aligned with known profiles. CONCLUSIONS: The INSPECTIO study supports the effectiveness of guideline-directed therapy and regular risk assessment to optimize treatment strategies in PAH. The increase in non-invasive low-risk criteria suggests a stabilization of disease over 12 months.
The human heart exhibits remarkable chamber-specific ion channel expression patterns that underlie the distinct electrophysiological properties of atrial versus ventricular myocardium. This comprehensive review examines...The human heart exhibits remarkable chamber-specific ion channel expression patterns that underlie the distinct electrophysiological properties of atrial versus ventricular myocardium. This comprehensive review examines the molecular architecture, biophysical properties, and functional roles of 79 ion channel subunits and related proteins across all four cardiac chambers based on quantitative transcriptomic data from non-diseased donor hearts. Understanding chamber-specific expression profiles is essential for comprehending cardiac electrophysiology, arrhythmia mechanisms, and the development of chamber-selective therapeutic strategies.
Preeclampsia (PE), a major hypertensive disorder of pregnancy, is increasingly recognized as a significant risk factor for cognitive decline and Alzheimer's disease (AD). Placental ischemia in PE leads to an anti-angioge...Preeclampsia (PE), a major hypertensive disorder of pregnancy, is increasingly recognized as a significant risk factor for cognitive decline and Alzheimer's disease (AD). Placental ischemia in PE leads to an anti-angiogenic state, characterized by elevated soluble FMS-like tyrosine kinase-1 (sFlt-1) and reduced placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), causing systemic endothelial dysfunction. These alterations may persist during the postpartum period, promoting cerebrovascular impairment, blood-brain barrier (BBB) disruption, and neuroinflammation. Furthermore, PE is associated with the release of AD-related proteins, including amyloid-beta (Aβ) and hyperphosphorylated tau protein. However, the potential link between AD and PE regarding the angiogenic and anti-angiogenic factors is not fully elucidated. This review aims to explore the shared pathophysiological pathways, focusing on the angiogenic and anti-angiogenic factors. The manuscript also evaluates the potential for repurposing pharmacological agents to mitigate the long-term risk of AD in women with a history of PE.
BACKGROUND: Thoracic aortic aneurysm and dissection (TAAD) is a kind of life-threatening cardiovascular condition with a poor prognosis, currently lacking effective drug therapies that can halt the progression of TAAD. T...BACKGROUND: Thoracic aortic aneurysm and dissection (TAAD) is a kind of life-threatening cardiovascular condition with a poor prognosis, currently lacking effective drug therapies that can halt the progression of TAAD. Tirzepatide, a dual GIP and GLP-1 receptor agonist used for type 2 diabetes and weight management, has shown cardioprotective potential, yet its effect on TAAD remains unknown. METHODS: A TAAD model in mice was developed by providing 0.5% β-aminopropionitrile (BAPN) for 28 days.Mice were categorized into control, tirzepatide-only, BAPN, and BAPN combined with tirzepatide.Tirzepatide (10 nmol/kg) was administered daily via intraperitoneal injection. Aortic morphology, incidence of TAAD, medial degeneration, inflammation, elastin integrity, and proteoglycan deposition were assessed by gross examination and histological analyses. Inflammatory cells infiltration and signaling pathways were evaluated by immunostaining and western blotting. In parallel, platelet-derived growth factor-BB (PDGF-BB) stimulated human aortic smooth muscle cells (HASMCs) were used as an in vitro model to examine the direct effects of TZP on VSMC phenotypic modulation. RESULTS: Treatment with tirzepatide led to a significant reduction in both the formation of TAAD (from 88.9% to 50.0%) and related deaths (from 83.3% to 38.9%). It also effectively suppressed the pathological expansion of the aortic diameter in the ascending, arch, and descending regions. Histological analysis revealed improved elastic fiber integrity and reduced degradation. Tirzepatide prevented VSMC phenotypic switching, reduced inflammatory cells infiltration, and lowered IL-1β, IL-6, and MCP-1 levels. It also downregulated NLRP3 and caspase-1 expression. In vitro, TZP directly reversed PDGF-BB-induced downregulation of VSMC contractile markers (MYH11, SMA, SM22, and CNN1) and mitigated cytoskeletal and morphological changes associated with phenotypic switching. CONCLUSION: Our findings indicate that tirzepatide curbs the development of TAAD in mice. The underlying mechanism likely involves the suppression of the NLRP3 inflammasome priming, a consequent reduction in vascular inflammation, and the preservation of the contractile state of VSMC. These findings highlight its potential as a novel therapeutic strategy for TAAD.