Enkhjargal Budbazar , Aylin Balmes , Danielle Elliott , Lisette Peres Tintin , Timo Kopp , Susanne Feil , Robert Feil , Tilman E. Schäffer , Francesca Seta
{"title":"Pharmacological activation of NO-sensitive guanylyl cyclase ameliorates obesity-induced arterial stiffness","authors":"Enkhjargal Budbazar , Aylin Balmes , Danielle Elliott , Lisette Peres Tintin , Timo Kopp , Susanne Feil , Robert Feil , Tilman E. Schäffer , Francesca Seta","doi":"10.1016/j.vph.2025.107503","DOIUrl":"10.1016/j.vph.2025.107503","url":null,"abstract":"<div><h3>Background & purpose</h3><div>Arterial stiffness, or loss of elastic compliance in large arteries, is an independent precursor of cardiovascular disease (CVD) [<span><span>1</span></span>] and dementia [<span><span>2</span></span>] for which currently there are no targeted therapies. We previously discovered that decreases in NO-sensitive guanylyl cyclase (NO-GC), the NO receptor which synthesizes cGMP, and in its target vasodilator-stimulated phosphoprotein (pVASP<sup>S239</sup>), lead to increased cytoskeletal actin polymerization in vascular smooth muscle cells (VSMCs) contributing to increased arterial stiffness [<span><span>3</span></span>]. In the current study, we tested whether activating NO-GC with an NO-GC activator (cinaciguat) modulates pVASP<sup>S239</sup> and cytoskeletal actin polymerization in VSMCs, thereby preventing obesity-induced arterial stiffness<em>.</em></div></div><div><h3>Experimental approach & key results</h3><div>Cinaciguat administration (5 mg/kg) to high fat, high sucrose diet (HFHS)-fed mice, our established model of arterial stiffness [<span><span>4</span></span>], (1) decreased pulse wave velocity, the in vivo index of arterial stiffness, without affecting blood pressure; (2) increased aortic pVASP<sup>S239</sup> levels; and (3) decreased actin polymerization, measured as ratio of filamentous (F) to globular (G) actin, compared to vehicle administration. In cultured VSMCs, cinaciguat (10 μmol/L) increased pVASP<sup>S239</sup> levels and decreased the F/G actin ratio at baseline and after stimulation with the cytokine tumor necrosis factor α (TNFα), which we previously showed is significantly increased in the aorta of HFHS-fed mice [<span><span>[4]</span></span>, <span><span>[5]</span></span>, <span><span>[6]</span></span>]. These effects were abrogated in aortas and VSMCs from mice with smooth muscle-specific cGKI deletion (cGKI<sup>SMKO</sup>), while being mimicked by a cell-permeable cGMP analog (8-Br-cGMP), which also decreased VSMC stiffness in vitro.</div></div><div><h3>Conclusions & implications</h3><div>Collectively, our data strongly support the notion that pharmacological NO-GC activation would be beneficial in decreasing obesity-associated arterial stiffness by decreasing VSMC cytoskeletal actin hyper-polymerization. If translated to humans, NO-GC activators could become a viable approach to clinically treat arterial stiffness, which remains an unmet medical need.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"159 ","pages":"Article 107503"},"PeriodicalIF":3.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144095155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lucas Tramujas , Alleh Nogueira , Nicole Felix , Israel Maia , Pedro G.M. de Barros e Silva , Alexandre B. Cavalcanti , Alexandre Abizaid
{"title":"Trends in colchicine use across the spectrum of coronary artery disease","authors":"Lucas Tramujas , Alleh Nogueira , Nicole Felix , Israel Maia , Pedro G.M. de Barros e Silva , Alexandre B. Cavalcanti , Alexandre Abizaid","doi":"10.1016/j.vph.2025.107502","DOIUrl":"10.1016/j.vph.2025.107502","url":null,"abstract":"","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"159 ","pages":"Article 107502"},"PeriodicalIF":3.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144080834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Single-cell RNA sequencing (scRNA-seq) and its insights into cellular heterogeneity in atherosclerosis","authors":"Baixue Yu , Miron Sopic , Judith C. Sluimer","doi":"10.1016/j.vph.2025.107499","DOIUrl":"10.1016/j.vph.2025.107499","url":null,"abstract":"<div><div>Single-cell RNA sequencing (scRNA-seq) has transformed our understanding of cellular diversity in human biology, providing novel insights into disease mechanisms. In cardiovascular disease (CVD), scRNA-seq enables precise mapping of complex cell populations, uncovering unique cell types and states that influence disease progression and suggest new therapeutic targets. In atherosclerosis (AS), scRNA-seq has redefined plaque pathology by identifying distinct cell types, including endothelial cells (ECs), smooth muscle cells (SMCs), fibroblasts, macrophages, T cells, and B cells, each with specific roles in plaque stability, inflammation, and disease progression. In our review, we summarized these major cellular populations and their cellular heterogeneity in non-diseased and atherosclerotic aorta, as identified by scRNA-seq in mice and human tissues. We discussed conserved and species-specific subpopulations, their defining markers, and their functional implications in plaque progression. In addition, we integrated findings from scRNA-seq with experimental studies to highlight key molecular targets with therapeutic potential. In the future, these insights offer a refined cellular and molecular framework of atherosclerosis and may help the development of targeted interventions to promote plaque stabilization and reduce cardiovascular risk.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"159 ","pages":"Article 107499"},"PeriodicalIF":3.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144040035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Daniel G. Brieger , Karan Rao , Vinayak Nagaraja , Ravinay Bhindi , Usaid K. Allahwala
{"title":"The use of glycoprotein IIb/IIIa inhibitors in elective PCI – A systematic review and meta-analysis of randomised trials","authors":"Daniel G. Brieger , Karan Rao , Vinayak Nagaraja , Ravinay Bhindi , Usaid K. Allahwala","doi":"10.1016/j.vph.2025.107500","DOIUrl":"10.1016/j.vph.2025.107500","url":null,"abstract":"<div><h3>Background</h3><div>Glycoprotein IIb/IIIa inhibitors (GPIs) improve 30-day outcomes when used as an adjunct to percutaneous coronary intervention (PCI) in acute coronary syndromes, but their role in stable coronary artery disease (CAD) remains uncertain in the context of modern stents and oral antiplatelet therapy.</div></div><div><h3>Methodology</h3><div>A systematic search of PubMed, EMBASE, Central and <span><span>clinicaltrials.gov</span><svg><path></path></svg></span> databases was conducted from inception to October 2022. Randomised trials comparing GPI to placebo in elective PCI were included. Outcomes included target vessel revascularisation (TVR), stent thrombosis (ST) and a composite of TVR, myocardial infarction and death (MACE) at 30-days and 6–12 months. Bleeding was assessed using Thrombolysis In Myocardial Infarction bleeding score or equivalent. A random-effects model was used for all analyses.</div></div><div><h3>Results</h3><div>Of 2375 abstracts screened, 16 studies (6428 patients) were included. GPIs significantly reduced 30-day MACE (risk ratio [RR] 0.58, 95 % CI, 0.39–0.86, <em>p</em> < 0.01; number needed to treat = 33), intermediate-term MACE at 6–12 months (RR 0.67; 95 % CI, 0.49–0.92; <em>p</em> = 0.01) and ST (RR 0.29, 95 % CI, 0.10–0.83, <em>p</em> = 0.02). There was no significant difference in TVR or major bleeding, although minor bleeding was increased (RR 1.72, 95 % CI, 1.14–2.61, p = 0.01, number needed to harm = 77). Meta-regression suggested that the benefit of GPIs has diminished over time.</div></div><div><h3>Conclusion</h3><div>GPI use during elective PCI reduces MACE and ST whilst increasing minor bleeding. The observed benefit appears to have waned over time, highlighting the importance of selective use in patients at low bleeding risk.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"159 ","pages":"Article 107500"},"PeriodicalIF":3.5,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143912261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lotte Slenders , Marian Wesseling , Siting Wei , Arjan Boltjes , Daniek M.C. Kapteijn , Petra van de Kraak , Marie A.C. Depuydt , Koen H.M. Prange , Noortje A.M. van den Dungen , Ernest D. Benavente , Dominique, P.V. de Kleijn , Gert J. de Borst , Menno P.J. de Winther , Hester M. den Ruijter , Gary K. Owens , Gerard Pasterkamp , Michal Mokry
{"title":"Endothelial-to-mesenchymal transition gene signature derived from single-cell transcriptomics of human atherosclerotic tissue associates with stable plaque histological characteristics","authors":"Lotte Slenders , Marian Wesseling , Siting Wei , Arjan Boltjes , Daniek M.C. Kapteijn , Petra van de Kraak , Marie A.C. Depuydt , Koen H.M. Prange , Noortje A.M. van den Dungen , Ernest D. Benavente , Dominique, P.V. de Kleijn , Gert J. de Borst , Menno P.J. de Winther , Hester M. den Ruijter , Gary K. Owens , Gerard Pasterkamp , Michal Mokry","doi":"10.1016/j.vph.2025.107498","DOIUrl":"10.1016/j.vph.2025.107498","url":null,"abstract":"<div><h3>Background</h3><div>Endothelial cells within atherosclerotic plaques can differentiate into a mesenchymal-like phenotype through endothelial-to-mesenchymal transition (EndoMT). Our understanding of the molecular mechanisms underlying EndoMT in human atherosclerosis remains limited. Current gene expression signatures are often derived from <em>in vitro</em> experiments or animal studies and typically reflect genes upregulated in fully differentiated mesenchymal cell states, while genes upregulated during the process are omitted. To address this knowledge gap, we utilized <em>in silico</em> lineage tracing in single-cell transcriptomic (scRNA-seq) data from human plaque tissues to identify the EndoMT gene expression signature.</div></div><div><h3>Methods and results</h3><div>We constructed three candidate EndoMT lineages across subpopulations of ECs and SMCs in human carotid scRNA-seq data (<em>n</em> = 46). We examined gene expression over the course of these lineages and identified a core signature of 73 genes upregulated in EndoMT. Upregulation of those genes was confirmed in EndoMT trajectories of other human datasets derived from plaque tissue and in Cdh5-Cre<sup>ERT2</sup> Rosa-eYFP apoE<sup>−/−</sup> lineage-traced mice. Analysis of human carotid plaque bulk RNA-seq data (632 patients) found the association of core gene signature with fibrous and more stable histological phenotypes.</div></div><div><h3>Conclusion</h3><div>This study defines the core gene signature of EndoMT in human atherosclerotic plaques, which can serve as a reference for future studies and gene set enrichment analysis.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"159 ","pages":"Article 107498"},"PeriodicalIF":3.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143918192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bartłomiej Perek , Piotr Rzymski , Aleksandra Proch , Mateusz Puślecki , Barbara Poniedziałek , Andrzej Fal , Anna Komosa , Marek Jemielity , Przemysław Niedzielski
{"title":"Exploring the interplay between valvular and serum zinc and copper levels and disease markers in aortic stenosis","authors":"Bartłomiej Perek , Piotr Rzymski , Aleksandra Proch , Mateusz Puślecki , Barbara Poniedziałek , Andrzej Fal , Anna Komosa , Marek Jemielity , Przemysław Niedzielski","doi":"10.1016/j.vph.2025.107497","DOIUrl":"10.1016/j.vph.2025.107497","url":null,"abstract":"<div><div>Aortic stenosis (AS) is a progressive condition characterized by valve calcification and significant morbidity, often requiring invasive intervention. The AS pathophysiology is multifaceted, with evidence suggesting a role for trace elements. However, whether zinc (Zn) and copper (Cu) are associated with valve calcification is unclear. This exploratory study assessed the Zn and Cu levels in the serum and aortic valves of AS patients undergoing surgical valve replacement and explored the relationships between trace elements and clinical and biochemical parameters to better understand their potential roles in AS pathophysiology. An inverse relationship was observed between serum Zn levels and systolic pressure gradients across the valve (<em>p</em> < 0.0001). Zn accumulation was identified in calcified aortic valves, suggesting a systemic redistribution of Zn during disease progression. The valvular Cu/Zn ratio was reversed (<1) compared to that in serum. The lipoprotein(a), an inflammatory marker, was positively correlated with serum Cu levels (<em>p</em> = 0.0007) and the Cu/Zn ratio (<em>p</em> = 0.02). However, no direct association was found between valvular Cu content and the AS severity. The findings suggest that Zn depletion in serum, coupled with its accumulation in calcified valves, reflects a disease-driven redistribution mechanism that may serve a protective role against calcification progression. Additionally, the study highlights a potential interplay between Cu metabolism and inflammatory processes in AS. Further research is required to determine whether therapeutic modulation of Zn levels could offer benefits in AS management.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"159 ","pages":"Article 107497"},"PeriodicalIF":3.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143870747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aleš Kvasnička , David Friedecký , Barbora Piskláková , Jakub Rozhon , Karel Pavelka , Blanka Stibůrková
{"title":"Ceramide-based risk score: A novel laboratory tool for cardiovascular risk stratification in hyperuricemia and gout","authors":"Aleš Kvasnička , David Friedecký , Barbora Piskláková , Jakub Rozhon , Karel Pavelka , Blanka Stibůrková","doi":"10.1016/j.vph.2025.107495","DOIUrl":"10.1016/j.vph.2025.107495","url":null,"abstract":"<div><div>Gout and hyperuricemia increase cardiovascular disease risk, highlighting the need for improved risk stratification. In this pilot study, we evaluated the Coronary Event Risk Test (CERT) in 94 hyperuricemic and 196 gout patients, and 53 controls. Plasma ceramides were determined by liquid chromatography–mass spectrometry. Elevated CERT scores (≥7) occurred in 11.7 % (2-fold increase) of hyperuricemic and 31.12 % (5.5-fold increase) of gout patients compared to controls. Additionally, both hyperuricemic and gout patients with increased CERT also exhibited higher levels of inflammation and atherogenic index of plasma, both of which were significantly associated with CERT. Incorporating CERT into routine care may enhance risk stratification and guide targeted interventions in this patient population.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"159 ","pages":"Article 107495"},"PeriodicalIF":3.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143835082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Epitranscriptomics in atherosclerosis: Unraveling RNA modifications, editing and splicing and their implications in vascular disease","authors":"Victoria Stopa , Dimitra Dafou , Korina Karagianni , A. Yaël Nossent , Rosienne Farrugia , Yvan Devaux , Miron Sopic , AtheroNET COST Action CA21153 (www.atheronet.eu)","doi":"10.1016/j.vph.2025.107496","DOIUrl":"10.1016/j.vph.2025.107496","url":null,"abstract":"<div><div>Atherosclerosis remains a leading cause of morbidity and mortality worldwide, driven by complex molecular mechanisms involving gene regulation and post-transcriptional processes. Emerging evidence highlights the critical role of epitranscriptomics, the study of chemical modifications occurring on RNA molecules, in atherosclerosis development. Epitranscriptomics provides a new layer of regulation in vascular health, influencing cellular functions in endothelial cells, smooth muscle cells, and macrophages, thereby shedding light on the pathogenesis of atherosclerosis and presenting new opportunities for novel therapeutic targets. This review provides a comprehensive overview of the epitranscriptomic landscape, focusing on key RNA modifications such as N6-methyladenosine (m6A)<strong>,</strong> 5-methylcytosine (m<sup>5</sup>C)<strong>,</strong> pseudouridine (Ψ), RNA editing mechanisms including A-to-I and C-to-U editing and RNA isoforms. The functional implications of these modifications in RNA stability, alternative splicing, and microRNA biology are discussed, with a focus on their roles in inflammatory signaling, lipid metabolism, and vascular cell adaptation within atherosclerotic plaques. We also highlight how these modifications influence the generation of RNA isoforms, potentially altering cellular phenotypes and contributing to disease progression. Despite the promise of epitranscriptomics, significant challenges remain, including the technical limitations in detecting RNA modifications in complex tissues and the need for deeper mechanistic insights into their causal roles in atherosclerotic pathogenesis. Integrating epitranscriptomics with other omics approaches, such as genomics, proteomics, and metabolomics, holds the potential to provide a more holistic understanding of the disease.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"159 ","pages":"Article 107496"},"PeriodicalIF":3.5,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143835083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lokman H. Tanriverdi , Annie Barrett , Asanish Kalyanasundaram , Mohammad A. Zafar , Bulat A. Ziganshin , John A. Elefteriades
{"title":"Efficacy of beta-blocker agents on clinical outcomes in patients with thoracic aortic aneurysm: A systematic review and meta-analysis of randomized controlled trials","authors":"Lokman H. Tanriverdi , Annie Barrett , Asanish Kalyanasundaram , Mohammad A. Zafar , Bulat A. Ziganshin , John A. Elefteriades","doi":"10.1016/j.vph.2025.107494","DOIUrl":"10.1016/j.vph.2025.107494","url":null,"abstract":"<div><h3>Objective</h3><div>Studies investigating the efficacy of β-blocker agents for patients with thoracic aortic aneurysm (TAA) have produced heterogeneous and conflicting results. We assess the effects of β-blockers on clinical outcomes in patients with TAA.</div></div><div><h3>Methods</h3><div>A systematic literature search was performed through Ovid MEDLINE, EMBASE, Web of Science, Pubmed and Cochrane CENTRAL, all from inception to April 30, 2024. Randomized controlled trials (RCTs) exploring the effect of β-blocker agents in patients with TAA were considered for inclusion, with no population restriction. Inverse variance–weighted random-effects model was used. The overall risk of bias assessment was conducted by Cochrane Risk of Bias 2 tool. The primary outcome was aortic events during follow-up.</div></div><div><h3>Results</h3><div>We included a total of 161 patients with TAA (mean age, 27.6 years; 80 [49.7 %] male, mean follow-up 6.7 years) in 4 RCTs. The pooled risk ratio in the β-blocker arm for aortic events was 0.74 [95 % CI (0.20; 2.71), I<sup>2</sup>: 0 %, <em>p</em> = 0.64, low certainty of evidence (CoE)] when compared to placebo or no treatment in patients with TAA. The pooled risk ratios for aortic dissection or death (all-cause mortality) or in the β-blocker arm were 0.45 (95 % CI (0.10; 1.98), I<sup>2</sup>: 0 %, <em>p</em> = 0.29, low CoE) and 0.58 (95 % CI (0.15; 2.24), I<sup>2</sup>: 0 %, <em>p</em> = 0.43, low CoE), respectively. The risks of aortic dissection, rupture, or death were comparable, regardless of agent, disease, and age.</div></div><div><h3>Conclusion</h3><div>We found no evidence of benefit from β-blocker treatment for patients with TAA. More robust RCTs are needed to establish evidence-based recommendations.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"159 ","pages":"Article 107494"},"PeriodicalIF":3.5,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143807712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}