Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"<i>Fusobacterium nucleatum-</i>Derived Isoleucine Exacerbates Aneurysm by Inducing Ferroptosis in Vascular Smooth Muscle Cells.","authors":"Liang Chen, Lu Lin, Zheyu Wang, Lu Yu, Bichen Ren, Siyuan Zhou, Penghui Wang, Yao Li, Eryi Lu, Zhihui Dong","doi":"10.1161/ATVBAHA.126.324050","DOIUrl":"10.1161/ATVBAHA.126.324050","url":null,"abstract":"<p><strong>Background: </strong>Bacterial communities and their metabolites are increasingly recognized as key contributors to cardiovascular disease, yet their role and mechanistic involvement in abdominal aortic aneurysm (AAA) pathogenesis remain insufficiently defined.</p><p><strong>Methods: </strong>Dental plaques from patients with AAA and matched healthy controls were subjected to metagenomic sequencing, and corresponding plasma samples underwent untargeted metabolomic profiling. In vivo, mice were topically exposed in the oral cavity to <i>Fusobacterium nucleatum</i> (Fn) followed by AngII (angiotensin II) infusion to evaluate its impact on AAA progression. A homologous recombination-based <i>ilvE</i> deletion strategy was used to confirm the role of Fn in isoleucine biosynthesis. Molecular assays were performed to assess ferroptosis-related signatures and histone acetylation in smooth muscle cells, while chromatin immunoprecipitation-quantitative polymerase chain reaction verified the specific acetylation target. In addition, dietary restriction of isoleucine was introduced in the AAA murine model to explore therapeutic relevance.</p><p><strong>Results: </strong>Patients with AAA showed a marked enrichment of Fn in dental plaque, and topical application of Fn aggravated AngII-induced AAA in mice. Elevated plasma isoleucine concentrations were observed in both human AAA and experimental models. Genetic deletion of <i>ilvE</i> in Fn diminished bacterial isoleucine release and mitigated AAA development in mice. Mechanistic analyses revealed that Fn-derived isoleucine promoted ferroptosis in smooth muscle cells through H3K9ac (histone H3 lysine 9 acetylation)-dependent transcriptional activation of <i>ACSL4</i> (acyl-CoA [coenzyme A] synthetase long-chain family member 4), a core regulator of ferroptosis. Dietary isoleucine restriction in the AngII-induced model reduced H3K9ac, suppressed ferroptosis, and alleviated aneurysmal progression.</p><p><strong>Conclusions: </strong>Fn-derived isoleucine drives ferroptosis in smooth muscle cells via H3K9ac-mediated activation of ACSL4, delineating a microbiota-metabolite-epigenetic axis in AAA pathogenesis and nominating dental plaque Fn abundance and circulating isoleucine as exploratory biomarker candidates requiring larger, independent validation.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324050"},"PeriodicalIF":8.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13384373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148040593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sleep, Neural Circulatory Control, and Cardiovascular Disease: A Mechanistic Review.","authors":"Shahid Karim, Saifullah Khan, Virend K Somers","doi":"10.1161/ATVBAHA.125.324076","DOIUrl":"10.1161/ATVBAHA.125.324076","url":null,"abstract":"<p><p>Sleep is an active period of profound autonomic fluctuation, cycling between the parasympathetic dominance of nonrapid eye movement sleep and the sympathetic/parasympathetic volatility of rapid eye movement sleep. Sleep-disordered breathing, a spectrum of disorders marked by recurrent ventilatory instability and intermittent hypoxia during sleep, particularly obstructive sleep apnea, pathologically amplifies this volatility, transforming sleep into a nightly cascade of severe autonomic and hemodynamic stress. The cardinal features of sleep-disordered breathing, intermittent hypoxia, recurrent arousals, and marked intrathoracic pressure swings, act synergistically to drive chronic, 24-hour sympathetic overactivity, chemoreflex sensitization, and maladaptive neuroplasticity. These effects are mediated at a cellular level by oxidative stress, systemic inflammation, endothelial dysfunction, and neuroendocrine dysregulation. This persistent autonomic reset provides a direct mechanistic link to cardiovascular consequences. It is likely a primary driver of hypertension, blunting the nocturnal blood pressure dip and promoting sustained 24-hour sympathoexcitation. It fosters a proarrhythmic substrate for atrial fibrillation through mechanical stress, which drives atrial remodeling and autonomic conflict. Furthermore, sleep-disordered breathing contributes to myocardial ischemia by increasing myocardial oxygen demand and promoting a prothrombotic state. Beyond chronic disease, sleep-related autonomic shifts can act as acute triggers for malignant arrhythmias in individuals with vulnerable substrates, such as inherited channelopathies, a risk that may be significantly amplified by comorbid sleep-disordered breathing. This review delineates the critical neural and cellular pathways connecting sleep, autonomic dysregulation, and cardiovascular risk.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324076"},"PeriodicalIF":8.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13464502/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial Continuum and Capillary Specialization in Pulmonary Vascular Development.","authors":"Amanda Ceas, Anastasia Jimenez, Yun Liu, Mariana De Niz, Lisandra Vila Ellis","doi":"10.1161/ATVBAHA.126.322483","DOIUrl":"10.1161/ATVBAHA.126.322483","url":null,"abstract":"<p><p>Pulmonary vascular development requires coordinated growth, remodeling, and specialization of the endothelial network to support airway branching and alveolar formation. Recent advances in single-cell and spatial transcriptomics have revealed that endothelial cells are organized along a transcriptional arteriovenous spectrum while simultaneously adopting region-specific identities within the capillary bed. In particular, the emergence of distinct alveolar capillary populations, including capillary endothelial cell type 1 and capillary endothelial cell type 2 cells, highlights previously unappreciated heterogeneity. Parallel studies further demonstrate that macrovascular and microvascular identities are influenced by positional context, vessel caliber, and flow-associated transcriptional programs. Together, these insights redefine how endothelial specialization is established during lung development. Here, we review current understanding of pulmonary vascular morphogenesis, endothelial fate specification, and capillary diversification and discuss how emerging imaging platforms may help connect molecular identity with spatial organization and dynamic cellular behavior.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e322483"},"PeriodicalIF":8.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13336269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148366776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Platelet RIP2 Limits Dense Granule Release and Thrombosis via DOCK8-Cdc42.","authors":"Jianjun Zhang, Zhiling Zhang, Guanxing Pan, Yangyang Liu, Lin Chang, Liang Hu, Zhiyong Qi, Yan Zhang, Si Zhang, Jianlin Qiao, Xiaodong Xi, Kesheng Dai, Jianzeng Dong, Zhongren Ding","doi":"10.1161/ATVBAHA.125.323791","DOIUrl":"10.1161/ATVBAHA.125.323791","url":null,"abstract":"<p><strong>Background: </strong>RIP2 (receptor-interacting protein kinase 2) is an essential mediator of inflammation and innate immunity downstream of PRRs (pattern recognition receptors). It is reported that RIP2 is expressed on platelets, while its role in platelet activation, thrombosis, and myocardial infarction, and whether these effects are mediated through the PRR pathway, remains unknown.</p><p><strong>Methods: </strong>In vitro assays of platelet aggregation, dense and α-granule secretion, spreading, and clot retraction, along with an ex vivo microfluidic whole blood perfusion assay, and in vivo models of FeCl₃-induced mesenteric arteriolar thrombosis and ischemia/reperfusion myocardial infarction, were used to assess the impact of RIP2 deficiency on platelet function. Immunoprecipitation followed by liquid chromatography-tandem mass spectrometry was performed to elucidate the mechanism by which RIP2 limits dense granule secretion in platelets. Furthermore, RIP2 expression levels in platelets from healthy donors and patients with coronary artery disease were measured by Western blotting to evaluate their clinical relevance.</p><p><strong>Results: </strong>Here, we show that RIP2 deficiency enhances platelet dense granule secretion in response to GPIb (platelet glycoprotein Ib) and GPVI (platelet glycoprotein VI) activation; platelet aggregation in whole blood and adhesion under arterial shear are also increased. Consistently, RIP2 inhibitor WEHI-345 potentiates human platelet dense granule secretion and inhibits RIP2 phosphorylation induced by thrombin and collagen. These phenotypes are translated into shorter bleeding time and accelerated FeCl₃-induced arterial thrombosis. Importantly, platelets from patients with coronary artery disease and mice with atherosclerosis express lower RIP2, and RIP2 deficiency worsens myocardial infarction and cardiac function in a mouse ischemia/reperfusion model. Mechanistically, we found that platelets express DOCK8 (dedicator of cytogenesis protein 8), which is sequestered by p-RIP2 (phosphorylated RIP2), causing inhibition of Cdc42 (cell division cycle 42) activation and subsequent dense granule release.</p><p><strong>Conclusions: </strong>RIP2 restrains platelet activation and thrombosis, thereby mitigating myocardial infarction. We identify a novel PRR-independent pathway, p-RIP2-DOCK8-Cdc42, which suppresses dense granule release downstream of GPIb and GPVI. Targeting the platelet RIP2 pathway may offer a therapeutic strategy against atherothrombotic diseases from early atherosclerosis to arterial thrombosis and myocardial infarction.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e323791"},"PeriodicalIF":8.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148216176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linking Lipidomics to Vulnerable Coronary Plaques: A PROSPECT II Substudy.","authors":"Tania Sharma, Tove Fall, Sergi Sayols-Baixeras, Akiko Maehara, Michael Maeng, Lars Kjøller-Hansen, Thomas Engstrøm, Ori Ben-Yehuda, Mitsuaki Matsumura, Ole Fröbert, Jonas Persson, Rune Wiseth, Alf Inge Larsen, J Gustav Smith, Gunnar Engström, Johan Ärnlöv, Jan Borén, Ramzi Y Khamis, Sotirios Tsimikas, Sasha Koul, Rebecca Rylance, Ziad A Ali, Stefan K James, Gregg W Stone, David Erlinge","doi":"10.1161/ATVBAHA.125.324430","DOIUrl":"10.1161/ATVBAHA.125.324430","url":null,"abstract":"<p><strong>Background: </strong>Lipidomics, the comprehensive profiling of circulating lipid species, has emerged as a powerful tool to investigate metabolic alterations underlying coronary atherosclerosis. Understanding the mechanisms driving high-risk vulnerable plaque formation and progression to myocardial infarction remains a key therapeutic priority. This study investigates associations between circulating lipid metabolites and imaging-defined features of vulnerable coronary plaque.</p><p><strong>Methods: </strong>Following revascularization, patients with myocardial infarction underwent 3-vessel coronary artery imaging with near-infrared spectroscopy and intravascular ultrasound to assess nonflow-limiting plaques for lipid core burden index and plaque burden. Multivariable models evaluated associations between 424 lipid metabolites in plasma, quantified by mass spectrometry, pan-coronary lipid, pan-coronary plaque burden, and high-risk vulnerable plaque measures (maximum lipid core burden index within any 4-mm segment across the entire lesion ≥324.7 and/or plaque burden ≥70%) in 877 patients. Findings were validated in the SCAPIS study (Swedish Cardiopulmonary Bioimage Study) using coronary computed tomography angiography-based measures of coronary artery calcium score and segment involvement score.</p><p><strong>Results: </strong>We identified 156 significant associations (<i>P</i><0.05) between lipid metabolites and coronary plaque characteristics across 39 metabolic pathways. Sphingomyelins were inversely associated with all plaque metrics, and 1-palmitoyl-2-oleoyl-GPE (glycero-3-phosphoethanolamine; 16:0/18:1), a phosphatidylethanolamine, was positively associated with all plaque metrics. After correcting for multiple testing, 27 lipid species across 7 pathways remained significant (q<0.05). The majority were linked to pan-coronary lipid burden, with the strongest inverse association observed for sphingomyelin d18:1/22:1, d18:2/22:0, and d16:1/24:1. Similar inverse patterns were seen for select dihydrosphingomyelins and fatty acid dicarboxylates. In contrast, 1-palmitoyl-2-oleoyl-GPE (16:0/18:1) remained positively associated with pan-coronary lipid. In the SCAPIS validation cohort, 19 of the 27 significant lipid associations were successfully replicated (q<0.05).</p><p><strong>Conclusions: </strong>This study is the first to demonstrate that sphingomyelins are negatively and 1-palmitoyl-2-oleoyl-GPE (16:0/18:1) positively associated with vulnerable coronary plaque features based on multimodality intracoronary imaging in patients with myocardial infarction. Moreover, these associations were validated in a large cohort using coronary computed tomography angiography-derived measures of plaque burden. These novel results may enable the development of new diagnostic and therapeutic strategies.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324430"},"PeriodicalIF":8.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13313029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phosphoproteomics in Vascular Biology and Disease: Illuminating Signaling in the Vessel.","authors":"Kayleigh Voos, Ming He, Gina M Many, Yabing Chen, Wei-Jun Qian","doi":"10.1161/ATVBAHA.126.323845","DOIUrl":"10.1161/ATVBAHA.126.323845","url":null,"abstract":"<p><p>Phosphoregulatory events underlie vascular responses to environmental and pathological stimuli, regulate hemostasis and thrombosis, and drive vascular remodeling in health and disease. Consequently, defining phosphorylation-dependent signaling networks in vascular physiology and pathology has enabled biomarker discovery and informed therapeutic interventions. Advances in mass spectrometry-based phosphoproteomics have enabled accurate and high-resolution mapping of dynamic phosphorylation events at the systems level, providing comprehensive mechanistic insights into vascular signaling and pathology. In this review, we contextualize phosphorylation in the vascular niche and summarize the current state of phosphoproteomics in vascular research, highlighting experimental design considerations, technological advances, quantification strategies, and data analysis approaches to uncover biological insights from large-scale phosphoproteomic data sets. Finally, we discuss recent discoveries in vascular signaling and disease, along with current challenges and emerging directions for applying phosphoproteomics to critical questions in vascular biology.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e323845"},"PeriodicalIF":8.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13297492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148216195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating Extracellular Mitochondria Perpetuate Endothelial Damage via Cardiolipin-Mediated Mitophagic Overload.","authors":"Fahimeh Varzideh, Urna Kansakar, Shivangi Pande, Stanislovas S Jankauskas, Gaetano Santulli","doi":"10.1161/ATVBAHA.126.325172","DOIUrl":"10.1161/ATVBAHA.126.325172","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e325172"},"PeriodicalIF":8.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13384196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148366795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding the Sex-Specific Architecture of Carotid Plaque Instability.","authors":"Ting Zhou, Huan Yang, Bo Liu","doi":"10.1161/ATVBAHA.126.325146","DOIUrl":"10.1161/ATVBAHA.126.325146","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e325146"},"PeriodicalIF":8.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13336249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148366845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage-Mediated Mechanisms of Vascular Remodeling in Arteriovenous Malformations.","authors":"Nhi Nguyen, Andrew D Spearman","doi":"10.1161/ATVBAHA.125.323163","DOIUrl":"10.1161/ATVBAHA.125.323163","url":null,"abstract":"<p><p>Arteriovenous malformations (AVMs) are vascular malformations that can occur in virtually all tissues throughout the body, most commonly in the brain, lungs, and cutaneous tissue. AVM pathophysiology is dynamic and multifactorial with multiple contributing cell types and biological processes. Inflammation and perivascular accumulation of macrophages are well-recognized components of AVM pathophysiology that have been demonstrated for decades in both patient AVM tissue and animal models. Despite the clinical and preclinical data identifying a role for macrophages in AVM pathophysiology, it remains poorly understood how macrophages mechanistically contribute to AVM initiation and progression. Recent single-cell RNA sequencing studies leveraging clinical AVM samples are beginning to shed new light on macrophage diversity in AVM tissue and direct macrophage-mediated effects on endothelial cell signaling pathways. This review will focus on fundamental aspects of AVM pathophysiology, mechanisms of macrophage-mediated vascular remodeling in AVMs, and potential future research directions focused on macrophage-mediated mechanisms in AVM pathophysiology.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e323163"},"PeriodicalIF":8.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microfibril Denudation Marks Early Aortic Vulnerability in SMAD3 Variant Carriers: A Multigenerational Study.","authors":"Paulina M Kowalewska, Hao Yin, Mofei Wang, Brittany Balint, Sahar Hoveyda, Usha Manian, Pei Jun Zhao, Joshua P Samsoondar, Kevin Yijun Fan, Zengxuan Nong, Caroline O'Neil, Matthew T J Hare, Julieta Lazarte, Sharan Goobie, Robert A Hegele, Michael W A Chu, J Geoffrey Pickering","doi":"10.1161/ATVBAHA.126.324690","DOIUrl":"10.1161/ATVBAHA.126.324690","url":null,"abstract":"<p><strong>Background: </strong>Individuals with Loeys-Dietz syndrome 3 are at risk for thoracic aortic dissection even if their aortas are not substantially dilated. A pathogenic variant of SMAD3 is a genetic trigger, but the cellular programs that underlie the heightened aortic risk remain poorly understood.</p><p><strong>Methods: </strong>We ascertained the cardiovascular profile of 57 individuals in a 4-generation family with a missense variant in SMAD3 (p.Arg287Gln). Aortic medial architectures were quantified from aortas harvested during thoracic aortic replacement surgery, with 2-dimensional and 3-dimensional profiling of the elastin-microfibril network. TGF-β (transforming growth factor beta)-dependent regulatory networks were investigated by whole-genome RNA sequencing of ascending aortic smooth muscle cells (SMCs) and bioinformatics-informed chromatin immunoprecipitation.</p><p><strong>Results: </strong>Cardiovascular phenotypes of family members harboring the SMAD3 variant included thoracic aortopathy, peripheral artery aneurysms and tortuosity, cerebrovascular disease, coronary artery dissections, and mitral valve prolapse. The median age at the first aortic event was 36.5 years. Ascending aortas were less dilated than the aortic root, with relatively intact lamellar structure and SMC content. However, early pathology was evident, with SMCs separated from elastic lamellae by a thin layer of glycosaminoglycans. Confocal reconstructions revealed that elastic fibers were poorly decorated by microfibrils, with reduced fibrillin-1, fibrillin-2, microfibril associated glycoprotein-2, fibulin-1 and fibulin-2. RNA sequencing of Loeys-Dietz syndrome 3 SMCs revealed reduced microfibril gene expression. Furthermore, PRRX2 (paired related homeobox 2) was found to be downregulated in Loeys-Dietz syndrome 3 SMCs in culture and in situ, occupies gene promoter sites for all 5 microfibrils, and mediates their expression in SMCs. SMAD3 overexpression rescued both <i>PRRX2</i> and microfibril expression.</p><p><strong>Conclusions: </strong>These findings identify SMCs delaminating from unsheathed elastic fibers as an incipient pathological program in Loeys-Dietz syndrome 3 aortas. They also uncover a SMAD3-PRRX2-microfibril axis that, being perturbed, could explain this disconnection phenomenon and contribute to risk.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324690"},"PeriodicalIF":8.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13384375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148216231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}