Circulation research最新文献

{"title":"RNA-Binding Protein MBNL2 Drives Cardiac Hypertrophy and Dysfunction by Facilitating TPM3 Splicing.","authors":"Yuanqi Shi, Siqi Sheng, Bin Wang, Pengcheng Lv, Jialiang Liu, Pengwei Dong, Jingyue Zhang, Jiuling Chen, Haiyu Zhang, Lin Lv, Jiale Yang, Dankun Luo, Yue Li, Zengxiang Dong","doi":"10.1161/CIRCRESAHA.125.328002","DOIUrl":"10.1161/CIRCRESAHA.125.328002","url":null,"abstract":"<p><strong>Background: </strong>Cardiac hypertrophy is a major contributor to heart failure development, making its prevention and treatment critical for reducing heart failure-associated mortality. Although alternative splicing is recognized as a key regulatory mechanism in myocardial hypertrophy, the precise pathways involved remain incompletely defined.</p><p><strong>Methods: </strong>To investigate the role of MBNL2 (muscleblind-like protein 2) in the heart, we overexpressed MBNL2 in cardiomyocytes via adeno-associated virus serotype 9 delivery. In addition, cardiomyocyte-specific MBNL2 knockout mice were generated, and transverse aortic constriction surgery or isoproterenol injection was performed to induce cardiac hypertrophy and dysfunction in mice. The underlying mechanisms were further investigated using RNA sequencing, alternative splicing analysis, and RNA immunoprecipitation.</p><p><strong>Results: </strong>MBNL2 expression was significantly increased in the heart tissues from patients with ischemic cardiomyopathy and in mice with cardiac hypertrophy. Cardiac-specific overexpression of MBNL2 induced cardiac hypertrophy and dysfunction. Mechanistically, MBNL2 promoted exon 9 skipping of TPM3 (tropomyosin 3), generating the TPM3 isoform lacking exon 9 (TPM3-Δe9). In neonatal mouse cardiomyocytes, TPM3-Δe9 knockdown partially reduced oxidative stress and mitigated mitochondrial damage induced by MBNL2 overexpression. Adeno-associated virus serotype 9-mediated knockdown of TPM3-Δe9 partially attenuated cardiac hypertrophy in MBNL2-overexpressing mice. Notably, cardiac-specific MBNL2 knockout or TPM3-Δe9 knockdown in mice attenuated cardiac dysfunction induced by transverse aortic constriction. Further, we found that elevated TPM3-Δe9 was associated with RNF20 (ring finger protein 20) and was accompanied by reduced RNF20 interaction with NCoR1 (nuclear receptor corepressor 1), increased NCoR1 expression, and decreased PPARα (peroxisome proliferator-activated receptor alpha) signaling. The protective effects of MBNL2 or TPM3-Δe9 knockdown in hypertrophic cardiomyocytes were partially reversed by treatment with the PPARα inhibitor GW6471.</p><p><strong>Conclusions: </strong>This study uncovers a novel, critical role for MBNL2 in pathological cardiac hypertrophy through regulation of TPM3 alternative splicing and mitochondrial function, highlighting MBNL2 as a potential therapeutic target for cardiac hypertrophy and dysfunction.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e328002"},"PeriodicalIF":18.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873262","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":"Deus Ex Mechano: Hydrostatic Pressure in Pulmonary Hypertension.","authors":"Shiza T Virk, Andrew J Bryant","doi":"10.1161/CIRCRESAHA.126.329683","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.126.329683","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"139 9","pages":"e329683"},"PeriodicalIF":18.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135128","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":"Cell Village Captures Populational Heterogeneity of Sunitinib Cardiotoxicity.","authors":"Ana Kojic, Yu Liu, Nadjet Belbachir, Chengyi Tu, Mengcheng Shen, Arianne Caudal, Thulaj Meharwade, Mehdi Belbachir, Kevin Ford, Karim Sallam, Joseph C Wu","doi":"10.1161/CIRCRESAHA.126.328704","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.126.328704","url":null,"abstract":"<p><strong>Background: </strong>TKIs (tyrosine kinase inhibitors) have transformed cancer therapy; however, cardiotoxicity remains a frequent adverse effect with variable susceptibility among patients. For sunitinib, a commonly prescribed TKI, the molecular programs and functional features underlying this variability are not well defined, and clinically actionable predictors of cardiotoxicity risk remain lacking.</p><p><strong>Methods: </strong>To investigate interindividual variability in sunitinib-induced cardiotoxic responses, we implemented the Cell Village platform consisting of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes from 20 healthy donors. Pooled iPSCs were differentiated into cardiomyocytes, treated with sunitinib for 72 hours, followed by harvesting for single-nucleus RNA sequencing. Donor identity was determined using single nucleotide polymorphism-based demultiplexing. Additionally, individual line-specific transcriptomic responses to sunitinib were integrated with quantitative functional phenotyping (including contractility, electrophysiology, and recovery efficacy following tocotrienol treatment) in iPSC-derived cardiomyocytes differentiated from a subset of 10 lines.</p><p><strong>Results: </strong>Sunitinib induced a robust global transcriptional response characterized by dysregulation of tyrosine kinase signaling, cytoskeletal organization, ion channels, and calcium-handling pathways. Although the pathway-level changes were shared, individual donor lines displayed heterogeneity in both gene expression patterns and functional impairment. Across functional parameters, relaxation velocity was the most consistently correlated with toxicity severity. Integration of each iPSC line's functional data with the corresponding transcriptomic signatures identified gene modules related to calcium handling and structural organization strongly correlated with donor-specific toxicity and recovery indices. Pharmacological validation using tocotrienol demonstrated partial, donor-dependent improvement of sunitinib-related iPSC-derived cardiomyocyte impairments.</p><p><strong>Conclusions: </strong>This proof-of-concept study establishes a scalable, donor-resolved platform that links pooled transcriptomic profiling with functional toxicity and recovery phenotypes in human cardiomyocytes. By linking molecular perturbations to functional outcomes across genetically diverse backgrounds, this approach provides a framework for dissecting interindividual variability in TKI-associated cardiotoxicity. More broadly, it provides a foundation for extending population-scale cardiotoxicity assessment to additional drugs and protective interventions.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135008","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":"3-Dimensional Human iPSC-Derived Cardiac Organoids for Antifibrotic Drug Screening.","authors":"Hao Zhang, Rihua Huang, Phung N Thai, Lu Ren, Rabindra V Shivnaraine, Wenjuan Zhu, Yuanyuan Dai, Wenqiang Liu, Mengjie Xie, Xiu Liu, Renke Tan, Xiaochun Yang, Xu Cao, Xuekun Wu, Matthew A Wu, Christopher Caridi, David Solow-Cordero, Joseph C Wu","doi":"10.1161/CIRCRESAHA.126.328797","DOIUrl":"10.1161/CIRCRESAHA.126.328797","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e328797"},"PeriodicalIF":18.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879286","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":"Cytomegalovirus Latency Fuels Inflammation Following Myocardial Infarction.","authors":"Eleni Dapergola, Marko Šustić, DiyaaElDin Ashour, Ebram Tharwat Melika, Maja Cokarić Brdovčak, Jelena Materljan Franki, Mijo Golemac, Berislav Lisnić, Ema Bellulovich, Valérie Boivin-Jahns, Tobias Krammer, Kenz Le Gouge, Lavinia Rech, Verena Stangl, Karl Kashofer, Peter P Rainer, Roland Jahns, Encarnita Mariotti-Ferrandiz, Hamid Marwan, Maxim Terekhov, Mohammadreza Keshtkar, Antoine-Emmanuel Saliba, Clement Cochain, Panagiota Arampatzi, Mugdha Srivastava, Sven Plein, Yasemin Ekinci, Ioakim Spyridopoulos, Stipan Jonjić, Ulrich Hofmann, Stefan Frantz, Ilija Brizić, Georg Gasteiger, Gustavo Campos Ramos","doi":"10.1161/CIRCRESAHA.125.327799","DOIUrl":"10.1161/CIRCRESAHA.125.327799","url":null,"abstract":"<p><strong>Background: </strong>Epidemiological studies have consistently associated cytomegalovirus (CMV) seropositivity with adverse cardiovascular outcomes. However, the mechanisms by which cytomegalovirus infection impacts pathophysiology in the heart remain poorly understood. In this study, we sought to dissect how latent murine cytomegalovirus infection impacts cardiac immune cell dynamics at steady-state and during postmyocardial infarction (MI) repair.</p><p><strong>Methods: </strong>Experimental MI studies were conducted in C57BL/6J mice previously infected with murine cytomegalovirus. In situ inflammatory responses were characterized by spectral flow cytometry, bulk and single-cell RNA/T-cell receptor (TCR) sequencing, whereas cardiac function was monitored by echocardiography and cardiac magnetic resonance imaging. Moreover, we retrospectively assessed the cytomegalovirus serostatus and associated T-cell expansions in a well-characterized patient cohort with longitudinal cardiac magnetic resonance imaging data available and performed bulk TCR sequencing on peripheral blood and myocardial samples to identify cytomegalovirus-specific TCRs.</p><p><strong>Results: </strong>Our findings show that exposure to murine cytomegalovirus induces long-term changes in the cardiac transcriptional profile and alterations in various cardiac-resident immune cell populations, including the establishment of virus-specific memory CD8⁺ T-cell residency. Compared with infarcted controls, mice previously exposed to murine cytomegalovirus exhibited stronger inflammatory responses marked by increased CD8⁺ T-cell infiltration and worsened cardiac function following MI. These observations in mice were supported by data from patients with cytomegalovirus seropositive MI, who harbored cytomegalovirus-responsive T cells in the heart.</p><p><strong>Conclusions: </strong>Our findings demonstrate that latent cytomegalovirus infection leads to long-term changes in the cardiac microenvironment, which ultimately impair post-MI healing outcomes.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e327799"},"PeriodicalIF":18.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148962967","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":"Blood Metabolomic Signatures of 1-Hour Glucose Predict Cardiometabolic Risk.","authors":"Yoriko Heianza, Minghao Kou, Xuan Wang, Qi Sun, Jennifer Rood, George A Bray, Lawrence J Appel, Frank B Hu, JoAnn E Manson, Frank M Sacks, Lu Qi","doi":"10.1161/CIRCRESAHA.125.327816","DOIUrl":"10.1161/CIRCRESAHA.125.327816","url":null,"abstract":"<p><strong>Background: </strong>Elevated 1-hour glucose levels during an oral glucose tolerance test strongly predict type 2 diabetes (T2D) and cardiovascular disease. We investigated whether the fasting blood metabolome predicting 1-hour glucose could be a target for improving β-cell function, long-term glycemic trajectories, and reducing the risks of T2D and coronary heart disease. We also investigated whether plasma microRNAs derived from key metabolic organs regulate changes in a metabolomic risk score (MRS) for predicting 1-hour glucose.</p><p><strong>Methods: </strong>Untargeted blood metabolomics and a frequently sampled 75-g oral glucose tolerance test were performed in participants from the OmniCarb trial (n=162). In an independent weight-loss dietary intervention trial (POUNDS Lost [Preventing Overweight Using Novel Dietary Strategies]), temporal changes in MRS and plasma microRNAs measured by genome-wide sequencing were analyzed. In addition, associations of MRS at baseline and its 10-year changes with long-term risk of incident T2D and coronary heart disease were prospectively investigated in the NHS (Nurses' Health Study).</p><p><strong>Results: </strong>We created a fasting blood MRS for predicting 1-hour glucose (Pearson <i>r</i>=0.8) and found significant associations with half-day (diurnal) postprandial glucose excursions and insulin secretion after 5-week controlled feeding interventions varying in carbohydrate amount and glycemic index. In the POUNDS Lost trial, diet-induced changes in MRSs were related to 2-year trajectories of glucose metabolism; circulating microRNAs regulating cardiometabolic abnormalities were pivotal factors influencing these changes. In the NHS, women in the top 20% of MRS had a multivariate-adjusted relative risk of 3.80 (95% CI, 2.22-6.51) for T2D and 1.48 (95% CI, 1.04-2.12) for coronary heart disease compared with those in the lowest 20%. In addition, 10-year increases in plasma metabolites related to 1-hour glucose were linearly associated with a higher risk of T2D.</p><p><strong>Conclusions: </strong>Our findings indicate that fasting blood metabolomic signatures predicting elevated 1-hour glucose reflect disease pathophysiology and could be targets for preventing T2D and coronary heart disease.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e327816"},"PeriodicalIF":18.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863689","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 Piezo1 Hyperactivity Drives Neurovascular Dysfunction in Hypertension.","authors":"Mohammad M Abd-Alhaseeb, Ahmed M Hashad, Hadi Esfandi, Curtis Plante, Xin Rui Lim, Reem M Aboushousha, Miguel Martin-Aragon Baudel, Manuel F Navedo, Benedek Erdos, Osama F Harraz","doi":"10.1161/CIRCRESAHA.126.328577","DOIUrl":"10.1161/CIRCRESAHA.126.328577","url":null,"abstract":"<p><strong>Background: </strong>Hypertension is a major driver of neurovascular dysfunction and cognitive decline, yet the molecular mechanisms linking elevated arterial pressure to impaired cerebral blood flow remain poorly defined. Piezo1, a mechanosensitive cation channel enriched in the brain endothelium, is a candidate mediator of cerebral blood flow deficits during hypertension.</p><p><strong>Methods: </strong>Using 2 distinct mouse models of hypertension-BPH/2J mice (genetically hypertensive strain) and angiotensin II-infused C57BL/6J mice-we assessed brain endothelial Piezo1 activity using patch-clamp electrophysiology. Endothelial-specific Piezo1 deletion models were used to evaluate the role of the channel in hypertension-associated cerebrovascular impairment. Cerebral blood flow responses were measured in vivo by laser speckle contrast imaging, and super-resolution nanoscopy was used to quantify Piezo1 nanoscale organization. Behavioral testing was used to assess cognition.</p><p><strong>Results: </strong>Genetic manipulation of endothelial Piezo1 had minimal impact on baseline blood pressure. However, cerebral endothelial Piezo1 activity was markedly elevated in different hypertension models. Deletion of endothelial Piezo1 protected against hypertension-induced cerebrovascular deficits, including impaired vasomotion, reduced functional hyperemia, and blunted CO₂-evoked hyperemia. Super-resolution imaging revealed that hypertension increased Piezo1 clustering, consistent with electrophysiological findings of enhanced channel coupling and open probability. Mechanistically, Piezo1 hyperactivity was PKC (protein kinase C)-dependent, and the PKC-Piezo1 spatial association was enhanced during hypertension. Importantly, PKC inhibition normalized brain endothelial Piezo1 activity, restored cerebral blood flow responses, and rescued cognitive performance.</p><p><strong>Conclusions: </strong>Hypertension increased the gain of Piezo1 function in brain endothelial cells, promoting dysfunctional neurovascular signaling and cognitive impairment. Targeting Piezo1 or PKC signaling selectively restored cerebrovascular regulation. This work identifies a mechanosensitive pathway that could be leveraged to protect the hypertensive brain.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126751","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":"Multimodality Molecular Profiling Nominates Targetable Mechanisms in Progressive RV Dysfunction","authors":"Madelyn J. Blake,Jenna B. Mendelson,Jacob D. Sternbach,Minwoo Kim,Rashmi M. Raveendran,Ryan A. Moon,Lynn M. Hartweck,Walt Tollison,John P. Carney,Todd Markowski,LeeAnn Higgins,Sally E. Prins,Felipe Kazmirczak,Kurt W. Prins","doi":"10.1161/circresaha.126.328649","DOIUrl":"https://doi.org/10.1161/circresaha.126.328649","url":null,"abstract":"BACKGROUND: Right ventricular dysfunction (RVD) is a robust predictor of mortality in multiple cardiovascular diseases. Currently, it remains unclear whether the severity of RVD corresponds to distinct cellular and molecular alterations, and this has important implications for defining optimal therapeutic targets. To address this knowledge gap, we performed a multiomic evaluation of pulmonary artery banded pigs with differing degrees of right ventricular (RV) compromise. METHODS: Pulmonary artery banded pigs were stratified into mild and severe RVD groups based on RV ejection fraction (mild RVD, 38±4%; severe RVD, 20±8%). RV tissue from control, mild RVD, and severe RVD animals was analyzed using single-nucleus RNA sequencing, mitochondrial and cytoplasmic proteomics, and phosphoproteomics. Histological analyses corroborated multiomic findings. RESULTS: Cardiac magnetic resonance imaging revealed progressive structural and functional alterations in mild and severe RVD pigs. Single-nucleus RNA sequencing demonstrated that advancing RVD was associated with loss of cardiomyocytes, accumulation of efferocytosis-impaired macrophages, and dysregulated endothelial cells and pericytes. Combined transcriptomic and proteomic analyses showed escalating impairments of complex cardiomyocyte metabolism with worsening RVD. RV microvasculature was compromised with severe RVD as there were alterations in endothelial cell/pericyte genetic regulation, colocalization patterns in RV sections, and increased cardiomyocyte HIF1A (hypoxia-inducible factor 1 alpha) transcript expression. Analysis of both mitochondrial and global proteostasis revealed greater compromise in mitochondrial proteostasis, including downregulation of mitochondrial proteases, chaperones, and ribosomes. Paradoxically, cytoplasmic ribosomes were upregulated in severe RVD. The predicted kinome and phosphatome were uniquely altered in mild RVD as compared with severe RVD. Finally, integration of multiomic approaches identified activation of the ribotoxic stress response, impaired macrophage efferocytosis, and insufficient mitochondrial unfolded protein response as potential contributors to severe RVD. Multispecies comparison suggested that the ribotoxic stress response was the most conserved pathogenic response in RVD. CONCLUSIONS: Our multiomic analysis defines the cellular and molecular landscape of progressive RVD and nominates druggable pathways that may promote progressive RVD. Future studies are needed to determine how engaging these pathways influences RV phenotypes.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"15 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087950","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":"RUNX3-ERG Cooperation Orchestrates Endothelial Gene Regulation and Vascular Homeostasis","authors":"Jihye You,Minhyuk Kim,So Hee Bae,Li Kang,Jing Ma,Seunghwan Ha,Ji-Hak Jeong,Suk-Chul Bae,You Mie Lee","doi":"10.1161/circresaha.125.327641","DOIUrl":"https://doi.org/10.1161/circresaha.125.327641","url":null,"abstract":"BACKGROUND: Transcriptional regulation is fundamental to vascular homeostasis, ensuring vessel stability and function. Disruption of this regulation underlies pathological angiogenesis in cancer and vascular malformations. While RUNX3 (Runt-related transcription factor 3), a Runt-domain transcription factor, is established as a tumor suppressor and regulator of lymphocyte development, its role in endothelial cells has remained unknown. METHODS: To define the vascular function of RUNX3, we generated endothelial-specific RUNX3 knockout mice and analyzed postnatal retinal angiogenesis and oxygen-induced retinopathy. Mechanistic insights were obtained through ATAC-sequencing data analysis, coimmunoprecipitation, proximity ligation assay, electrophoretic mobility shift assay, and ChIP-qPCR. RESULTS: Loss of endothelial RUNX3 induced hypersprouting angiogenesis with excessive tip cell formation and reduced DLL4 (delta-like ligand 4) expression. RUNX3 deficiency disrupted vascular integrity by lowering VE-cadherin (vascular endothelial cadherin) and claudin-5 levels, while increasing ICAM1 (intercellular adhesion molecule 1) expression, retinal hemorrhage, and leukocyte infiltration. In the oxygen-induced retinopathy model, endothelial RUNX3 deletion aggravated pathological neovascularization. Mechanistically, RUNX3 cooperated with ERG (ETS-related gene) at ETS:RUNX motifs to regulate genes controlling sprouting ( DLL4 ), junctional stability ( CDH5 , CLDN5 ), and leukocyte adhesion ( ICAM1 ). RUNX3 formed complexes with ERG, p300, and HDAC3 (histone deacetylase 3), and proximity ligation assays showed that these interactions were enriched in the nucleus upon VEGF-A (vascular endothelial growth factor-A) stimulation. ChIP-qPCR further demonstrated that RUNX3 was required for the recruitment of these coregulators to target loci. Through differential coregulator engagement, RUNX3 functioned bidirectionally, acting as a transcriptional activator of CDH5 , CLDN5 , and DLL4 while serving as a repressor of ICAM1 . Consistently, single-cell transcriptome analysis of human arteriovenous malformations revealed dysregulated RUNX3 and target gene expression, underscoring translational relevance. CONCLUSIONS: This study provides the first evidence that RUNX3 is a pivotal transcriptional coordinator in endothelial cells. By integrating ERG and chromatin regulators at ETS:RUNX motifs, RUNX3 safeguards the balance between angiogenic activation and vascular stability. These findings establish RUNX3 as a gatekeeper of endothelial transcriptional identity and highlight its potential as a therapeutic target in pathological angiogenesis.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"1 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149092263","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":"Arterial Resident But Not Monocyte-Derived Macrophages Require Endothelial CSF1","authors":"Marwan G. Althagafi,Hisham M. Ibrahim,Sharon J. Hyduk,Stylianos Prattas,Mark Roufaiel,Edouard Al-chami,Corey A. Scipione,Chanele K. Polenz,Sarah A. Dick,Slava Epelman,Clinton S. Robbins,Myron I. Cybulsky","doi":"10.1161/circresaha.126.328541","DOIUrl":"https://doi.org/10.1161/circresaha.126.328541","url":null,"abstract":"BACKGROUND: Tissue-resident macrophages (T-RMøs) accumulate at sites predisposed to atherosclerosis in the healthy aortic intima. T-RMøs require local cues for their maintenance, but the niche signals governing their persistence in arterial tissue remain poorly defined. Here, we identify distinct, spatially compartmentalized sources of CSF1 (colony-stimulating factor 1) that regulate T-RMø populations in the healthy aorta and during atherosclerosis, a chronic inflammatory disease. METHODS: Conditional Csf1 gene deletion (global, endothelial, arterial endothelial, and mesenchymal cell) or systemic antibody blockade was performed in normal or hypercholesterolemic Ldlr –/– mice. Cx3cr1 lineage tracing of T-RMøs initiated before hypercholesterolemia distinguished these cells from monocyte-derived macrophages in atherosclerotic lesions. Bone marrow transplantation enabled lineage tracing of T-RMøs and Csf1 deletion in endothelial cells. Ccr2 lineage tracing directly assessed monocyte-derived macrophages. A novel en face immunoconfocal microscopy approach accurately enumerated macrophages in aortic lesions. RESULTS: Conditional Csf1 deletion revealed that arterial endothelial cell-derived CSF1 is essential for T-RMø steady-state maintenance. In contrast, adventitial macrophages rely on CSF1 produced by PDGFRβ-expressing mesenchymal, but not endothelial, cells. CSF1 primarily supports intimal macrophage proliferation and retention rather than survival. Postnatal parabiosis revealed only occasional clusters of parabiont blood monocyte-derived macrophages in the normal intima. During hypercholesterolemia-initiated atherogenesis, the abundance of T-RMøs increases then gradually declines, while an inflammatory response consisting of monocyte recruitment progressively expands the total number of lesion macrophages. Endothelial, but not mesenchymal, CSF1 is required for optimal macrophage accumulation in 4-week foam cell lesions. Lineage tracing showed that CSF1, specifically endothelial-derived CSF1, is required for the maintenance of T-RMøs, but not monocyte-derived macrophages, in atherosclerotic lesions. CONCLUSIONS: Our study uncovers a unique role of local endothelial cell CSF1 in maintaining the intimal, but not adventitial, T-RMø niche during homeostasis and early stages of atherosclerosis and reveals that maintenance of monocyte-derived macrophages in lesions is distinct.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"28 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149092164","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}