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
{"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":"https://doi.org/10.1038/s44161-025-00686-2","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":" ","pages":""},"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}
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
{"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":"<p><p>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.</p>","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":" ","pages":""},"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}
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
{"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":"https://doi.org/10.1038/s44161-025-00681-7","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144661224","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}
Yihui Yang, Emma Bränn, Jing Zhou, Dang Wei, Jacob Bergstedt, Fang Fang, Unnur A Valdimarsdóttir, Elizabeth Bertone-Johnson, Donghao Lu
{"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":"https://doi.org/10.1038/s44161-025-00684-4","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144621445","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}
Mireia Pampols-Perez, Carina Fürst, Oscar Sánchez-Carranza, Elena Cano, Jonathan Alexis Garcia-Contreras, Lisa Mais, Wenhan Luo, Sandra Raimundo, Eric L Lindberg, Martin Taube, Arnd Heuser, Anje Sporbert, Dagmar Kainmueller, Miguel O Bernabeu, Norbert Hübner, Holger Gerhardt, Gary R Lewin, Annette Hammes
{"title":"Mechanosensitive PIEZO2 channels shape coronary artery development.","authors":"Mireia Pampols-Perez, Carina Fürst, Oscar Sánchez-Carranza, Elena Cano, Jonathan Alexis Garcia-Contreras, Lisa Mais, Wenhan Luo, Sandra Raimundo, Eric L Lindberg, Martin Taube, Arnd Heuser, Anje Sporbert, Dagmar Kainmueller, Miguel O Bernabeu, Norbert Hübner, Holger Gerhardt, Gary R Lewin, Annette Hammes","doi":"10.1038/s44161-025-00677-3","DOIUrl":"10.1038/s44161-025-00677-3","url":null,"abstract":"<p><p>Coronary arteries develop under constant mechanical stress. However, the role of mechanosensitive ion channels in this process remains poorly understood. Here we show that the ion channel PIEZO2, which responds to mechanical stimuli, is expressed in specific coronary endothelial cell populations during a critical phase of coronary vasculature remodeling. These Piezo2<sup>+</sup> coronary endothelial cells show distinct transcriptional profiles and have mechanically activated ionic currents. Strikingly, PIEZO2 loss-of-function mouse embryos and mice with human pathogenic variants of PIEZO2 show abnormal coronary vessel development and cardiac left ventricular hyperplasia. We conclude that an optimal balance of PIEZO2 channel function contributes to proper coronary vessel formation, structural integrity and remodeling, and is likely to support normal cardiac function. Our study highlights the importance of mechanical cues in cardiovascular development and suggests that defects in this mechanosensing pathway may contribute to congenital heart conditions.</p>","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":" ","pages":"921-937"},"PeriodicalIF":9.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512905","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}
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
{"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":"<p><p>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.</p>","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":" ","pages":"904-920"},"PeriodicalIF":10.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12303357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565497","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}