Pub Date : 2025-07-16DOI: 10.1016/j.vph.2025.107522
Rafał Kolec , Michał Słaboszewski , Elżbieta Paszek , Mateusz Baran , Anetta Undas
Background
Serum lipopolysaccharide (LPS), a marker of gut dysbiosis and endotoxemia is associated with myocardial infarction (MI). We investigated factors affecting LPS changes in MI patients treated with percutaneous coronary intervention (PCI) and aimed to establish factors associated with the degree of LPS decrease following MI.
Methods
In 46 PCI-treated MI patients (mean age 57.2 [8.6]) years we measured LPS and zonulin, a marker of gut permeability, on admission, 30 and 60 days thereafter, inflammatory markers (interleukin [IL]-6, IL-18), P-selectin, and 8-isoprostaglandin F2α (8-isoPGF2α).
Results
The median initial LPS concentration was 44.0 (37.0–57.0) pg/mL and it fell by 11.3 % at 1 month, with a further 8.3 % drop after the second month, in association with zonulin, but not with P-selectin or inflammatory markers. LPS and zonulin at baseline correlated positively with 8-isoPGF2α. A < 10 % decrease in LPS was recorded in 20 (43.5 %) patients and was more frequent in smokers, those with a complete occlusion of the infarct-related artery (IRA) and a shorter symptom duration before PCI. LPS decrease <10 % was associated with a decline in IL-10 concentrations 30- and 60-days post MI. On multivariate analysis only current smoking and an initial complete IRA occlusion were independently associated with <10 % decrease in LPS at 1 month (OR 10.44; 95 % CI 2.13–51.21; p = 0.004 and OR 6.59; 95 % CI 1.21–35.88; p = 0.029, respectively).
Conclusions
This study is the first to show factors affecting post-MI changes in LPS, highlighting the role of smoking and initial complete IRA occlusion in persistent low-grade endotoxemia following MI.
血清脂多糖（LPS）是肠道生态失调和内毒素血症的标志物，与心肌梗死（MI）有关。我们研究了经皮冠状动脉介入治疗（PCI）后心肌梗死患者LPS变化的影响因素，旨在确定心肌梗死后LPS下降程度的相关因素。方法在46例PCI治疗的心肌梗死患者（平均年龄57.2[8.6]岁）入院时、入院后30和60天测量了LPS和zonulin（一种肠道通透性标志物）、炎症标志物（白细胞介素[IL]-6、IL-18）、p -选择素和8-异前列腺素F2α (8-isoPGF2α)。结果LPS初始浓度中位数为44.0 (37.0 ~ 57.0)pg/mL， 1个月后下降11.3%，2个月后进一步下降8.3%，与zonulin有关，但与p -选择素或炎症标志物无关。基线LPS和zonulin与8-isoPGF2α呈正相关。& lt;20例（43.5%）患者LPS下降10%，在吸烟者、梗死相关动脉（IRA）完全闭塞和PCI前症状持续时间较短的患者中更常见。心肌梗死后30天和60天，脂多糖降低10%与IL-10浓度下降有关。在多变量分析中，只有当前吸烟和首次完全阻断IRA与1个月时脂多糖降低10%独立相关(OR 10.44；95% ci 2.13-51.21；p = 0.004, OR = 6.59；95% ci 1.21-35.88；P = 0.029)。本研究首次揭示了影响心肌梗死后LPS变化的因素，强调了吸烟和初始完全IRA闭塞在心肌梗死后持续低级别内毒素血症中的作用。
{"title":"Changes in circulating lipopolysaccharide and zonulin following acute myocardial infarction: The impact of smoking","authors":"Rafał Kolec , Michał Słaboszewski , Elżbieta Paszek , Mateusz Baran , Anetta Undas","doi":"10.1016/j.vph.2025.107522","DOIUrl":"10.1016/j.vph.2025.107522","url":null,"abstract":"<div><h3>Background</h3><div>Serum lipopolysaccharide (LPS), a marker of gut dysbiosis and endotoxemia is associated with myocardial infarction (MI). We investigated factors affecting LPS changes in MI patients treated with percutaneous coronary intervention (PCI) and aimed to establish factors associated with the degree of LPS decrease following MI.</div></div><div><h3>Methods</h3><div>In 46 PCI-treated MI patients (mean age 57.2 [8.6]) years we measured LPS and zonulin, a marker of gut permeability, on admission, 30 and 60 days thereafter, inflammatory markers (interleukin [IL]-6, IL-18), P-selectin, and 8-isoprostaglandin F<sub>2α</sub> (8-isoPGF<sub>2α</sub>).</div></div><div><h3>Results</h3><div>The median initial LPS concentration was 44.0 (37.0–57.0) pg/mL and it fell by 11.3 % at 1 month, with a further 8.3 % drop after the second month, in association with zonulin, but not with P-selectin or inflammatory markers. LPS and zonulin at baseline correlated positively with 8-isoPGF<sub>2α</sub>. A < 10 % decrease in LPS was recorded in 20 (43.5 %) patients and was more frequent in smokers, those with a complete occlusion of the infarct-related artery (IRA) and a shorter symptom duration before PCI. LPS decrease <10 % was associated with a decline in IL-10 concentrations 30- and 60-days post MI. On multivariate analysis only current smoking and an initial complete IRA occlusion were independently associated with <10 % decrease in LPS at 1 month (OR 10.44; 95 % CI 2.13–51.21; <em>p</em> = 0.004 and OR 6.59; 95 % CI 1.21–35.88; <em>p</em> = 0.029, respectively).</div></div><div><h3>Conclusions</h3><div>This study is the first to show factors affecting post-MI changes in LPS, highlighting the role of smoking and initial complete IRA occlusion in persistent low-grade endotoxemia following MI.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107522"},"PeriodicalIF":3.5,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657095","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}
Pub Date : 2025-07-11DOI: 10.1016/j.vph.2025.107521
João P. Monteiro , Francesca Vacante , Azzurra L. De Pace , Matthew Bennett , Julie Rodor , Dónal O'Carroll , Joseph C. Wu , Thomas Quertermous , Andrew H. Baker
Advances in genome annotation have revealed a striking increase in the number and complexity of non-coding RNA (ncRNA) genes, particularly multi-transcript loci that harbor long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) within the same genomic region. These loci can often function as coordinated regulatory units, with their transcription modulated by shared cis-acting regulatory elements (CREs). Traditional gene manipulation approaches, which typically target individual transcripts, are insufficient to capture the full regulatory and therapeutic potential of these complex loci. Here, we present “cis-ON” a single-vector lentiviral delivery system based on CRISPR activation (CRISPRa), designed to simultaneously upregulate multiple noncoding RNA transcripts by targeting a single CRE.
We focused on the evolutionarily conserved MIR503HG locus, which encodes seven lncRNA isoforms and hosts the miR-424/503 cluster, both implicated in various cellular processes, including proliferation, angiogenesis, and endothelial-to-mesenchymal transition. Using integrative analysis of histone marks (H3K27Ac, H3K4Me3), DNase hypersensitivity, and CAGE-seq data, we identified the primary promoter of the MIR503HG locus. A dual fluorescent reporter screen selected optimal single guide RNAs (sgRNAs) for targeting this region. We then engineered cis-ON, a novel lentiviral system combining dCas9-VPR and sgRNA to enable a streamlined single-vector delivery approach. Transduction of primary human endothelial cells with this system robustly activated the entire locus including the MIR503HG isoforms and co-embedded miRNAs miR-424 and miR-503, demonstrating coordinated transcriptional regulation. Additionally, the neighboring LINC00629 lncRNA locus remained unaffected, highlighting regulatory specificity.
This approach demonstrates the feasibility of modulating complex ncRNA loci across a ∼ 10 kb genomic region by targeting a single CRE, bypassing limitations of transcriptspecific strategies. By enabling simultaneous upregulation of lncRNAs and miRNAs, the cis-ON platform provides a streamlined strategy for restoring regulatory networks disrupted in disease.
{"title":"Targeting Cis-regulatory elements for CRISPR-mediated transcriptional activation of the human MIR503HG locus","authors":"João P. Monteiro , Francesca Vacante , Azzurra L. De Pace , Matthew Bennett , Julie Rodor , Dónal O'Carroll , Joseph C. Wu , Thomas Quertermous , Andrew H. Baker","doi":"10.1016/j.vph.2025.107521","DOIUrl":"10.1016/j.vph.2025.107521","url":null,"abstract":"<div><div>Advances in genome annotation have revealed a striking increase in the number and complexity of non-coding RNA (ncRNA) genes, particularly multi-transcript loci that harbor long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) within the same genomic region. These loci can often function as coordinated regulatory units, with their transcription modulated by shared cis-acting regulatory elements (CREs). Traditional gene manipulation approaches, which typically target individual transcripts, are insufficient to capture the full regulatory and therapeutic potential of these complex loci. Here, we present “cis-ON” a single-vector lentiviral delivery system based on CRISPR activation (CRISPRa), designed to simultaneously upregulate multiple noncoding RNA transcripts by targeting a single CRE.</div><div>We focused on the evolutionarily conserved <em>MIR503HG</em> locus, which encodes seven lncRNA isoforms and hosts the <em>miR-424/503</em> cluster, both implicated in various cellular processes, including proliferation, angiogenesis, and endothelial-to-mesenchymal transition. Using integrative analysis of histone marks (H3K27Ac, H3K4Me3), DNase hypersensitivity, and CAGE-seq data, we identified the primary promoter of the <em>MIR503HG</em> locus. A dual fluorescent reporter screen selected optimal single guide RNAs (sgRNAs) for targeting this region. We then engineered cis-ON, a novel lentiviral system combining dCas9-VPR and sgRNA to enable a streamlined single-vector delivery approach. Transduction of primary human endothelial cells with this system robustly activated the entire locus including the <em>MIR503HG</em> isoforms and co-embedded miRNAs <em>miR-424</em> and <em>miR-503</em>, demonstrating coordinated transcriptional regulation. Additionally, the neighboring <em>LINC00629</em> lncRNA locus remained unaffected, highlighting regulatory specificity.</div><div>This approach demonstrates the feasibility of modulating complex ncRNA loci across a ∼ 10 kb genomic region by targeting a single CRE, bypassing limitations of transcriptspecific strategies. By enabling simultaneous upregulation of lncRNAs and miRNAs, the cis-ON platform provides a streamlined strategy for restoring regulatory networks disrupted in disease.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107521"},"PeriodicalIF":3.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144627290","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}
Pub Date : 2025-06-30DOI: 10.1016/j.vph.2025.107520
Mohammad Abdulelah , Chidubem Ezenna , Ancy Jenil-Franco , Kevin T. Jamouss , Mrinal Murali Krishna , Meghna Joseph , Kuan-Yu Chi , Talal Dahhan
Introduction
Pulmonary arterial hypertension (PAH) remains a life-threatening condition characterized by high morbidity and mortality. However, recent therapeutic advancements have offered a paradigm shift in terms of therapeutic goals.
Methods
We conducted a systematic review and meta-analysis of RCTs assessing clinical outcomes and safety of sotatercept when compared to placebo in PAH. Searches of Pubmed and Cochrane Central databases were performed through April 2025. The primary outcome was all-cause mortality. Secondary outcomes included improvements in 6MWD, WHO functional class, hemodynamics, NT-proBNP, and serious adverse events. Data were pooled using a random-effects model, with certainty of evidence assessed via GRADE methodology.
Results
Three RCTs comprising 601 patients were included. There was a non-significant trend toward reduced mortality (RR 0.49; 95 % CI 0.16 to 1.46; p = 0.11). Sotatercept was associated with significant improvements in 6MWD (MD 37.99 m; 95 % CI 6.47 to 69.52; p = 0.04) and WHO functional class (RR 2.04; 95 % CI 1.79 to 2.31; p = 0.002). Hemodynamic improvements included reductions in PVR (MD -237.73 dyn·s/cm5; 95 % CI -367.02 to −1.8.43; p = 0.02) and mPAP (MD -14.88 mmHg; 95 % CI -24.76 to −4.99; p = 0.02). Serious adverse events were similar (RR 0.79; 95 % CI 0.51 to 1.23; p = 0.15).
Conclusion
Sotatercept significantly improves functional and hemodynamic outcomes in PAH, with a favorable safety profile. While mortality benefits remain uncertain, these findings support its clinical utility as an emerging therapy in PAH.
肺动脉高压（PAH）仍然是一种危及生命的疾病，其特点是高发病率和死亡率。然而，最近的治疗进展在治疗目标方面提供了范式转变。方法：我们对随机对照试验进行了系统回顾和荟萃分析，评估索特西普与安慰剂在PAH中的临床结局和安全性。检索Pubmed和Cochrane Central数据库至2025年4月。主要结局为全因死亡率。次要结局包括6MWD、WHO功能分级、血流动力学、NT-proBNP和严重不良事件的改善。使用随机效应模型汇总数据，并通过GRADE方法评估证据的确定性。结果纳入3项随机对照试验，共601例患者。死亡率降低的趋势不显著(RR 0.49；95% CI 0.16 ~ 1.46；p = 0.11)。sotaterept与6MWD (MD 37.99 m；95% CI 6.47 ~ 69.52；p = 0.04)和WHO功能分类(RR 2.04；95% CI 1.79 - 2.31；p = 0.002)。血流动力学改善包括PVR降低(MD -237.73 dyn·s/cm5；95% CI -367.02 ~ - 1.8.43；p = 0.02)和mPAP (MD -14.88 mmHg；95% CI -24.76 ~ - 4.99；p = 0.02)。严重不良事件相似(RR 0.79；95% CI 0.51 ~ 1.23；p = 0.15)。结论索替赛普可显著改善PAH患者的功能和血流动力学结果，且具有良好的安全性。虽然死亡率效益仍不确定，但这些发现支持其作为PAH新兴疗法的临床应用。
{"title":"Clinical outcomes and safety of sotatercept in pulmonary arterial hypertension: A systematic review and meta-analysis of randomized controlled trials","authors":"Mohammad Abdulelah , Chidubem Ezenna , Ancy Jenil-Franco , Kevin T. Jamouss , Mrinal Murali Krishna , Meghna Joseph , Kuan-Yu Chi , Talal Dahhan","doi":"10.1016/j.vph.2025.107520","DOIUrl":"10.1016/j.vph.2025.107520","url":null,"abstract":"<div><h3>Introduction</h3><div>Pulmonary arterial hypertension (PAH) remains a life-threatening condition characterized by high morbidity and mortality. However, recent therapeutic advancements have offered a paradigm shift in terms of therapeutic goals.</div></div><div><h3>Methods</h3><div>We conducted a systematic review and meta-analysis of RCTs assessing clinical outcomes and safety of sotatercept when compared to placebo in PAH. Searches of Pubmed and Cochrane Central databases were performed through April 2025. The primary outcome was all-cause mortality. Secondary outcomes included improvements in 6MWD, WHO functional class, hemodynamics, NT-proBNP, and serious adverse events. Data were pooled using a random-effects model, with certainty of evidence assessed via GRADE methodology.</div></div><div><h3>Results</h3><div>Three RCTs comprising 601 patients were included. There was a non-significant trend toward reduced mortality (RR 0.49; 95 % CI 0.16 to 1.46; <em>p</em> = 0.11). Sotatercept was associated with significant improvements in 6MWD (MD 37.99 m; 95 % CI 6.47 to 69.52; <em>p</em> = 0.04) and WHO functional class (RR 2.04; 95 % CI 1.79 to 2.31; <em>p</em> = 0.002). Hemodynamic improvements included reductions in PVR (MD -237.73 dyn·s/cm<sup>5</sup>; 95 % CI -367.02 to −1.8.43; <em>p</em> = 0.02) and mPAP (MD -14.88 mmHg; 95 % CI -24.76 to −4.99; p = 0.02). Serious adverse events were similar (RR 0.79; 95 % CI 0.51 to 1.23; <em>p</em> = 0.15).</div></div><div><h3>Conclusion</h3><div>Sotatercept significantly improves functional and hemodynamic outcomes in PAH, with a favorable safety profile. While mortality benefits remain uncertain, these findings support its clinical utility as an emerging therapy in PAH.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107520"},"PeriodicalIF":3.5,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144535025","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}
Pub Date : 2025-06-25DOI: 10.1016/j.vph.2025.107519
Yunhua Yang , Shaoxin Gong , Na Liang , Zhouxin Li , Xiaoyu Duan , Tong Xie , Xiaoyong Lei , Aiping Wang
Pulmonary hypertension is a progressive vascular disease characterized by pulmonary vascular remodeling, with high mortality and poor prognosis despite advances in medical therapy. Recently, histone modification therapies for pulmonary hypertension have received more attention. Studies have shown that abnormal histone modifications and the enzymes responsible for these alterations can drive pulmonary vascular cell proliferation, migration, and anti-apoptosis by regulating chromatin structure and gene expression, thereby promoting pulmonary vascular remodeling in pulmonary hypertension. This review illustrates histone modifications, including methylation, acetylation, lactylation, and SUMOylation, and the enzymes responsible for these modifications, exploring their role and pathophysiological mechanism in pulmonary hypertension. In addition, the review summarizes the small molecule modulators currently under development and their efficacy in various preclinical models of pulmonary hypertension. Comprehending the function of histone modifications in pulmonary hypertension will help identify new biomarkers and molecular targets and facilitate personalized treatments for this severe disease.
{"title":"The role of histone modifications in pulmonary hypertension: From mechanisms to therapeutic targets","authors":"Yunhua Yang , Shaoxin Gong , Na Liang , Zhouxin Li , Xiaoyu Duan , Tong Xie , Xiaoyong Lei , Aiping Wang","doi":"10.1016/j.vph.2025.107519","DOIUrl":"10.1016/j.vph.2025.107519","url":null,"abstract":"<div><div>Pulmonary hypertension is a progressive vascular disease characterized by pulmonary vascular remodeling, with high mortality and poor prognosis despite advances in medical therapy. Recently, histone modification therapies for pulmonary hypertension have received more attention. Studies have shown that abnormal histone modifications and the enzymes responsible for these alterations can drive pulmonary vascular cell proliferation, migration, and anti-apoptosis by regulating chromatin structure and gene expression, thereby promoting pulmonary vascular remodeling in pulmonary hypertension. This review illustrates histone modifications, including methylation, acetylation, lactylation, and SUMOylation, and the enzymes responsible for these modifications, exploring their role and pathophysiological mechanism in pulmonary hypertension. In addition, the review summarizes the small molecule modulators currently under development and their efficacy in various preclinical models of pulmonary hypertension. Comprehending the function of histone modifications in pulmonary hypertension will help identify new biomarkers and molecular targets and facilitate personalized treatments for this severe disease.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107519"},"PeriodicalIF":3.5,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512583","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}
Pub Date : 2025-06-25DOI: 10.1016/j.vph.2025.107518
Fern Williams , Kristy Martin , Thomas R. Scott , David Clark , Merce Fuentes Amell , Neil J. Spratt , Daniel J. Beard , Kirsten G. Coupland
Good leptomeningeal collateral vessels (LMC) are associated with smaller lesion volume and better patient outcomes from ischaemic stroke, but their architecture varies greatly between individuals. Statins can stimulate angiogenesis and show promise for stimulating cerebral collaterogenesis. Statins could thus improve LMC grade and ensure all patients receive positive outcomes from treatment. This potentially explains why statin treatment is effective given prior to stroke in pre-clinical models, but not prescribed afterwards in clinical trials.
LMC-rich C57Bl/6 and LMC-poor BALB/c 12-week-old male mice were randomised to receive daily oral simvastatin (10 mg/kg) or vehicle for 4 weeks. The cerebrovasculature was silicone-perfused, allowing LMC numbers and dimensions to be analysed. Values for tortuosity, vascularity and LMC resistance were calculated.
In BALB/c, estimated resistance was lower with simvastatin treatment (vehicle: 0.104 ± 0.09, simvastatin: 0.023 ± 0.02; p = 0.04) and LMC numbers were greater (vehicle: 1.6 ± 1.6, simvastatin: 4.0 ± 3.2; p = 0.04). In C57Bl/6, there was no difference to resistance, but LMCs were smaller in diameter (vehicle: 16.3 ± 1.8 μm, simvastatin: 14.0 ± 1.4 μm, p = 0.008). Statin-treated C57Bl/6 also had more arterial branchpoints (left hemisphere, vehicle: 363.8 ± 55 per cm2, simvastatin: 417.3 ± 58 per cm2, p = 0.007; right, vehicle: 315.1 ± 40 per cm2, simvastatin: 397.5 ± 43 per cm2, p < 0.0001).
We have observed signs of collaterogenesis and angiogenesis, providing evidence that statins stimulate growth of LMCs. Greatest benefit was seen in LMC-poor BALB/c, suggesting that patients with poor LMC circulation stand to gain most from LMC-enhancing therapies. Patients receiving statins prior to stroke have likely developed better LMCs, leading to better stroke outcomes. These findings should stimulate investigation of further safe, widely-available LMC-enhancing therapies.
{"title":"Effects of simvastatin treatment on leptomeningeal collateral vessels: resistance, number and diameter","authors":"Fern Williams , Kristy Martin , Thomas R. Scott , David Clark , Merce Fuentes Amell , Neil J. Spratt , Daniel J. Beard , Kirsten G. Coupland","doi":"10.1016/j.vph.2025.107518","DOIUrl":"10.1016/j.vph.2025.107518","url":null,"abstract":"<div><div>Good leptomeningeal collateral vessels (LMC) are associated with smaller lesion volume and better patient outcomes from ischaemic stroke, but their architecture varies greatly between individuals. Statins can stimulate angiogenesis and show promise for stimulating cerebral collaterogenesis. Statins could thus improve LMC grade and ensure all patients receive positive outcomes from treatment. This potentially explains why statin treatment is effective given prior to stroke in pre-clinical models, but not prescribed afterwards in clinical trials.</div><div>LMC-rich C57Bl/6 and LMC-poor BALB/c 12-week-old male mice were randomised to receive daily oral simvastatin (10 mg/kg) or vehicle for 4 weeks. The cerebrovasculature was silicone-perfused, allowing LMC numbers and dimensions to be analysed. Values for tortuosity, vascularity and LMC resistance were calculated.</div><div>In BALB/c, estimated resistance was lower with simvastatin treatment (vehicle: 0.104 ± 0.09, simvastatin: 0.023 ± 0.02; <em>p</em> = 0.04) and LMC numbers were greater (vehicle: 1.6 ± 1.6, simvastatin: 4.0 ± 3.2; <em>p</em> = 0.04). In C57Bl/6, there was no difference to resistance, but LMCs were smaller in diameter (vehicle: 16.3 ± 1.8 μm, simvastatin: 14.0 ± 1.4 μm, <em>p</em> = 0.008). Statin-treated C57Bl/6 also had more arterial branchpoints (left hemisphere, vehicle: 363.8 ± 55 per cm2, simvastatin: 417.3 ± 58 per cm2, <em>p</em> = 0.007; right, vehicle: 315.1 ± 40 per cm2, simvastatin: 397.5 ± 43 per cm2, <em>p</em> < 0.0001).</div><div>We have observed signs of collaterogenesis and angiogenesis, providing evidence that statins stimulate growth of LMCs. Greatest benefit was seen in LMC-poor BALB/c, suggesting that patients with poor LMC circulation stand to gain most from LMC-enhancing therapies. Patients receiving statins prior to stroke have likely developed better LMCs, leading to better stroke outcomes. These findings should stimulate investigation of further safe, widely-available LMC-enhancing therapies.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107518"},"PeriodicalIF":3.5,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512582","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}
Pub Date : 2025-06-22DOI: 10.1016/j.vph.2025.107517
Maria Rosa Montinari , Sergio Minelli , John D. Horowitz , Raffaele De Caterina
For over 150 years, nitrates have been a cornerstone in the treatment of cardiovascular disease. Nitroglycerin — synthesized by Italian chemist Ascanio Sobrero in 1847 — was initially used in explosives, as the main component of dynamite, by Alfred Nobel. The Scottish physician Lauder Brunton first used amyl nitrite for angina in 1867, and in 1879 the English physician William Murrell described the benefits of nitroglycerin for angina pectoris. Organic nitrates, including nitroglycerin, act as nitric oxide donors, sharing the mechanism of NO release, which induces vasodilation. This paper reviews the fascinating history of nitroglycerin and nitroderivatives, the related discovery of nitric oxide as a cardiovascular signaling molecule, and the 1998 Nobel Prize awarded for this discovery. The paper also succinctly explores current and future roles of nitric oxide donors in cardiovascular treatment.
{"title":"Explosive discovery, surprising future: The extraordinary journey of nitroglycerin, nitroderivatives and nitric oxide","authors":"Maria Rosa Montinari , Sergio Minelli , John D. Horowitz , Raffaele De Caterina","doi":"10.1016/j.vph.2025.107517","DOIUrl":"10.1016/j.vph.2025.107517","url":null,"abstract":"<div><div>For over 150 years, nitrates have been a cornerstone in the treatment of cardiovascular disease. Nitroglycerin — synthesized by Italian chemist Ascanio Sobrero in 1847 — was initially used in explosives, as the main component of dynamite, by Alfred Nobel. The Scottish physician Lauder Brunton first used amyl nitrite for angina in 1867, and in 1879 the English physician William Murrell described the benefits of nitroglycerin for angina pectoris. Organic nitrates, including nitroglycerin, act as nitric oxide donors, sharing the mechanism of NO release, which induces vasodilation. This paper reviews the fascinating history of nitroglycerin and nitroderivatives, the related discovery of nitric oxide as a cardiovascular signaling molecule, and the 1998 Nobel Prize awarded for this discovery. The paper also succinctly explores current and future roles of nitric oxide donors in cardiovascular treatment.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107517"},"PeriodicalIF":3.5,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144470863","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}
Pub Date : 2025-06-20DOI: 10.1016/j.vph.2025.107516
Amandeep Rashid Mondal , Ashish Misra
Atherosclerosis is a leading cause of cardiovascular morbidity and mortality worldwide, driven by complex interactions among various plaque cell types, including endothelial cells, macrophages, and smooth muscle cells. Traditional therapies targeting systemic risk factors such as cholesterol and blood pressure fail to directly address the underlying mechanisms governing plaque formation and progression. Recent advances in cell-specific therapies offer new avenues for targeting the cellular and molecular processes driving atherosclerosis. This Review explores innovative strategies including nanoparticles, viral vectors and CRISPR-Cas9 technology, which have the potential to modulate gene expression and behaviour within plaques cells to alleviate disease. By focusing on the specific roles of key cell types in atherosclerosis, these emerging therapies promise to provide more precise, effective, and personalised treatment options without inducing off-target effects. Moreover, insights gained from successful applications of these technologies in oncology are considered for potential repurposing in atherosclerosis-related disease. As these cell-specific approaches advance through preclinical and clinical development, they may significantly enhance our ability to treat atherosclerosis at its cellular roots, offering new hope for reducing the burden of cardiovascular disease.
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Pub Date : 2025-06-11DOI: 10.1016/j.vph.2025.107515
Lubomir T. Lubomirov , Simon Jasinski-Bergner , Kangbo Li , Doris Metzler , Tatiana Korotkova , Jürgen Hescheler , Gabriele Pfitzer , Vladimir T. Todorov , René Mantke , Thomas Enzmann , Hendrik Borgmann , Olaf Grisk
Objective
This study tested if arterial reactivity to soluble guanylate cyclase (sGC)/protein kinase G (PKG) pathway activation depends on age, vessel localization as well as diameter and investigated the molecular mechanisms involved in sGC activator-induced vasodilation in human arteries.
Methods
sGC/PKG were stimulated by sodium nitroprusside (SNP) or the sGC activator cinaciguat. Mesenteric and intrarenal arteries from young and aged mice as well as from patients who underwent elective colon resection or nephrectomy were investigated by wire myography. Phosphorylation of the regulatory 20-kDa light-chain of myosin at serine 19 (MLC20-S19) and targeting-subunit-of-myosin-phosphatase at threonine 853 and serine 668 (MYPT1-T853 and MYPT1-S668) were determined by Western blot.
Results
In murine vessels, SNP- and cinaciguat-induced vasodilation was significantly less in intrarenal than in mesenteric arteries and not age-dependent. Human intrarenal and mesenteric arteries showed a similar vasodilation in response to SNP and cinaciguat. In both vascular beds arteries with a lumen diameter < 700 μm showed a stronger cinaciguat-induced vasodilation than arteries with a lumen diameter > 700 μm. Cinaciguat (0.1 μmol/l) increased PKG-dependent MYPT1-S668 phosphorylation in <700 μm vessels but not in >700 μm vessels. Cinaciguat significantly reduced MLC20-S19 phosphorylation only in <700 μm mesenteric arteries.
Conclusions
In contrast to murine arteries, SNP- and cinaciguat-induced vasodilation is similar in human intrarenal and mesenteric arteries. In the human vasculature, small diameter arteries are more responsive to sGC activation than large diameter vessels irrespective of the degree of MLC20-S19 phosphorylation.
{"title":"Vascular diameter determines sensitivity to soluble guanylate cyclase activation in human mesenteric and renal arteries","authors":"Lubomir T. Lubomirov , Simon Jasinski-Bergner , Kangbo Li , Doris Metzler , Tatiana Korotkova , Jürgen Hescheler , Gabriele Pfitzer , Vladimir T. Todorov , René Mantke , Thomas Enzmann , Hendrik Borgmann , Olaf Grisk","doi":"10.1016/j.vph.2025.107515","DOIUrl":"10.1016/j.vph.2025.107515","url":null,"abstract":"<div><h3>Objective</h3><div>This study tested if arterial reactivity to soluble guanylate cyclase (sGC)/protein kinase G (PKG) pathway activation depends on age, vessel localization as well as diameter and investigated the molecular mechanisms involved in sGC activator-induced vasodilation in human arteries.</div></div><div><h3>Methods</h3><div>sGC/PKG were stimulated by sodium nitroprusside (SNP) or the sGC activator cinaciguat. Mesenteric and intrarenal arteries from young and aged mice as well as from patients who underwent elective colon resection or nephrectomy were investigated by wire myography. Phosphorylation of the regulatory 20-kDa light-chain of myosin at serine 19 (MLC<sub>20</sub>-S19) and targeting-subunit-of-myosin-phosphatase at threonine 853 and serine 668 (MYPT1-T853 and MYPT1-S668) were determined by Western blot.</div></div><div><h3>Results</h3><div>In murine vessels, SNP- and cinaciguat-induced vasodilation was significantly less in intrarenal than in mesenteric arteries and not age-dependent. Human intrarenal and mesenteric arteries showed a similar vasodilation in response to SNP and cinaciguat. In both vascular beds arteries with a lumen diameter < 700 μm showed a stronger cinaciguat-induced vasodilation than arteries with a lumen diameter > 700 μm. Cinaciguat (0.1 μmol/l) increased PKG-dependent MYPT1-S668 phosphorylation in <700 μm vessels but not in >700 μm vessels. Cinaciguat significantly reduced MLC<sub>20</sub>-S19 phosphorylation only in <700 μm mesenteric arteries.</div></div><div><h3>Conclusions</h3><div>In contrast to murine arteries, SNP- and cinaciguat-induced vasodilation is similar in human intrarenal and mesenteric arteries. In the human vasculature, small diameter arteries are more responsive to sGC activation than large diameter vessels irrespective of the degree of MLC<sub>20</sub>-S19 phosphorylation.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107515"},"PeriodicalIF":3.5,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289237","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}
Pub Date : 2025-05-16DOI: 10.1016/j.vph.2025.107503
Enkhjargal Budbazar , Aylin Balmes , Danielle Elliott , Lisette Peres Tintin , Timo Kopp , Susanne Feil , Robert Feil , Tilman E. Schäffer , Francesca Seta
Background & purpose
Arterial stiffness, or loss of elastic compliance in large arteries, is an independent precursor of cardiovascular disease (CVD) [1] and dementia [2] 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 (pVASPS239), lead to increased cytoskeletal actin polymerization in vascular smooth muscle cells (VSMCs) contributing to increased arterial stiffness [3]. In the current study, we tested whether activating NO-GC with an NO-GC activator (cinaciguat) modulates pVASPS239 and cytoskeletal actin polymerization in VSMCs, thereby preventing obesity-induced arterial stiffness.
Experimental approach & key results
Cinaciguat administration (5 mg/kg) to high fat, high sucrose diet (HFHS)-fed mice, our established model of arterial stiffness [4], (1) decreased pulse wave velocity, the in vivo index of arterial stiffness, without affecting blood pressure; (2) increased aortic pVASPS239 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 pVASPS239 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 [[4], [5], [6]]. These effects were abrogated in aortas and VSMCs from mice with smooth muscle-specific cGKI deletion (cGKISMKO), while being mimicked by a cell-permeable cGMP analog (8-Br-cGMP), which also decreased VSMC stiffness in vitro.
Conclusions & implications
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.
{"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}
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