Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"Vascular HIF2 Signaling Prevents Cardiomegaly, Alveolar Congestion, and Capillary Remodeling During Chronic Hypoxia.","authors":"Teresa Albendea-Gomez, Susana Mendoza-Tamajon, Rosana Castro-Mecinas, Beatriz Escobar, Susana Ferreira Rocha, Sonia Urra-Balduz, Jose Angel Nicolas-Avila, Eduardo Oliver, Maria Villalba-Orero, Silvia Martin-Puig","doi":"10.1161/ATVBAHA.124.321780","DOIUrl":"10.1161/ATVBAHA.124.321780","url":null,"abstract":"<p><strong>Background: </strong>Hypoxia is associated with the onset of cardiovascular diseases including cardiac hypertrophy and pulmonary hypertension. HIF2 (hypoxia inducible factor 2) signaling in the endothelium mediates pulmonary arterial remodeling and subsequent elevation of the right ventricular systolic pressure during chronic hypoxia. Thus, novel therapeutic opportunities for pulmonary hypertension based on specific HIF2 inhibitors have been proposed. Nevertheless, HIF2 relevance beyond the pulmonary endothelium or in the cardiac adaptation to hypoxia remains elusive. Wt1 (Wilms tumor 1) lineage contributes to the heart and lung vascular compartments, including pericytes, endothelial cells, and smooth muscle cells.</p><p><strong>Methods: </strong>Here, we describe the response to chronic hypoxia of a novel HIF2 mutant mouse model in the Wt1 lineage (<i>Hif2/Wt1</i> cKO [conditional knockout]), characterizing structural and functional aspects of the heart and lungs by means of classical histology, immunohistochemistry, flow cytometry, echocardiography, and lung ultrasound analysis.</p><p><strong>Results: </strong><i>Hif2/Wt1</i> cKO is protected against pulmonary remodeling and increased right ventricular systolic pressure induced by hypoxia, but displays alveolar congestion, inflammation, and hemorrhages associated with microvascular instability. Furthermore, lack of HIF2 in the Wt1 lineage leads to cardiomegaly, capillary remodeling, right and left ventricular hypertrophy, systolic dysfunction, and left ventricular dilation, suggesting pulmonary-independent cardiac direct roles of HIF2 in hypoxia. These structural defects are partially restored upon reoxygenation, while cardiac functional parameters remain altered.</p><p><strong>Conclusions: </strong>Our results indicate that cardiopulmonary HIF2 signaling prevents excessive vascular proliferation during chronic hypoxia and define novel protective roles of HIF2 to warrant stable microvasculature and organ function.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e78-e98"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021579","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":"Circulating ANGPTL3/8 Concentrations Are Associated With an Atherogenic Lipoprotein Profile and Increased CHD Risk in Swedish Population-Based Studies.","authors":"Karin Leander, Yan Q Chen, Max Vikström, Angela Silveira, Rachel M Fisher, Robert J Konrad, Ferdinand M van 't Hooft","doi":"10.1161/ATVBAHA.124.321308","DOIUrl":"10.1161/ATVBAHA.124.321308","url":null,"abstract":"<p><strong>Background: </strong>Binding of ANGPTL (angiopoietin-like protein)-3 to ANGPTL8 generates a protein complex (ANGPTL3/8) that strongly inhibits LPL (lipoprotein lipase) activity, as compared with ANGPTL3 alone, suggesting that ANGPTL3/8 concentrations are critical for the regulation of circulation lipoprotein concentrations and subsequent increased coronary heart disease (CHD) risk. To test this hypothesis in humans, we evaluated the associations of circulating free ANGPTL3 and ANGPTL3/8 complex concentrations with lipoprotein concentrations and CHD risk in 2 prospective cohort studies.</p><p><strong>Methods: </strong>Fasting blood samples were obtained in conjunction with the baseline evaluation of 9479 subjects from 2 population-based Swedish cohorts of middle-aged men and women. Standard biochemical blood analyses, including all lipid/lipoprotein measurements, were performed in these samples at baseline. Additional serum samples were stored at -80 °C and used at a later stage for ANGPTL3 and ANGPTL3/8 concentration measurements. Information about incident CHD was obtained for both cohorts by matching to the Swedish National Patient Register and the Cause of Death Register.</p><p><strong>Results: </strong>ANGPTL3 concentrations showed modest, positive associations with all lipoprotein concentrations but were not associated with CHD risk. In contrast, ANGPTL3/8 concentrations were associated in both cohorts with an atherogenic lipoprotein profile (characterized by increased triglyceride and LDL [low-density lipoprotein] concentrations and reduced HDL [high-density lipoprotein] concentrations). In the combined cohort, ANGPTL3/8 was associated with increased CHD risk. Hazard ratio per 1 SD increase was 1.10 (95% CI, 1.03-1.17) after adjustment for age, sex, cohort, smoking, and hypertension.</p><p><strong>Conclusions: </strong>Elevated concentrations of ANGPTL3/8, but not ANGPTL3, are associated with an atherogenic lipoprotein profile and increased CHD risk in humans.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"443-451"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063428","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":"Reevaluating Anti-Inflammatory Therapy: Targeting Senescence to Balance Anti-Cancer Efficacy and Vascular Disease.","authors":"Bernardo Casso-Chapa, Norma Alicia Vazquez González, Nhat-Tu Le, Nicolas L Palaskas, Kevin T Nead, Lydia P Eutsey, Venkata S K Samanthapudi, Abigail M Osborn, Jonghae Lee, Gilbert Mejia, Oanh Hoang, Steven H Lin, Anita Deswal, Joerg Herrmann, Guangyu Wang, James L Kirkland, Sunil Krishnan, Xander H T Wehrens, Eduardo N Chini, Syed Wamique Yusuf, Cezar A Iliescu, Abhishek Jain, Jared K Burks, Erin Seeley, Philip L Lorenzi, Khanh M Chau, Keila C Ostos-Mendoza, Isabella M Grumbach, Paul S Brookes, Nordin M J Hanssen, Menno P J de Winther, Laurent Yvan-Charvet, Sivareddy Kotla, Keri Schadler, Jun-Ichi Abe","doi":"10.1161/ATVBAHA.124.319870","DOIUrl":"10.1161/ATVBAHA.124.319870","url":null,"abstract":"<p><p>Modulating immune function is a critical strategy in cancer and atherosclerosis treatments. For cancer, boosting or maintaining the immune system is crucial to prevent tumor growth. However, in vascular disease, mitigating immune responses can decrease inflammation and slow atherosclerosis progression. Anti-inflammatory therapy, therefore, presents a unique dilemma for cancer survivors: while it may decrease cardiovascular risk, it might also promote cancer growth and metastasis by suppressing the immune response. Senescence presents a potentially targetable solution to this challenge; senescence increases the risk of both cancer therapy resistance and vascular disease. Exercise, notably, shows promise in delaying this premature senescence, potentially improving cancer outcomes and lowering vascular disease risk post-treatment. This review focuses on the long-term impact of cancer therapies on vascular health. We underscore the importance of modulating senescence to balance cancer treatment's effectiveness and its vascular impact, and we emphasize investigating the role of exercise-mediated suppression of senescence in improving cancer survivorship.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"372-385"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11864897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999216","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":"Semaglutide Improves Myocardial Perfusion and Performance in a Large Animal Model of Coronary Artery Disease.","authors":"Christopher Stone, Dwight D Harris, Mark Broadwin, Meghamsh Kanuparthy, Ju-Woo Nho, Keertana Yalamanchili, Jad Hamze, M Ruhul Abid, Frank W Sellke","doi":"10.1161/ATVBAHA.124.321850","DOIUrl":"10.1161/ATVBAHA.124.321850","url":null,"abstract":"<p><strong>Background: </strong>Coronary artery disease is the leading cause of death worldwide. It imposes an enormous symptomatic burden on patients, leaving many with residual disease despite optimal procedural therapy and up to one-thirds with debilitating angina amenable neither to procedures, nor to current pharmacological options. Semaglutide (SEM), a GLP-1 (glucagon-like peptide 1) agonist originally approved for management of diabetes, has garnered substantial attention for its capacity to attenuate cardiovascular risk. Although subgroup analyses in patients indicate promise, studies explicitly designed to isolate the impact of SEM on the sequelae of coronary artery disease, independently of comorbid diabetes or obesity, are lacking.</p><p><strong>Methods: </strong>Yorkshire swine (n=17) underwent placement of an ameroid constrictor around the left circumflex coronary artery to induce coronary artery disease. Oral SEM was initiated postoperatively at 1.5 mg and scaled up in 2 weeks to 3 mg in treatment animals (n=8) for a total of 5 weeks, while control animals (n=9) received no drug. All then underwent myocardial harvest with acquisition of perfusion and functional data using microsphere injection and pressure-volume loop catheterization. Immunoblotting, immunohistochemistry, and immunofluorescence were performed on the most ischemic myocardial segments for mechanistic elucidation.</p><p><strong>Results: </strong>SEM animals exhibited improved left ventricular ejection fraction, both at rest and during rapid myocardial pacing (both <i>P</i><0.03), accompanied by increased perfusion to the most ischemic myocardial region at rest and during rapid pacing (both <i>P</i><0.03); reduced perivascular and interstitial fibrosis (both <i>P</i><0.03); and apoptosis (<i>P</i>=0.008). These changes were associated with increased activation of the endothelial-protective AMPK (AMP-activated protein kinase) pathway (<i>P</i>=0.005), coupled with downstream increases in eNOS (endothelial NO synthase; <i>P</i>=0.014).</p><p><strong>Conclusions: </strong>This study reveals the capacity of oral SEM to augment cardiac function in the chronically ischemic heart in a highly translational large animal model, likely through AMPK-mediated improvement in endothelial function and perfusion to the ischemic myocardium.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"285-297"},"PeriodicalIF":7.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812089","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":"SGK1-Mediated Vascular Smooth Muscle Cell Phenotypic Transformation Promotes Thoracic Aortic Dissection Progression.","authors":"Shuai Leng, Haijie Li, Pengfei Zhang, Zhiqiao Dang, Baowei Shao, Shishan Xue, Yansong Ning, Xilong Teng, Leilei Zhang, Honglu Wang, Na Li, Fengquan Zhang, Wenqian Yu","doi":"10.1161/ATVBAHA.124.321421","DOIUrl":"10.1161/ATVBAHA.124.321421","url":null,"abstract":"<p><strong>Background: </strong>The occurrence of thoracic aortic dissection (TAD) is closely related to the transformation of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic phenotype. The role of SGK1 (serum- and glucocorticoid-regulated kinase 1) in VSMC phenotypic transformation and TAD occurrence is unclear.</p><p><strong>Methods: </strong>Four-week-old male Sgk1^F/F (<i>Sgk1</i> floxed) and Sgk1^F/F;Tagln^Cre (smooth muscle cell-specific <i>Sgk1</i> knockout) mice were administered β-aminopropionitrile monofumarate for 4 weeks to model TAD. The SGK1 inhibitor GSK650394 was administered daily via intraperitoneal injection to treat the mouse model of TAD. Immunopurification and mass spectrometry were used to identify proteins that interact with SGK1. Immunoprecipitation, immunofluorescence colocalization, and GST (glutathione S-transferase) pull-down were used to detect molecular interactions between SGK1 and SIRT6 (sirtuin 6). RNA-sequencing analysis was performed to evaluate changes in the SIRT6 transcriptome. Quantitative chromatin immunoprecipitation was used to determine the target genes regulated by SIRT6. Functional experiments were also conducted to investigate the role of SGK1-SIRT6-MMP9 (matrix metalloproteinase 9) in VSMC phenotypic transformation. The effect of SGK1 regulation on target genes was evaluated in human and mouse TAD samples.</p><p><strong>Results: </strong>Sgk1^F/F;Tagln^Cre or pharmacological blockade of Sgk1 inhibited the formation and rupture of β-aminopropionitrile monofumarate-induced TADs in mice and reduced the degradation of the ECM (extracellular matrix) in vessels. Mechanistically, SGK1 promoted the ubiquitination and degradation of SIRT6 by phosphorylating SIRT6 at Ser338, thereby reducing the expression of the SIRT6 protein. Furthermore, SIRT6 transcriptionally inhibits the expression of MMP9 through epigenetic modification, forming the SGK1-SIRT6-MMP9 regulatory axis, which participates in the ECM signaling pathway. Additionally, our data showed that the lack of SGK1-mediated inhibition of ECM degradation and VSMC phenotypic transformation is partially dependent on the regulatory effect of SIRT6-MMP9.</p><p><strong>Conclusions: </strong>These findings highlight the key role of SGK1 in the pathogenesis of TAD. A lack of SGK1 inhibits VSMC phenotypic transformation by regulating the SIRT6-MMP9 axis, providing insights into potential epigenetic strategies for TAD treatment.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"238-259"},"PeriodicalIF":7.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779063","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":"High-Density Lipoprotein Lipid and Protein Cargo and Cholesterol Efflux Capacity Before and After Bariatric Surgery.","authors":"Sohail Zahid, Florencia Schlamp, Michael A Gildea, Bing-Xue Lin, Ariya Chaloemtoem, Marcin Falis, Manish Parikh, Edward A Fisher, Thorsten Hornemann, Tomas Vaisar, Sean P Heffron","doi":"10.1161/ATVBAHA.124.321686","DOIUrl":"10.1161/ATVBAHA.124.321686","url":null,"abstract":"<p><strong>Background: </strong>Cholesterol efflux capacity (CEC) of HDL (high-density lipoprotein) is inversely associated with incident cardiovascular events, independent of HDL cholesterol. Obesity is characterized by low HDL cholesterol and impaired HDL function, such as CEC. Bariatric surgery, including Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), broadly leads to improved cardiovascular outcomes, but impacts on risk factors differ by procedure, with greater improvements in weight loss, blood pressure, and glycemic control after RYGB, but greater improvements in HDL cholesterol and CEC levels after SG. This study sought to determine effects of RYGB and SG on HDL protein and lipid cargo and investigate associations with CEC changes.</p><p><strong>Methods: </strong>We prospectively studied nondiabetic, premenopausal Hispanic women with severe obesity not using lipid medications undergoing RYGB (n=31) or SG (n=36). Anthropometric measurements and blood sampling were obtained before and at 6 and 12 months after surgery. HDL was isolated from plasma, and quantitative proteomic and lipidomic assessments were performed with LC-MS/MS (liquid chromatography with tandem mass spectrometry). CEC was assessed ex vivo using apoB-depleted serum.</p><p><strong>Results: </strong>Participants experienced similar, significant weight loss over 12 months following bariatric surgery (38.0±10.4 kg) regardless of the procedure. Relative quantities of 47 proteins (34 increased, 13 decreased) and 150 lipids (71 increased, 79 decreased) carried on HDL were significantly altered following either surgical procedure. Proteins with similar aggregate response patterns were clustered into 15 groups (5 increased, 5 decreased, 5 minimal change) and lipids with similar aggregate responses into 25 groups (7 increased, 11 decreased, 7 minimal change). Network mediation analyses suggested that changes in 4 protein and 2 lipid clusters mediated changes in ABCA1 (ATP-binding cassette transporter A1) CEC and that 1 lipid cluster mediated changes in non-ABCA1 CEC. The protein and lipid clusters that mediated changes in CEC were distinct between SG and RYGB.</p><p><strong>Conclusions: </strong>Bariatric surgery produces substantial changes in HDL lipid and protein cargo, and specific changes may mediate changes in HDL function in CEC. Further study of these mechanisms may lead to improved interventions to reduce cardiovascular risk in patients with obesity.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e48-e62"},"PeriodicalIF":7.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11808664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913760","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":"Placental Pathology and Blood Pressure at Age 7: A Longitudinal Discordant Twin Analysis.","authors":"Alexa A Freedman, Gregory E Miller, Andrew D Franklin, Lauren S Keenan-Devlin, Stephen E Gilman, Ann Borders, Sadiya S Khan, Linda M Ernst","doi":"10.1161/ATVBAHA.124.321666","DOIUrl":"10.1161/ATVBAHA.124.321666","url":null,"abstract":"<p><strong>Background: </strong>Evidence suggests that the intrauterine environment shapes offspring cardiovascular disease risk. Although placental dysfunction may be an important pathophysiologic pathway, numerous parental and pregnancy characteristics that influence offspring blood pressure are strong confounders of the mechanistic role of the placenta in observational analyses of singletons. Therefore, we leverage twin- and sibling-based comparison designs to determine whether placental pathology is associated with offspring blood pressure at age 7 while mitigating major sources of confounding.</p><p><strong>Methods: </strong>Data are from pregnant participants and their offspring in the Collaborative Perinatal Project, a longitudinal pregnancy cohort conducted from 1959 to 1965 in the United States. After delivery, placentas were systematically examined for lesions indicative of maternal vascular malperfusion (MVM) and acute inflammation. Blood pressure was assessed at a follow-up research visit when the offspring were 7 years old. Linear fixed-effects models were used to estimate associations between within-twin or sibling discordance in placental pathology and differences in blood pressure at age 7.</p><p><strong>Results: </strong>Overall, 193 twin pairs were eligible for inclusion, and 23.3% had placentas discordant for MVM. In a fixed-effect analysis, a twin with high-grade MVM had a higher systolic blood pressure <i>Z</i> score by 0.56 SDs than their co-twin without MVM (95% CI, 0.06-1.05) or a 5.7-mm Hg difference (95% CI, 0.6-10.8). Associations were consistent in a sensitivity analysis restricted to dichorionic twins and in a secondary analysis of 759 MVM-discordant sibling pairs. Acute placental inflammation was not associated with blood pressure at age 7.</p><p><strong>Conclusions: </strong>MVM in the placenta is associated with higher offspring blood pressure in mid-childhood, independent of parental and pregnancy characteristics that twins have in common. The findings support the role of the placenta and the intrauterine environment in the developmental origins of cardiovascular health.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"312-322"},"PeriodicalIF":7.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852309","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":"Extracellular Vesicles From Preeclampsia Disrupt the Blood-Brain Barrier by Reducing CLDN5.","authors":"Hermes Sandoval, Belén Ibáñez, Moisés Contreras, Felipe Troncoso, Fidel O Castro, Diego Caamaño, Lidice Mendez, Estefanny Escudero-Guevara, Francisco Nualart, Hiten D Mistry, Lesia O Kurlak, Manu Vatish, Jesenia Acurio, Carlos Escudero","doi":"10.1161/ATVBAHA.124.321077","DOIUrl":"10.1161/ATVBAHA.124.321077","url":null,"abstract":"<p><strong>Background: </strong>The physiopathology of life-threatening cerebrovascular complications in preeclampsia is unknown. We investigated whether disruption of the blood-brain barrier, generated using circulating small extracellular vesicles (sEVs) from women with preeclampsia or placentae cultured under hypoxic conditions, impairs the expression of tight junction proteins, such as CLDN5 (claudin-5), mediated by VEGF (vascular endothelial growth factor), and activation of KDR (VEGFR2 [VEGF receptor 2]).</p><p><strong>Methods: </strong>We perform a preclinical mechanistic study using sEVs isolated from plasma of pregnant women with normal pregnancy (sEVs-NP; n=9), sEVs isolated from plasma of women with preeclampsia (sEVs-PE; n=9), or sEVs isolated from placentas cultured in normoxia (sEVs-Nor; n=10) or sEVs isolated from placentas cultured in hypoxia (sEVs-Hyp; n=10). The integrity of the blood-brain barrier was evaluated using in vitro (human [hCMEC/D3] and mouse [BEND/3 (brain endothelial cell 3)] brain endothelial cell lines) and in vivo (nonpregnant C57BL/6J mice [4-5 months old; n=13] injected with sEVs-Hyp) models.</p><p><strong>Results: </strong>sEVs-PE and sEVs-Hyp reduced total and membrane-associated protein CLDN5 levels (<i>P</i><0.05). These results were negated with sEVs-PE sonication. sEVs-Hyp injected into nonpregnant mice generated neurological deficits and blood-brain barrier disruption, specifically in the posterior area of the brain, associated with brain endothelial cell uptake of sEVs, sEVs-Hyp high extravasation, and reduction in CLDN5 levels in the brain cortex. Furthermore, sEVs-PE and sEVs-sHyp had higher VEGF levels than sEVs-NP and sEVs-Nor. Human brain endothelial cells exposed to sEVs-PE exhibited a reduction in the activation of KDR. Reduction in CLDN5 observed in cells treated with sEVs-Hyp was further enhanced in cells treated with KDR selective inhibitor.</p><p><strong>Conclusions: </strong>sEVs-PE disrupts the blood-brain barrier, an effect replicated with sEVs-Hyp, and involves reduced CLDN5 and elevated VEGF contained within these vesicles. However, our results do not support the participation of KDR activation in the downregulation of CLDN5 observed with sEVs-Hyp. These findings will improve our understanding of the pathophysiology of cerebrovascular alterations in women with preeclampsia.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"298-311"},"PeriodicalIF":7.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812067","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":"Heterogeneous Cardiac-Derived and Neural Crest-Derived Aortic Smooth Muscle Cells Exhibit Similar Transcriptional Changes After TGFβ Signaling Disruption.","authors":"Pengwei Ren, Bo Jiang, Abdulrahman H M Hassab, Guangxin Li, Wei Li, Roland Assi, George Tellides","doi":"10.1161/ATVBAHA.124.321706","DOIUrl":"10.1161/ATVBAHA.124.321706","url":null,"abstract":"<p><strong>Background: </strong>Smooth muscle cells (SMCs) of cardiac and neural crest origin contribute to the developing proximal aorta and are linked to disease propensity in adults.</p><p><strong>Methods: </strong>We analyzed single-cell transcriptomes of aortic SMCs from adult mice to determine basal states and changes after disrupting TGFβ (transforming growth factor-β) signaling necessary for aortic homeostasis.</p><p><strong>Results: </strong>A minority of Myh11 lineage-marked SMCs differentially expressed genes suggestive of embryological origin. Additional analyses in Nkx2-5 and Wnt1 lineage-marked SMCs derived from cardiac and neural crest progenitors, respectively, showed both lineages contributed to a major common cluster and each lineage to a minor distinct cluster. Common cluster SMCs extended from root to arch, cardiac subset cluster SMCs from root to ascending, and neural crest subset cluster SMCs were restricted to the arch. The neural crest subset cluster had greater expression of a subgroup of TGFβ-dependent genes. Nonetheless, conditional deletion of TGFβ receptors resulted in similar transcriptional changes among all SMC clusters. Several disease-associated transcriptional responses were comparable among SMC clusters in a mouse model of Marfan syndrome aortopathy, while many embryological markers of murine aortic SMCs were not detected in adult human aortas.</p><p><strong>Conclusions: </strong>There are multiple subtypes of cardiac-derived and neural crest-derived SMCs with shared or distinctive transcriptional profiles; neural crest subset cluster SMCs with increased expression of certain TGFβ-inducible genes are not spatially linked to the aortic root predisposed to aneurysms from aberrant TGFβ signaling; and loss of TGFβ responses after receptor deletion is uniform among SMC clusters.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"260-276"},"PeriodicalIF":7.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12053597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852307","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":"Artificial Intelligence and Machine Learning in Preeclampsia.","authors":"Anita T Layton","doi":"10.1161/ATVBAHA.124.321673","DOIUrl":"10.1161/ATVBAHA.124.321673","url":null,"abstract":"<p><p>Preeclampsia is a multisystem hypertensive disorder that manifests itself after 20 weeks of pregnancy, along with proteinuria. The pathophysiology of preeclampsia is incompletely understood. Artificial intelligence, especially machine learning with its capability to identify patterns in complex data, has the potential to revolutionize preeclampsia research. These data-driven techniques can improve early diagnosis, personalize risk assessment, uncover the disease's molecular basis, optimize treatments, and enable remote monitoring. This brief review discusses the recent applications of artificial intelligence and machine learning in preeclampsia management and research, including the improvements these approaches have brought, along with their challenges and limitations.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"165-171"},"PeriodicalIF":7.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913759","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}