Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"Profibrinolytic Factors and Cancer Progression, Metastasis, and Survival.","authors":"Yohei Hisada, Nigel Mackman","doi":"10.1161/ATVBAHA.124.321603","DOIUrl":"10.1161/ATVBAHA.124.321603","url":null,"abstract":"<p><p>The primary role of the fibrinolytic system is to degrade fibrin clots. However, the fibrinolytic system is often activated in patients with cancer and may affect cancer progression, metastasis, and patient survival. Clinical studies have shown that elevated plasma levels of uPA (urokinase plasminogen activator) are associated with cancer progression in patients with prostate, bladder, and cervical cancers, whereas high plasma levels of soluble uPAR (uPA receptor) are associated with progression and metastasis in prostate, breast, bladder, and colorectal cancers. Elevated levels of plasmin-α₂-antiplasmin complexes, a marker of activation of the fibrinolytic system, have been linked to reduced survival in patients with soft tissue sarcoma, lung, and metastatic breast cancers. Studies with mouse models have shown that uPA, uPAR, tPA (tissue-type plasminogen activator), and plasmin contribute to tumor growth, metastasis, and survival. For instance, uPA and uPAR can activate kinase signaling pathways in cancer cells, whereas tPA can activate LRP1 (lipoprotein receptor-related protein 1), which enhances tumor growth and metastasis. Plasmin can degrade the extracellular matrix, which would increase cancer cell migration. In addition, it can release extracellular matrix-bound growth factors, which could increase tumor growth and angiogenesis. Taken together, these studies suggest that the fibrinolytic system promotes cancer progression and metastasis through multiple mechanisms.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1732-1741"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991521","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":"Neutrophil Integrin α9 Impairs Efferocytosis and Worsens Long-Term Recovery After Subarachnoid Hemorrhage.","authors":"Harpreet Kaur, Nilesh Pandey, Lakshmi Chandaluri, Nirvana Shaaban, Dhananjay Kumar, Rajan Pandit, Alexa Martinez, Sumit Kumar Anand, Sandeep Das, Sumati Rohilla, Fabio Arias, Erika Reece, Ravinder Reddy Gaddam, Kevin S Murnane, Ajit Vikram, Rajesh Mohandas, Xiaolu Zhang, Mohammad Alfrad Nobel Bhuiyan, Xiao-Hong Lu, A Wayne Orr, Oren Rom, Arif Yurdagul, Nirav Dhanesha","doi":"10.1161/ATVBAHA.125.323072","DOIUrl":"10.1161/ATVBAHA.125.323072","url":null,"abstract":"<p><strong>Background: </strong>Neutrophil infiltration exacerbates brain injury after subarachnoid hemorrhage (SAH). Integrin α9, expressed on neutrophils, facilitates their adhesion and transendothelial migration, leading to aggravated inflammatory responses and neuronal apoptosis. Insufficient clearance of apoptotic neurons by microglia and infiltrating blood-derived macrophages (defective efferocytosis) contributes to persistent inflammation and poor SAH recovery. This study investigated the role of neutrophil integrin α9 in neuronal apoptosis, microglia/macrophage efferocytosis, and SAH outcomes.</p><p><strong>Methods: </strong>Neutrophil-specific <i>α9</i>^<i>-/-</i> (<i>α9</i>^<i>fl/fl</i><i>Mrp8Cre</i>^<i>-/+</i>) and littermate control (<i>α9</i>^<i>fl/fl</i><i>Mrp8Cre</i>^<i>-/-</i>) mice were subjected to the endovascular perforation model to induce SAH. Sensorimotor and cognitive function were assessed for up to 4 weeks post-SAH using neurological severity score, corner and cylinder tests, Y-maze, and novel object recognition. In vitro and in vivo functional assays were conducted to assess the effect of integrin α9-dependent neutrophil transendothelial migration on efferocytosis of apoptotic neurons. Neutrophil infiltration, cerebral inflammation, neuronal apoptosis, and MMP (matrix metalloproteinase)-9 were quantified 24 hours post-SAH.</p><p><strong>Results: </strong>Mice subjected to SAH exhibited increased integrin α9 levels on infiltrated neutrophils compared with sham surgery controls. Neutrophil-specific <i>α9</i>^<i>-/-</i> mice demonstrated improved long-term sensorimotor and cognitive recovery, reduced neutrophil infiltration, and decreased MMP-9 expression and neuronal apoptosis. Importantly, neutrophil-specific <i>α9</i>^<i>-/-</i> mice exhibited reduced brain neutrophil elastase levels and enhanced efferocytosis. Mechanistic studies have revealed that the reduced transendothelial migration of <i>α9</i>^<i>-/-</i> neutrophils directly contributed to the enhanced microglia/macrophage efferocytosis of apoptotic neurons. Pharmacological targeting of integrin α9 with macitentan significantly improved SAH outcomes by reducing neutrophil infiltration and enhancing efferocytosis. Comparable SAH outcomes in both macitentan-treated controls and neutrophil-specific <i>α9</i>^<i>-/-</i> mice suggested that the therapeutic effects of macitentan were mediated by inhibition of neutrophil integrin α9.</p><p><strong>Conclusions: </strong>Our study revealed a novel role for neutrophil integrin α9 in sensorimotor function and cognitive recovery after SAH, suggesting it as a potential therapeutic target for SAH.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e497-e511"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12333561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752190","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":"Atherosclerotic Plaque Instability and Rupture: Recommended Mouse Models to Empower Clinically Relevant Discoveries, Diagnostics, and Therapeutics.","authors":"Jonathan Noonan, Luis Cardoso, Alex Bobik, Karlheinz Peter","doi":"10.1161/ATVBAHA.125.321011","DOIUrl":"10.1161/ATVBAHA.125.321011","url":null,"abstract":"<p><strong>Clinical problem: </strong>Atherosclerotic plaque instability/rupture is the major driver of myocardial infarction and stroke, the leading causes of cardiovascular morbidity/mortality. However, the mechanisms leading to plaque rupture are poorly understood. This limits our ability to establish sensitive and diagnostic tools to identify plaques that are prone to rupture and to develop much-needed plaque-stabilizing therapies.</p><p><strong>Recommendations: </strong>The diagnostic identification and therapeutic stabilization of unstable plaques are considered the holy grail of cardiovascular medicine, holding the potential to significantly reduce cardiovascular morbidity/mortality. To achieve this, it is vital that preclinical models reflect plaque instability/rupture as observed in patients. This will allow mechanistic discoveries, the development of diagnostic tools, and treatment options to identify and stabilize rupture-prone, unstable atherosclerotic plaques. This can be achieved using appropriate, research question-dependent, but currently underutilized mouse models with direct translational relevance.</p><p><strong>Summary of strengths and weaknesses of mouse models for atherosclerosis: </strong>Conventional mouse models of atherosclerosis, LDLR^-/^- (low-density lipoprotein receptor) and ApoE^-/- (apolipoprotein E) mice fed a high-fat diet, do not develop unstable atherosclerosis and plaque rupture as observed in patients with myocardial infarction. Modification of these mice with additional gene mutations (eg, in SRB1 [scavenger receptor class B type 1] and Fbn1 [fibrillin-1]^C1039G+/^-) induces the development of unstable plaques and plaque rupture. However, some genetic approaches pose challenges as they can generate additional phenotypes and comorbidities and may not be commercially available or simple to breed. In contrast, surgically induced models of plaque instability/rupture (eg, carotid tandem stenosis or transverse aortic constriction) can easily be used in any athero-susceptible mouse in which a single gene mutation increases atherogenic lipids or can be combined with newer atherosclerosis-inducing approaches (eg, AAV-PCSK9 [proprotein convertase subtilisin/kexin type 9]) to cause unstable atherosclerotic disease. Such increasingly used surgical approaches are suitable for detailed mechanistic studies as they reflect most characteristics of human plaque instability/rupture and can be adapted to many different experimental conditions and research questions.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"45 10","pages":"1707-1714"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136345","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":"Multiplex Apolipoprotein Panel Improves Cardiovascular Event Prediction and Cardiovascular Outcome by Identifying Patients Who Benefit From Targeted PCSK9 Inhibitor Therapy.","authors":"Esther Reijnders, Patrick Bossuyt, J Wouter Jukema, L Renee Ruhaak, Fred Romijn, Michael Szarek, Stella Trompet, Deepak Bhatt, Vera Bittner, Rafael Diaz, Sergio Fazio, Irena Stevanovic, Shaun Goodman, Robert Harrington, Harvey White, Philippe Gabriel Steg, Gregory Schwartz, Christa Cobbaert","doi":"10.1161/ATVBAHA.124.322336","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.322336","url":null,"abstract":"<p><strong>Background: </strong>Residual cardiovascular risk remains, despite achieving low-density lipoprotein cholesterol targets with high-intensity statins. Traditional risk scores are suboptimal. This study evaluated the prognostic utility of a 9-plex apolipoprotein panel in recent patients with acute coronary syndrome on statins and its role in predicting treatment benefit by alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, enabling precision medicine.</p><p><strong>Methods: </strong>Baseline serum samples from 11 843 participants in the ODYSSEY OUTCOMES trial (https://www.clinicaltrials.gov; Unique identifier: NCT01663402) were analyzed using mass spectrometry to measure Apo(a), Apo AI, Apo AII, Apo AIV, ApoB, Apo CI, Apo CII, Apo CIII, ApoE. Using logistic regression, probabilities of major adverse cardiovascular events (MACE) and all-cause death over a median follow-up of 2.9 years were estimated based on baseline apolipoproteins and lipid concentrations. Clinical performance was assessed by comparing the area under the curve (AUC) of 3 models: the apolipoprotein panel, the lipid panel (total cholesterol, high-density lipoprotein cholesterol, and triglycerides), and a combination. In addition, prediction models estimating the treatment benefit of alirocumab by the apolipoprotein panel were developed.</p><p><strong>Results: </strong>The prognostic performance of the apolipoprotein panel for MACE showed an AUC (95% CI) of 0.648 (0.626-0.670), compared with 0.579 (0.557-0.602) for the lipid panel. For all-cause death, the apolipoprotein panel had an AUC of 0.699 (0.664-0.733), while the lipid panel had an AUC of 0.599 (0.564-0.635). Adding the apolipoprotein panel significantly improved the performance of the conventional lipid panel (<i>P</i><0.0001): AUC, 0.659 (0.637-0.681) for MACE and 0.724 (0.691-0.756) for all-cause death. Higher risk for MACE based on the baseline apolipoprotein panel was found to predict greater treatment benefit with alirocumab.</p><p><strong>Conclusions: </strong>A multiplex apolipoprotein panel led to better prediction of MACE and all-cause death, beyond lipids, in patients with postacute coronary syndrome on optimized statin therapy. The panel also predicts the treatment benefit of alirocumab. Further validation of this approach is now needed, and if confirmed and improved, it could lead to better disease prediction and management in the future.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136311","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":"Dexamethasone Suppresses Endotheliopathy and Endothelial-Induced Coagulopathy in COVID-19.","authors":"Aurélien Philippe, Romy Younan, Nicolas Gendron, Nicolas Peron, Xavier Loyer, Jeanne Rancic, Caroline Hauw-Berlemont, Paul Billoir, Bertrand Hermann, Lina Khider, Olivier Sanchez, Gilles Chatelier, Chantal M Boulanger, Jean-Luc Diehl, David M Smadja","doi":"10.1161/ATVBAHA.125.322774","DOIUrl":"https://doi.org/10.1161/ATVBAHA.125.322774","url":null,"abstract":"<p><strong>Background: </strong>Endotheliopathy and coagulopathy are known complications of COVID-19, with a significant association with mortality. Although dexamethasone is the standard of care for patients with severe COVID-19, its precise mode of action remains elusive. We aim to investigate the functional consequences of dexamethasone treatment on COVID-19-associated procoagulant endotheliopathy.</p><p><strong>Methods: </strong>First, during the 7 days after hospitalization, we measured several endothelial and coagulopathy biomarkers in a prospective cohort of patients with COVID-19 with acute respiratory distress syndrome (ARDS) who were either treated or not with both dexamethasone and therapeutic UFH (unfractionated heparin). Second, we developed an in vitro thrombin generation assay on cultured human endothelial cells to measure the ability of stimulated endothelial colony-forming cells to activate coagulation in normal plasma, which is expressed as an endogenous thrombin potential (ETP).</p><p><strong>Results: </strong>Among the cohort of 44 ARDS COVID-19 patients, 23 patients treated with dexamethasone and therapeutic UFH had significantly decreased von Willebrand Factor, Ang-2 (angiopoietin-2), soluble E-selectin, and d-dimer levels over 7 days. To differentiate the effect of UFH and dexamethasone on endotheliopathy, we used the thrombin generation assay and showed that endothelial colony-forming cell stimulation with dexamethasone but not UFH-in addition to a cocktail of proinflammatory cytokines (to mimic the cytokine storm of severe COVID-19)-significantly decreased ETP in comparison to proinflammatory cytokines only. Moreover, in another cohort of 331 patients with COVID-19 of varying severity, the endothelial colony-forming cell stimulation with the plasma of 87 ARDS patients showed significantly higher ETP (1260 nmol/L per minute [interquartile range, 1140-1260]) compared with 75 non-ARDS patients (1024 nmol/L per minute [interquartile range, 915-1200]; <i>P</i><0.001). Finally, 94 dexamethasone-treated ARDS patients had significantly lower ETP (962.8 nmol/L per minute [interquartile range, 782.9-1112]) in contrast to 75 nondexamethasone-treated ARDS patients (1,260 nmol/L per minute [interquartile range, 1140-1359]; <i>P</i><0.001). ETP could help predict in-hospital mortality in a Kaplan-Meier estimator analysis (<i>P</i>=0.0002).</p><p><strong>Conclusions: </strong>Our data suggest that dexamethasone protects against COVID-19 endothelium-induced coagulopathy. These findings are in line with the decreased prevalence of venous thrombosis among hospitalized patients with COVID-19 treated with dexamethasone.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136318","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":"Metabolically Abnormal Obesity and Carotid Plaque Vulnerability: A Vessel Wall MRI Study Linking Obesity Phenotypes to Atherosclerotic Instability.","authors":"Sai Shao, Yan Sun, Honglu Shi, Rui Li, Qinjian Sun, Bin Yao, Hiroko Watase, Daniel S Hippe, Chun Yuan, Guangbin Wang, Quan Zhang, Xihai Zhao","doi":"10.1161/ATVBAHA.125.323413","DOIUrl":"https://doi.org/10.1161/ATVBAHA.125.323413","url":null,"abstract":"<p><strong>Background: </strong>Carotid plaque vulnerability, driven by metabolic dysfunction and obesity, is a critical determinant of ischemic stroke risk. However, the heterogeneity of obesity phenotypes-defined by metabolic health-remains underexplored in cardiovascular risk stratification. Therefore, this study employs high-resolution magnetic resonance vessel wall imaging to assess differences in high-risk carotid plaque features among obesity subtypes stratified by metabolic dysfunction and body mass index.</p><p><strong>Methods: </strong>This multicenter, cross-sectional study of 1037 Chinese adults with symptomatic carotid atherosclerosis utilized magnetic resonance vessel wall imaging to assess differences in high-risk carotid plaque features-intraplaque hemorrhage (IPH), lipid-rich necrotic core, and fibrous cap rupture-across 4 obesity phenotype subgroups: metabolically healthy normal weight (MHNW), metabolically abnormal normal weight, metabolically healthy obese (MHO), and metabolically abnormal obese (MAO).</p><p><strong>Results: </strong>Of 1037 eligible patients, the proportion of patients in MHNW, metabolically abnormal normal weight, MHO, and MAO groups was 51.6% (n=535), 6.9% (n=72), 16.7% (n=173), and 24.8% (n=257), respectively. Both prevalences of high-risk carotid plaque (22.5% versus 16.6% in MHNW; <i>P</i>=0.002) and IPH (17.1% versus 10.1% in MHNW; <i>P</i><0.001) in the MAO group were higher than those in the MHNW and MHO groups (all <i>P</i><0.05). The MHO group exhibited plaque stability similar to MHNW, whereas metabolically abnormal normal weight had greater maximum wall thickness (<i>P</i>=0.004) than MHO and higher IPH prevalence than MHNW (<i>P</i>=0.054). Several carotid plaque morphological variables significantly differed among the 4 groups (all <i>P</i><0.05). In further adjusted logistic regression models, MAO was independently associated with IPH (<i>P</i>=0.015), alongside male sex, advanced age, and antihypertensive agent use.</p><p><strong>Conclusions: </strong>This study redefines the role of obesity in atherosclerosis by prioritizing metabolic health over body mass index, demonstrating that MAO is independently associated with IPH and exhibits elevated high-risk carotid plaque/IPH prevalence versus MHNW/MHO. The robustness of IPH as a metabolic instability indicator warrants particular attention.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT02017756.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079064","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":"Nrf2 Deficiency in Müller Cells Exacerbates Pathological Neovascularization in Ischemic Retinopathy.","authors":"Zhenhua Xu, Lingli Zhou, Jie Wang, Hongkwan Cho, Yingxue Cao, Le Shi, Shirley Wu, Yangyiran Xie, Jiang Qian, Elia J Duh","doi":"10.1161/ATVBAHA.125.323301","DOIUrl":"https://doi.org/10.1161/ATVBAHA.125.323301","url":null,"abstract":"<p><strong>Background: </strong>Müller cells are the major retinal glial cell type and pivotal regulators of pathological neovascularization in ischemic retinopathy. There is great interest in identifying factors that govern Müller cells in vascular regulation. Nrf2 (NF-E2-related factor 2) plays a major protective role in regulating oxidative stress and inflammation. Our group previously discovered that both global and neuroretinal Nrf2 deficiency suppress retinal revascularization and promote pathological neovascularization in a mouse model of oxygen-induced retinopathy. Here, we investigate the cell-intrinsic role of Nrf2 in Müller cells on retinal angiogenesis.</p><p><strong>Methods: </strong>The role of Müller cell Nrf2 in retinal angiogenesis was investigated in cell culture and the mouse oxygen-induced retinopathy model. Human retinal endothelial cells were cocultured with primary Müller cells transfected with Nrf2 small-interference RNA. Müller cell-specific Nrf2 knockout mice were subjected to oxygen-induced retinopathy. RNA-seq analysis of a Müller cell-specific RiboTag transcriptome was conducted in wild-type and Nrf2-deficient Müller cells.</p><p><strong>Results: </strong>Silencing Nrf2 in primary Müller cells increased angiogenic activity in retinal endothelial cells. Müller cell-specific Nrf2 deficiency exacerbated pathological neovascularization in oxygen-induced retinopathy, associated with increased Müller cell gliosis and upregulation of retinal Tnfα (tumor necrosis factor alpha). Müller cell Nrf2 deficiency resulted in dysregulation of multiple genes involved in acute-phase response, inflammation, and angiogenesis, including increased expression of <i>Lcn2</i> (lipocalin-2) and <i>Fgf2</i>, both of which promoted angiogenesis in human retinal endothelial cells. Blocking LCN2 with a neutralizing antibody attenuated pathological neovascularization and vaso-obliteration, suggesting LCN2 is a key mediator of aberrant angiogenic response in Müller cell-specific Nrf2 deficiency.</p><p><strong>Conclusions: </strong>Nrf2 in Müller cells plays an integral protective role in modulating retinal angiogenesis and inflammatory responses in ischemic retinopathy. Nrf2 is an important regulator of Müller cell state in retinal ischemia and governs the Müller cell transcriptional program, including LCN2, a novel regulator of angiogenesis. This highlights pharmacological activation of Nrf2 as a therapeutic strategy for pathological neovascularization in ischemic retinopathy.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079434","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":"Inhibition of BMPER Mitigates Pulmonary Hypertension by Modulating LRP1-YAP Interaction in Smooth Muscle Cells.","authors":"Hua Mao, Claire M Li, Bing Sun, Christopher Ward, Alan Waich-Cohen, Ivan O Rosas, Howard J Huang, Harry Karmouty-Quintana, Liang Xie, Lavannya M Pandit, Xinchun Pi","doi":"10.1161/ATVBAHA.124.322189","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.322189","url":null,"abstract":"<p><strong>Background: </strong>BMPER (bone morphogenetic protein-binding endothelial regulator) is a secreted protein that is highly expressed in endothelial cells. It regulates the BMP (bone morphogenetic protein) pathway during vascular development and adulthood. Mutations in the BMP pathway are recognized as risk factors for pulmonary arterial hypertension group 1 pulmonary hypertension (PH). However, the roles of BMPER in pulmonary arterial hypertension remain unknown.</p><p><strong>Methods: </strong>We assessed BMPER expression in Group 1 pulmonary arterial hypertension patient samples and examined its role in vascular remodeling using in vivo and in vitro approaches.</p><p><strong>Results: </strong>BMPER level was elevated in pulmonary arterial hypertension lungs and significantly associated with pulmonary vascular resistance, but was not increased in patient plasma. Global and endothelial cell-specific depletion of BMPER in a mouse model of hypoxia-induced PH displayed attenuation in pulmonary artery smooth muscle cell proliferation, a hallmark of pulmonary vascular remodeling, and reduced right ventricular pressures. Conversely, adeno-associated virus-assisted BMPER overexpression targeted to the pulmonary endothelium led to the spontaneous development of PH. Mechanistically, BMPER promoted YAP (yes-associated protein 1) activation through the release of YAP sequestration by LRP1 (low-density lipoprotein receptor-related protein 1), a BMPER endocytic receptor, in the membrane of pulmonary artery smooth muscle cells. Moreover, the protective effect of BMPER depletion can be reversed by simultaneous depletion of LRP1 in mice with hypoxia-induced PH.</p><p><strong>Conclusions: </strong>Collectively, these results implicate secreted BMPER as a discrete regulator for pulmonary vascular remodeling and suggest its inhibition as a new potential therapeutic strategy against PH.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079118","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":"SUV39H1; the SUV Among Epigenetic Regulators of Smooth Muscle Cell Phenotype.","authors":"Vivian de Waard","doi":"10.1161/ATVBAHA.125.323381","DOIUrl":"https://doi.org/10.1161/ATVBAHA.125.323381","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079369","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":"Biological Sex and Cardiovascular Disease Prevention in Systemic Arterial Hypertension.","authors":"Eva Gerdts, Susana Novella, Yvan Devaux, Paolo Magni, Hans Peter Marti, Miron Sopić, Georgios Kararigas","doi":"10.1161/ATVBAHA.125.322092","DOIUrl":"https://doi.org/10.1161/ATVBAHA.125.322092","url":null,"abstract":"<p><p>Biological sex influences the life course development of blood pressure, systemic arterial hypertension, and hypertension-associated complications through neural, hormonal, renal, and epigenetic mechanisms. Sex hormones influence blood pressure regulation through interaction with several main regulatory systems, including the autonomic nervous system, the renin-angiotensin-aldosterone system, endothelin, and renal mechanisms. The modulation of vascular function by sex hormones varies over the lifespan. A more progressive decline in vascular endothelial function and an increase in vascular remodeling and arterial stiffness with aging are found in female individuals. Epigenetic mechanisms, including DNA methylation, histone modifications, and noncoding microRNAs, may be implicated in systemic arterial hypertension development and complications. Overall, current knowledge highlights the importance of including biological sex as a critical factor in understanding systemic arterial hypertension pathophysiology and advancing cardiovascular prevention.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032657","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}