Pub Date : 2025-07-29DOI: 10.1038/s44161-025-00686-2
Yingjun Ding, Junxiong Chen, Songlan Liu, Jennifer M. Hays, Xiaowu Gu, Jonathan D. Wren, Constantin Georgescu, Darlene N. Reuter, Beibei Liu, Furong He, Xuejun Wang, Quan Wei, Jie Wang, Bharathiraja Subramaniyan, Zhiping Wu, Kiran Kodali, Alaina M. Reagan, Willard M. Freeman, Cindy K. Miranti, Anna Csiszar, Zoltan Ungvari, Kamiya Mehla, Matthew S. Walters, Michael H. Elliott, Junmin Peng, Tomoharu Kanie, James F. Papin, Franklin A. Hays, Xin A. Zhang
Tetraspanins affect metastasis, stemness and angiogenesis, but their roles in inflammation remain to be further clarified. Here we show that endothelial ablation of tetraspanin Cd82 markedly reduces vascular inflammation by mitigating endothelial leakage. Mechanistically, by limiting the anchorages of Cdc42 activator FARP1 and RhoA inhibitor Rnd3 to the plasma membrane (PM), CD82 confines Cdc42 but maintains RhoA activity in endothelial cells, to facilitate endothelium activation. These signaling regulatory effects depend on the ability of CD82 to coalesce and retain accessible cholesterol (AC) at the PM, whereas simvastatin overturns CD82 effects by lowering AC. CD82 supports non-vesicular transfer of AC to the PM through oxysterol-binding protein-related proteins (ORPs). Thus, CD82 and AC promote vascular leakage, whereas statin and ORP inhibitor restrain vascular leakage by decreasing AC. These findings reveal an unconventional anti-inflammation role and mechanism for statin and conceptualize tetraspanin-mediated, AC-mediated and cholesterol transfer-mediated balancing of antagonistic GTPase signaling pathways as regulatory mechanisms for vascular leakage. By regulating the level of accessible cholesterol on endothelial cells via OSBP/ORP-mediated transport, tetraspanin tunes the balance of Cdc42 and RhoA activities to affect vascular inflammation. Reducing accessible cholesterol by statin treatment or blocking its non-vesicular transport by OSBP/ORP inhibition can limit vascular inflammation.
{"title":"Tetraspanin-enriched membrane domains regulate vascular leakage by altering membrane cholesterol accessibility to balance antagonistic GTPases","authors":"Yingjun Ding, Junxiong Chen, Songlan Liu, Jennifer M. Hays, Xiaowu Gu, Jonathan D. Wren, Constantin Georgescu, Darlene N. Reuter, Beibei Liu, Furong He, Xuejun Wang, Quan Wei, Jie Wang, Bharathiraja Subramaniyan, Zhiping Wu, Kiran Kodali, Alaina M. Reagan, Willard M. Freeman, Cindy K. Miranti, Anna Csiszar, Zoltan Ungvari, Kamiya Mehla, Matthew S. Walters, Michael H. Elliott, Junmin Peng, Tomoharu Kanie, James F. Papin, Franklin A. Hays, Xin A. Zhang","doi":"10.1038/s44161-025-00686-2","DOIUrl":"10.1038/s44161-025-00686-2","url":null,"abstract":"Tetraspanins affect metastasis, stemness and angiogenesis, but their roles in inflammation remain to be further clarified. Here we show that endothelial ablation of tetraspanin Cd82 markedly reduces vascular inflammation by mitigating endothelial leakage. Mechanistically, by limiting the anchorages of Cdc42 activator FARP1 and RhoA inhibitor Rnd3 to the plasma membrane (PM), CD82 confines Cdc42 but maintains RhoA activity in endothelial cells, to facilitate endothelium activation. These signaling regulatory effects depend on the ability of CD82 to coalesce and retain accessible cholesterol (AC) at the PM, whereas simvastatin overturns CD82 effects by lowering AC. CD82 supports non-vesicular transfer of AC to the PM through oxysterol-binding protein-related proteins (ORPs). Thus, CD82 and AC promote vascular leakage, whereas statin and ORP inhibitor restrain vascular leakage by decreasing AC. These findings reveal an unconventional anti-inflammation role and mechanism for statin and conceptualize tetraspanin-mediated, AC-mediated and cholesterol transfer-mediated balancing of antagonistic GTPase signaling pathways as regulatory mechanisms for vascular leakage. By regulating the level of accessible cholesterol on endothelial cells via OSBP/ORP-mediated transport, tetraspanin tunes the balance of Cdc42 and RhoA activities to affect vascular inflammation. Reducing accessible cholesterol by statin treatment or blocking its non-vesicular transport by OSBP/ORP inhibition can limit vascular inflammation.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 8","pages":"1011-1033"},"PeriodicalIF":10.8,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144746364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-22DOI: 10.1038/s44161-025-00685-3
Veer Sangha, Lovedeep Singh Dhingra, Arya Aminorroaya, Philip M. Croon, Nikhil V. Sikand, Sounok Sen, Matthew W. Martinez, Martin S. Maron, Harlan M. Krumholz, Folkert W. Asselbergs, Evangelos K. Oikonomou, Rohan Khera
Hypertrophic cardiomyopathy (HCM) is frequently underdiagnosed. Although deep learning (DL) models using raw electrocardiographic (ECG) voltage data can enhance detection, their use at the point of care is limited. Here we report the development and validation of a DL model that detects HCM from images of 12-lead ECGs across layouts. The model was developed using 124,553 ECGs from 66,987 individuals at the Yale New Haven Hospital (YNHH), with HCM features determined by concurrent imaging (cardiac magnetic resonance (CMR) or echocardiography). External validation included ECG images from MIMIC-IV, the Amsterdam University Medical Center (AUMC) and the UK Biobank (UKB), where HCM was defined by CMR (YNHH, MIMIC-IV and AUMC) and diagnosis codes (UKB). The model demonstrated robust performance across image formats and sites (areas under the receiver operating characteristic curve (AUROCs): 0.95 internal testing; 0.94 MIMIC-IV; 0.92 AUMC; 0.91 UKB). Discriminative features localized to anterior/lateral leads (V4 and V5) regardless of layout. This approach enables scalable, image-based screening for HCM across clinical settings. Sangha, Dhingra et al. develop and validate a deep learning model to diagnose hypertrophic cardiomyopathy from electrocardiographic images, demonstrating its effectiveness across multiple 12-lead layouts.
{"title":"Identification of hypertrophic cardiomyopathy on electrocardiographic images with deep learning","authors":"Veer Sangha, Lovedeep Singh Dhingra, Arya Aminorroaya, Philip M. Croon, Nikhil V. Sikand, Sounok Sen, Matthew W. Martinez, Martin S. Maron, Harlan M. Krumholz, Folkert W. Asselbergs, Evangelos K. Oikonomou, Rohan Khera","doi":"10.1038/s44161-025-00685-3","DOIUrl":"10.1038/s44161-025-00685-3","url":null,"abstract":"Hypertrophic cardiomyopathy (HCM) is frequently underdiagnosed. Although deep learning (DL) models using raw electrocardiographic (ECG) voltage data can enhance detection, their use at the point of care is limited. Here we report the development and validation of a DL model that detects HCM from images of 12-lead ECGs across layouts. The model was developed using 124,553 ECGs from 66,987 individuals at the Yale New Haven Hospital (YNHH), with HCM features determined by concurrent imaging (cardiac magnetic resonance (CMR) or echocardiography). External validation included ECG images from MIMIC-IV, the Amsterdam University Medical Center (AUMC) and the UK Biobank (UKB), where HCM was defined by CMR (YNHH, MIMIC-IV and AUMC) and diagnosis codes (UKB). The model demonstrated robust performance across image formats and sites (areas under the receiver operating characteristic curve (AUROCs): 0.95 internal testing; 0.94 MIMIC-IV; 0.92 AUMC; 0.91 UKB). Discriminative features localized to anterior/lateral leads (V4 and V5) regardless of layout. This approach enables scalable, image-based screening for HCM across clinical settings. Sangha, Dhingra et al. develop and validate a deep learning model to diagnose hypertrophic cardiomyopathy from electrocardiographic images, demonstrating its effectiveness across multiple 12-lead layouts.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 8","pages":"991-1000"},"PeriodicalIF":10.8,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-17DOI: 10.1038/s44161-025-00682-6
Simon J. Cleary
Protease-activated receptor 1 (PAR1) allows platelets and blood endothelial cells to respond to coagulation. Research in mouse models has uncovered a new role for PAR1 — enabling pulmonary collecting lymphatics to transform their intercellular junctions from ‘zippers’ into ‘buttons’ for additional interstitial fluid drainage during acute lung injury.
{"title":"Collecting lymphatics unzip to drain injured lungs","authors":"Simon J. Cleary","doi":"10.1038/s44161-025-00682-6","DOIUrl":"10.1038/s44161-025-00682-6","url":null,"abstract":"Protease-activated receptor 1 (PAR1) allows platelets and blood endothelial cells to respond to coagulation. Research in mouse models has uncovered a new role for PAR1 — enabling pulmonary collecting lymphatics to transform their intercellular junctions from ‘zippers’ into ‘buttons’ for additional interstitial fluid drainage during acute lung injury.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 8","pages":"959-961"},"PeriodicalIF":10.8,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144661223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-17DOI: 10.1038/s44161-025-00681-7
Chou Chou, Camila Ceballos Paredes, Barbara Summers, Jade Palmer-Johnson, Anjali Trivedi, Aneel Bhagwani, Kasper B. Hansen, Anders S. Kristensen, Stefka Gyoneva, Sharon A. Swanger, Stephen F. Traynelis, Hasina Outtz Reed
The lung lymphatic vasculature is capable of remarkable increases in lymphatic drainage in settings of inflammation and edema; however, the mechanisms driving this are not clear. Here we show that lung injury transforms the configuration of lung lymphatic endothelial cell junctions from a continuous ‘zippered’ configuration to a discontinuous and permeable ‘button’ configuration. Despite similarity to the junctional changes often seen in leaky and dysfunctional blood vessels, we find that the shift to button junctions in the lymphatic vasculature has an opposite effect, resulting in augmented lung lymphatic drainage. Mechanistically, we demonstrate that lung lymphatic button junction formation in models of lung injury is dependent on the thrombin receptor protease-activated receptor 1, a known mediator of blood vessel permeability. These results uncover a previously unknown role for the thrombin receptor protease-activated receptor 1 in the lymphatic vasculature that promotes a similar change in junction morphology as seen in blood vessels, but with a disparate effect on lymphatic function. Chou et al. demonstrate that activation of the thrombin receptor protease-activated receptor 1 in the lung lymphatic vasculature mediates morphological changes in lymphatic endothelial cell junctions to augment lung lymphatic drainage in models of lung injury.
{"title":"The thrombin receptor PAR1 orchestrates changes in lymphatic endothelial cell junction morphology to augment lymphatic drainage during lung injury","authors":"Chou Chou, Camila Ceballos Paredes, Barbara Summers, Jade Palmer-Johnson, Anjali Trivedi, Aneel Bhagwani, Kasper B. Hansen, Anders S. Kristensen, Stefka Gyoneva, Sharon A. Swanger, Stephen F. Traynelis, Hasina Outtz Reed","doi":"10.1038/s44161-025-00681-7","DOIUrl":"10.1038/s44161-025-00681-7","url":null,"abstract":"The lung lymphatic vasculature is capable of remarkable increases in lymphatic drainage in settings of inflammation and edema; however, the mechanisms driving this are not clear. Here we show that lung injury transforms the configuration of lung lymphatic endothelial cell junctions from a continuous ‘zippered’ configuration to a discontinuous and permeable ‘button’ configuration. Despite similarity to the junctional changes often seen in leaky and dysfunctional blood vessels, we find that the shift to button junctions in the lymphatic vasculature has an opposite effect, resulting in augmented lung lymphatic drainage. Mechanistically, we demonstrate that lung lymphatic button junction formation in models of lung injury is dependent on the thrombin receptor protease-activated receptor 1, a known mediator of blood vessel permeability. These results uncover a previously unknown role for the thrombin receptor protease-activated receptor 1 in the lymphatic vasculature that promotes a similar change in junction morphology as seen in blood vessels, but with a disparate effect on lymphatic function. Chou et al. demonstrate that activation of the thrombin receptor protease-activated receptor 1 in the lung lymphatic vasculature mediates morphological changes in lymphatic endothelial cell junctions to augment lung lymphatic drainage in models of lung injury.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 8","pages":"964-975"},"PeriodicalIF":10.8,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12343296/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144661224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-15DOI: 10.1038/s44161-025-00674-6
We demonstrate a clear regulatory role for O-GlcNAcylation in cellular reprogramming and uncover potential molecular pathways conducive to enhancing perfusion restoration in ischemic tissue. These findings offer a promising avenue for the development of novel therapeutic interventions targeting vascular ischemia.
{"title":"A novel metabolic–epigenetic axis regulates vascular recovery","authors":"","doi":"10.1038/s44161-025-00674-6","DOIUrl":"10.1038/s44161-025-00674-6","url":null,"abstract":"We demonstrate a clear regulatory role for O-GlcNAcylation in cellular reprogramming and uncover potential molecular pathways conducive to enhancing perfusion restoration in ischemic tissue. These findings offer a promising avenue for the development of novel therapeutic interventions targeting vascular ischemia.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 7","pages":"797-798"},"PeriodicalIF":10.8,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144644320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-11DOI: 10.1038/s44161-025-00684-4
Yihui Yang, Emma Bränn, Jing Zhou, Dang Wei, Jacob Bergstedt, Fang Fang, Unnur A. Valdimarsdóttir, Elizabeth Bertone-Johnson, Donghao Lu
Several lines of evidence indicate a potential link between premenstrual disorders (PMDs) and cardiovascular diseases (CVDs). However, it remains unclear whether women with PMDs have a higher risk of CVDs. Here we present a Swedish nationwide population-based matched cohort study from 2001 to 2022 and a sibling matched cohort to address familial confounding. A total of 99,411 women with PMDs were included in the population analysis and 36,061 women with PMDs in the sibling analysis. Compared with individuals without PMDs, women with PMDs had a higher risk of any CVD (adjusted hazard ratio = 1.11 (95% confidence interval: 1.08–1.13) in the population analysis and 1.10 (95% confidence interval: 1.06–1.15) in the sibling analysis). The risk was particularly pronounced for PMDs diagnosed before 25 years of age and PMDs with comorbid perinatal depression. Our study shows that women who received a PMD diagnosis in specialist or primary care are at a higher risk of CVDs. Yang et al. draw evidence from population-based and sibling cohort studies to reveal that women suffering from premenstrual disorders are at an increased risk of cardiovascular disease.
{"title":"Premenstrual disorders and risk of cardiovascular diseases","authors":"Yihui Yang, Emma Bränn, Jing Zhou, Dang Wei, Jacob Bergstedt, Fang Fang, Unnur A. Valdimarsdóttir, Elizabeth Bertone-Johnson, Donghao Lu","doi":"10.1038/s44161-025-00684-4","DOIUrl":"10.1038/s44161-025-00684-4","url":null,"abstract":"Several lines of evidence indicate a potential link between premenstrual disorders (PMDs) and cardiovascular diseases (CVDs). However, it remains unclear whether women with PMDs have a higher risk of CVDs. Here we present a Swedish nationwide population-based matched cohort study from 2001 to 2022 and a sibling matched cohort to address familial confounding. A total of 99,411 women with PMDs were included in the population analysis and 36,061 women with PMDs in the sibling analysis. Compared with individuals without PMDs, women with PMDs had a higher risk of any CVD (adjusted hazard ratio = 1.11 (95% confidence interval: 1.08–1.13) in the population analysis and 1.10 (95% confidence interval: 1.06–1.15) in the sibling analysis). The risk was particularly pronounced for PMDs diagnosed before 25 years of age and PMDs with comorbid perinatal depression. Our study shows that women who received a PMD diagnosis in specialist or primary care are at a higher risk of CVDs. Yang et al. draw evidence from population-based and sibling cohort studies to reveal that women suffering from premenstrual disorders are at an increased risk of cardiovascular disease.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 8","pages":"1001-1010"},"PeriodicalIF":10.8,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12343293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144621445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-09DOI: 10.1038/s44161-025-00654-w
The use of cancer immunotherapies is expanding to patients resistant to current therapies, and emerging regulators of immune checkpoints such as agonist antibodies that directly activate immune responses are being studied. Although these therapeutics are promising, this study highlights the potential for cardiac immune-related adverse events.
{"title":"Agonistic immune checkpoint regulator may harm the heart","authors":"","doi":"10.1038/s44161-025-00654-w","DOIUrl":"10.1038/s44161-025-00654-w","url":null,"abstract":"The use of cancer immunotherapies is expanding to patients resistant to current therapies, and emerging regulators of immune checkpoints such as agonist antibodies that directly activate immune responses are being studied. Although these therapeutics are promising, this study highlights the potential for cardiac immune-related adverse events.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 7","pages":"799-800"},"PeriodicalIF":10.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-04DOI: 10.1038/s44161-025-00673-7
Shuang Li, Alexander J. Lu, Eric S. Nagueh, Yanqiang Li, Michael Graber, Kaylee N. Carter, Elisa Morales, Crystina L. Kriss, Kaifu Chen, Junchen Liu, Guangyu Wang, John P. Cooke, Li Lai
The restoration of the microvasculature is essential to cardiovascular regeneration. Our previous work demonstrated that angiogenic transdifferentiation of fibroblasts into endothelial cells facilitates vascular recovery following limb ischemia and is accompanied by a metabolic shift toward glycolysis. However, a comprehensive characterization of the metabolic alterations that contribute to the transdifferentiation process is still lacking. Here we identify a marked upregulation of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the substrate for O-GlcNAcylation, during transdifferentiation. Enhancing this pathway promotes, whereas inhibiting it impairs, the efficiency of transdifferentiation. Mechanistically, we demonstrate that O-GlcNAcylation facilitates chromatin remodeling through modification of HIRA, a histone chaperone responsible for de novo deposition of the noncanonical histone variant H3.3, a process intimately linked to transcriptional activation. These findings are further supported by in vivo lineage tracing and conditional knockout mouse models. Collectively, our study demonstrates that O-GlcNAcylation enhances angiogenic transdifferentiation through a metabolic-and-epigenetic-coupled mechanism, thereby strengthening vascular recovery. Li, Lu et al. demonstrate that O-GlcNAcylation enhances angiogenic transdifferentiation from fibroblasts to endothelial cells through a HIRA-dependent H3.3 deposition mechanism and facilitates vascular regeneration.
{"title":"O-GlcNAcylation promotes angiogenic transdifferentiation to reverse vascular ischemia","authors":"Shuang Li, Alexander J. Lu, Eric S. Nagueh, Yanqiang Li, Michael Graber, Kaylee N. Carter, Elisa Morales, Crystina L. Kriss, Kaifu Chen, Junchen Liu, Guangyu Wang, John P. Cooke, Li Lai","doi":"10.1038/s44161-025-00673-7","DOIUrl":"10.1038/s44161-025-00673-7","url":null,"abstract":"The restoration of the microvasculature is essential to cardiovascular regeneration. Our previous work demonstrated that angiogenic transdifferentiation of fibroblasts into endothelial cells facilitates vascular recovery following limb ischemia and is accompanied by a metabolic shift toward glycolysis. However, a comprehensive characterization of the metabolic alterations that contribute to the transdifferentiation process is still lacking. Here we identify a marked upregulation of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the substrate for O-GlcNAcylation, during transdifferentiation. Enhancing this pathway promotes, whereas inhibiting it impairs, the efficiency of transdifferentiation. Mechanistically, we demonstrate that O-GlcNAcylation facilitates chromatin remodeling through modification of HIRA, a histone chaperone responsible for de novo deposition of the noncanonical histone variant H3.3, a process intimately linked to transcriptional activation. These findings are further supported by in vivo lineage tracing and conditional knockout mouse models. Collectively, our study demonstrates that O-GlcNAcylation enhances angiogenic transdifferentiation through a metabolic-and-epigenetic-coupled mechanism, thereby strengthening vascular recovery. Li, Lu et al. demonstrate that O-GlcNAcylation enhances angiogenic transdifferentiation from fibroblasts to endothelial cells through a HIRA-dependent H3.3 deposition mechanism and facilitates vascular regeneration.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 7","pages":"904-920"},"PeriodicalIF":10.8,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-04DOI: 10.1038/s44161-025-00672-8
Leili Jafari, Christoph B. Wiedenroth, Steffen D. Kriechbaum, Dimitri Grün, Prakash Chelladurai, Stefan Guenther, Carsten Kuenne, Alicia M. Späth, Anoop V. Cherian, Christian Troidl, Jochen Wilhelm, Stanislav Keranov, Till Keller, Baktybek Kojonazarov, Ralph T. Schermuly, Stefan Guth, Oliver Dörr, Holger Nef, Mario Boehm, Edda Spiekerkoetter, Przemyslaw Leszek, Zoltan V. Varga, Peter Ferdinandy, Hossein A. Ghofrani, Peter Dorfmüller, Norbert Weißmann, Christian W. Hamm, Eckhard Mayer, Werner Seeger, Christoph Liebetrau, Soni Savai Pullamsetti
Chronic thromboembolic pulmonary hypertension (CTEPH) leads to progressive right ventricular (RV) dysfunction. Pulmonary endarterectomy (PEA) is an established treatment for these patients; however, the molecular mechanisms underlying RV remodeling and recovery remain poorly understood. Here we show that RNA sequencing and histological analysis of RV free wall and septal biopsies from patients with CTEPH reveal extracellular matrix enrichment and cytoskeletal remodeling before PEA. These changes were consistent across an exploratory and confirmatory cohort. Post-PEA samples showed reversal of both histological and transcriptional abnormalities. Key signaling molecules—ANKRD1, IL7R and SERPINE1—were implicated in fibrotic and proliferative pathways, as confirmed in human tissues and experimental models. Our findings identify a reversible gene expression and structural remodeling signature in the RV, linking hemodynamic unloading with molecular recovery. These insights suggest potential therapeutic targets to modulate maladaptive RV remodeling in CTEPH and improve outcomes beyond surgical intervention. Through RNA profiling of right ventricular tissue from patients with chronic thromboembolic pulmonary hypertension, Jafari et al. uncover mechanisms underlying disease severity-associated remodeling, identify key signaling molecules involved in fibrotic and proliferative pathways, and reveal processes driving right ventricular recovery after pulmonary endarterectomy.
{"title":"Transcriptional changes of the extracellular matrix in chronic thromboembolic pulmonary hypertension govern right ventricle remodeling and recovery","authors":"Leili Jafari, Christoph B. Wiedenroth, Steffen D. Kriechbaum, Dimitri Grün, Prakash Chelladurai, Stefan Guenther, Carsten Kuenne, Alicia M. Späth, Anoop V. Cherian, Christian Troidl, Jochen Wilhelm, Stanislav Keranov, Till Keller, Baktybek Kojonazarov, Ralph T. Schermuly, Stefan Guth, Oliver Dörr, Holger Nef, Mario Boehm, Edda Spiekerkoetter, Przemyslaw Leszek, Zoltan V. Varga, Peter Ferdinandy, Hossein A. Ghofrani, Peter Dorfmüller, Norbert Weißmann, Christian W. Hamm, Eckhard Mayer, Werner Seeger, Christoph Liebetrau, Soni Savai Pullamsetti","doi":"10.1038/s44161-025-00672-8","DOIUrl":"10.1038/s44161-025-00672-8","url":null,"abstract":"Chronic thromboembolic pulmonary hypertension (CTEPH) leads to progressive right ventricular (RV) dysfunction. Pulmonary endarterectomy (PEA) is an established treatment for these patients; however, the molecular mechanisms underlying RV remodeling and recovery remain poorly understood. Here we show that RNA sequencing and histological analysis of RV free wall and septal biopsies from patients with CTEPH reveal extracellular matrix enrichment and cytoskeletal remodeling before PEA. These changes were consistent across an exploratory and confirmatory cohort. Post-PEA samples showed reversal of both histological and transcriptional abnormalities. Key signaling molecules—ANKRD1, IL7R and SERPINE1—were implicated in fibrotic and proliferative pathways, as confirmed in human tissues and experimental models. Our findings identify a reversible gene expression and structural remodeling signature in the RV, linking hemodynamic unloading with molecular recovery. These insights suggest potential therapeutic targets to modulate maladaptive RV remodeling in CTEPH and improve outcomes beyond surgical intervention. Through RNA profiling of right ventricular tissue from patients with chronic thromboembolic pulmonary hypertension, Jafari et al. uncover mechanisms underlying disease severity-associated remodeling, identify key signaling molecules involved in fibrotic and proliferative pathways, and reveal processes driving right ventricular recovery after pulmonary endarterectomy.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 7","pages":"857-875"},"PeriodicalIF":10.8,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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