Pub Date : 2025-02-17DOI: 10.1016/j.vph.2025.107472
Alberto Álvarez-Aznar , Malavika Desai , Michael M. Orlich , Elisa Vázquez-Liébanas , Ralf H. Adams , Cord Brakebusch , Konstantin Gaengel
Aims
Mural cells constitute the outer lining of blood vessels and are essential for vascular development and function. Mural cell loss or malfunction has been associated with numerous diseases including diabetic retinopathy, stroke and amyotrophic lateral sclerosis. In this work, we investigate the role of CDC42 in mural cells in vivo, using the developing mouse retina as a model.
Methods
In this study, we generated a mouse model for Cdc42 deletion in mural cells by crossing Pdgfrb-CreERT2 mice with Cdc42flox/flox mice. This model (Cdc42iΔMC) allowed us to investigate the role of CDC42 in pericytes and smooth muscle cells in the developing and adult retinal vasculature.
Results
We find that, during postnatal development, CDC42 is required in both, pericytes and smooth muscle cells to maintain proper cell morphology, mural cell coverage and distribution. During retinal angiogenesis, Cdc42-depleted pericytes lag behind the sprouting front and exhibit decreased proliferation. Consequently, capillaries at the sprouting front remain pericyte deprived, become dilated and are prone to increased vascular leakage. In addition, arteries and arterioles deviate from their normal growth directions and trajectory. While in the adult retina, mural cell coverage normalizes and pericytes adopt a normal morphology, smooth muscle cell morphologies remain abnormal and arteriolar branching angles are markedly reduced.
Conclusions
Our findings demonstrate that CDC42 is required for mural cell migration and proliferation and suggest that mural cells are essential for normal morphogenesis and patterning of the developing retinal vasculature.
{"title":"Cdc42 is crucial for mural cell migration, proliferation and patterning of the retinal vasculature","authors":"Alberto Álvarez-Aznar , Malavika Desai , Michael M. Orlich , Elisa Vázquez-Liébanas , Ralf H. Adams , Cord Brakebusch , Konstantin Gaengel","doi":"10.1016/j.vph.2025.107472","DOIUrl":"10.1016/j.vph.2025.107472","url":null,"abstract":"<div><h3>Aims</h3><div>Mural cells constitute the outer lining of blood vessels and are essential for vascular development and function. Mural cell loss or malfunction has been associated with numerous diseases including diabetic retinopathy, stroke and amyotrophic lateral sclerosis. In this work, we investigate the role of CDC42 in mural cells <em>in vivo</em>, using the developing mouse retina as a model.</div></div><div><h3>Methods</h3><div>In this study, we generated a mouse model for <em>Cdc42</em> deletion in mural cells by crossing <em>Pdgfrb-CreER</em><sup><em>T2</em></sup> mice with <em>Cdc42flox/flox</em> mice. This model (<em>Cdc42</em><sup><em>iΔMC</em></sup>) allowed us to investigate the role of CDC42 in pericytes and smooth muscle cells in the developing and adult retinal vasculature.</div></div><div><h3>Results</h3><div>We find that, during postnatal development, CDC42 is required in both, pericytes and smooth muscle cells to maintain proper cell morphology, mural cell coverage and distribution. During retinal angiogenesis, <em>Cdc42</em>-depleted pericytes lag behind the sprouting front and exhibit decreased proliferation. Consequently, capillaries at the sprouting front remain pericyte deprived, become dilated and are prone to increased vascular leakage. In addition, arteries and arterioles deviate from their normal growth directions and trajectory. While in the adult retina, mural cell coverage normalizes and pericytes adopt a normal morphology, smooth muscle cell morphologies remain abnormal and arteriolar branching angles are markedly reduced.</div></div><div><h3>Conclusions</h3><div>Our findings demonstrate that CDC42 is required for mural cell migration and proliferation and suggest that mural cells are essential for normal morphogenesis and patterning of the developing retinal vasculature.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"159 ","pages":"Article 107472"},"PeriodicalIF":3.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143459673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-09DOI: 10.1016/j.vph.2025.107471
Rían W. Manville , Samuel N. Baldwin , Olivia H. Schaub , Thomas A. Jepps , Geoffrey W. Abbott
{"title":"Vasorelaxant effects of 3-methoxycatechol are not via direct activation of voltage-gated potassium channels","authors":"Rían W. Manville , Samuel N. Baldwin , Olivia H. Schaub , Thomas A. Jepps , Geoffrey W. Abbott","doi":"10.1016/j.vph.2025.107471","DOIUrl":"10.1016/j.vph.2025.107471","url":null,"abstract":"","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"159 ","pages":"Article 107471"},"PeriodicalIF":3.5,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400355","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 : 2025-02-07DOI: 10.1016/j.vph.2025.107466
Jung Sun Kim , Minju Park , Yoon-A Park , Da Hoon Lee , Seo-A Choi , Eun Jeong Jang , Jeong Yee , Dong-Hyeok Kim , Tae-Jin Song , Junbeom Park , Hye Sun Gwak
Background
The development of cerebral infarction is multifactorial, including both environmental and genetic factors. This study assessed the association between fibroblast growth factor (FGF)-related gene polymorphisms and the incidence of cerebral infarction among patients on direct oral anticoagulants (DOACs).
Methods
Patients over 18 years old with atrial fibrillation who were receiving DOACs for cerebral infarction prevention at Ewha Womans University Mokdong Hospital and Ewha Womans University Seoul Hospital were enrolled in this analysis. Twenty-one single nucleotide polymorphisms (SNPs) from FGF1, FGF2, and FGFR1 were examined. In multivariable logistic regression analysis, three models (Model I: demographic factors only, Model II: demographic factors and genetic factors, and Model III: genetic factors and the CHA2DS2-VASc score) were constructed to identify the risk factors related to cerebral infarction.
Results
Among the 536 candidate patients, 21 (3.9 %) experienced cerebral infarction while taking DOACs. From Model I and Model II, age ≥ 75 years and previous thromboembolic event history increased the risk of cerebral infarction. For genetic factors in Model II and III, FGF1 rs1596776 GG, FGFR1 rs6996321 AA, and FGFR1 rs7012413 TT genotypes were associated with a higher risk of cerebral infarction. The area under the receiver operating curve increased from 0.747 (Model I) to 0.822 (Model II) by adding genetic factors, demonstrating better model performance.
Conclusions
This study uncovered the association between FGF-related gene polymorphisms and cerebral infarction among patients with atrial fibrillation undergoing DOAC therapy.
{"title":"Effects of FGF-related gene polymorphisms on cerebral infarction in patients treated with direct oral anticoagulants","authors":"Jung Sun Kim , Minju Park , Yoon-A Park , Da Hoon Lee , Seo-A Choi , Eun Jeong Jang , Jeong Yee , Dong-Hyeok Kim , Tae-Jin Song , Junbeom Park , Hye Sun Gwak","doi":"10.1016/j.vph.2025.107466","DOIUrl":"10.1016/j.vph.2025.107466","url":null,"abstract":"<div><h3>Background</h3><div>The development of cerebral infarction is multifactorial, including both environmental and genetic factors. This study assessed the association between fibroblast growth factor (FGF)-related gene polymorphisms and the incidence of cerebral infarction among patients on direct oral anticoagulants (DOACs).</div></div><div><h3>Methods</h3><div>Patients over 18 years old with atrial fibrillation who were receiving DOACs for cerebral infarction prevention at Ewha Womans University Mokdong Hospital and Ewha Womans University Seoul Hospital were enrolled in this analysis. Twenty-one single nucleotide polymorphisms (SNPs) from <em>FGF1</em>, <em>FGF2</em>, and <em>FGFR1</em> were examined. In multivariable logistic regression analysis, three models (Model I: demographic factors only, Model II: demographic factors and genetic factors, and Model III: genetic factors and the CHA<sub>2</sub>DS<sub>2</sub>-VASc score) were constructed to identify the risk factors related to cerebral infarction.</div></div><div><h3>Results</h3><div>Among the 536 candidate patients, 21 (3.9 %) experienced cerebral infarction while taking DOACs. From Model I and Model II, age ≥ 75 years and previous thromboembolic event history increased the risk of cerebral infarction. For genetic factors in Model II and III, <em>FGF1</em> rs1596776 GG, <em>FGFR1</em> rs6996321 AA, and FGFR1 rs7012413 TT genotypes were associated with a higher risk of cerebral infarction. The area under the receiver operating curve increased from 0.747 (Model I) to 0.822 (Model II) by adding genetic factors, demonstrating better model performance.</div></div><div><h3>Conclusions</h3><div>This study uncovered the association between <em>FGF</em>-related gene polymorphisms and cerebral infarction among patients with atrial fibrillation undergoing DOAC therapy.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"158 ","pages":"Article 107466"},"PeriodicalIF":3.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143383397","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 : 2025-02-03DOI: 10.1016/j.vph.2025.107470
Matteo Calligaris , Aneta Aleksova , Alessandra Lucia Fluca , Milijana Janjusevic , Giada Carpi , Daniele Stefanizzi , Sara Carnevali , Francesco Curcio , Annibale Alessandro Puca , Monica Cattaneo , Antonio Paolo Beltrami
In recent years, the role of the cardiac microvasculature in modulating the symptoms and disease progression of patients affected by cardiac pathology has been reconsidered. The term cardiac microvascular disease (CMD) describes the set of functional and/or structural alterations of the cardiac microvasculature that reduce the ability of the heart to adequately increase its coronary blood flow to keep up with increased metabolic demand. CMD is involved in the evolution of heart disease of both ischemic and non-ischemic origin as well as in cardiac aging. The primary actors involved in this process are the cells of the stromal compartment, whose nature and biology are now investigated to a new level of detail thanks to single-cell omics studies. Recent studies on the genetics of extreme longevity have identified a polymorphic haplotype variant of the BPIFB4 gene that confers prolonged life span and health span, atheroprotective advantages, and an improved immune response.
The aim of this review was to focus on the beneficial effects of the longevity-associated variant (LAV) of BPIFB4 on cardiac microvascular cell biology, providing novel and exciting mechanisms of its action directed against the development or progression of many age-related cardiovascular diseases, thus emphasizing its translational therapeutic potential.
{"title":"Protective role of the longevity-associated BPIFB4 gene on cardiac microvascular cells and cardiac aging","authors":"Matteo Calligaris , Aneta Aleksova , Alessandra Lucia Fluca , Milijana Janjusevic , Giada Carpi , Daniele Stefanizzi , Sara Carnevali , Francesco Curcio , Annibale Alessandro Puca , Monica Cattaneo , Antonio Paolo Beltrami","doi":"10.1016/j.vph.2025.107470","DOIUrl":"10.1016/j.vph.2025.107470","url":null,"abstract":"<div><div>In recent years, the role of the cardiac microvasculature in modulating the symptoms and disease progression of patients affected by cardiac pathology has been reconsidered. The term cardiac microvascular disease (CMD) describes the set of functional and/or structural alterations of the cardiac microvasculature that reduce the ability of the heart to adequately increase its coronary blood flow to keep up with increased metabolic demand. CMD is involved in the evolution of heart disease of both ischemic and non-ischemic origin as well as in cardiac aging. The primary actors involved in this process are the cells of the stromal compartment, whose nature and biology are now investigated to a new level of detail thanks to single-cell omics studies. Recent studies on the genetics of extreme longevity have identified a polymorphic haplotype variant of the BPIFB4 gene that confers prolonged life span and health span, atheroprotective advantages, and an improved immune response.</div><div>The aim of this review was to focus on the beneficial effects of the longevity-associated variant (LAV) of BPIFB4 on cardiac microvascular cell biology, providing novel and exciting mechanisms of its action directed against the development or progression of many age-related cardiovascular diseases, thus emphasizing its translational therapeutic potential.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"158 ","pages":"Article 107470"},"PeriodicalIF":3.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-02DOI: 10.1016/j.vph.2025.107469
Rahul Rajala , Courtney T. Griffin
{"title":"Kinome profiling: A veritable Rosetta Stone for protease-activated receptor 1 biased signaling","authors":"Rahul Rajala , Courtney T. Griffin","doi":"10.1016/j.vph.2025.107469","DOIUrl":"10.1016/j.vph.2025.107469","url":null,"abstract":"","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"158 ","pages":"Article 107469"},"PeriodicalIF":3.5,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190635","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}
Osteonectin, a secreted glycoprotein, plays a role in muscle-wasting disease. However, its role in chronic heart failure (CHF) -induced systemic inflammation and postural control is unknown. Here we aim to assess the potential association of soluble osteonectin with cardiac dysfunction and postural imbalance in CHF. The cardiac function, physical performance, including short physical performance battery (SPPB) for balance, handgrip strength (HGS), and the levels of plasma osteonectin and c-reactive protein (CRP) were assessed in controls (n = 56) and CHF patients (n = 286) presented with ischemic and non-ischemic CHF. CHF patients exhibited significantly lower HGS and postural balance accompanied by higher cardiac contractile dysfunction. Regardless of HF etiologies, the osteonectin and CRP levels were significantly higher in CHF patients vs. controls. The osteonectin exhibited a significant inverse correlation with left ventricular ejection fraction (LVEF) in both ischemic (r2 = 0.13, P < 0.0001) and non-ischemic (r2 = 0.18, P < 0.0001) CHF patients. Similarly, osteonectin has shown a strong negative correlation with cumulative SPPB score in both ischemic (r2 = 0.19, P < 0.0001) and non-ischemic (r2 = 0.22, P < 0.0001) patients. Further SPPB balance-based analysis demonstrated lower LVEF and markedly elevated osteonectin and CRP (P < 0.0001), particularly in patients with poor postural balance compared to those with relatively good balance. Importantly, osteonectin demonstrated significantly higher sensitivity and specificity for CHF diagnosis on ROC curve analysis. Taken together, higher osteonectin level is associated with LV dysfunction and postural imbalance irrespective of CHF etiologies. It may serve as a biomarker for physical disability and contractile dysfunction in CHF patients.
{"title":"Circulating osteonectin predicts postural imbalance and cardiac dysfunction in heart failure","authors":"Firdos Ahmad , Asima Karim , Javaidullah Khan , Rizwan Qaisar","doi":"10.1016/j.vph.2025.107468","DOIUrl":"10.1016/j.vph.2025.107468","url":null,"abstract":"<div><div>Osteonectin, a secreted glycoprotein, plays a role in muscle-wasting disease. However, its role in chronic heart failure (CHF) -induced systemic inflammation and postural control is unknown. Here we aim to assess the potential association of soluble osteonectin with cardiac dysfunction and postural imbalance in CHF. The cardiac function, physical performance, including short physical performance battery (SPPB) for balance, handgrip strength (HGS), and the levels of plasma osteonectin and c-reactive protein (CRP) were assessed in controls (<em>n</em> = 56) and CHF patients (<em>n</em> = 286) presented with ischemic and non-ischemic CHF. CHF patients exhibited significantly lower HGS and postural balance accompanied by higher cardiac contractile dysfunction. Regardless of HF etiologies, the osteonectin and CRP levels were significantly higher in CHF patients vs. controls. The osteonectin exhibited a significant inverse correlation with left ventricular ejection fraction (LVEF) in both ischemic (r<sup>2</sup> = 0.13, <em>P</em> < 0.0001) and non-ischemic (r<sup>2</sup> = 0.18, P < 0.0001) CHF patients. Similarly, osteonectin has shown a strong negative correlation with cumulative SPPB score in both ischemic (r<sup>2</sup> = 0.19, <em>P</em> < 0.0001) and non-ischemic (r<sup>2</sup> = 0.22, <em>P</em> < 0.0001) patients. Further SPPB balance-based analysis demonstrated lower LVEF and markedly elevated osteonectin and CRP (P < 0.0001), particularly in patients with poor postural balance compared to those with relatively good balance. Importantly, osteonectin demonstrated significantly higher sensitivity and specificity for CHF diagnosis on ROC curve analysis. Taken together, higher osteonectin level is associated with LV dysfunction and postural imbalance irrespective of CHF etiologies. It may serve as a biomarker for physical disability and contractile dysfunction in CHF patients.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"158 ","pages":"Article 107468"},"PeriodicalIF":3.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075641","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 : 2025-01-31DOI: 10.1016/j.vph.2025.107467
Zuomei Zeng , Xinyue Wang , Hongjuan Wang , Leiyu Tian , Lidan Cui , Jian Guo , Yucai Chen
Background
Pulmonary hypertension (PH) is a serious vascular disease characterized by pulmonary vascular remodeling. Xuefu Zhuyu decoction (XFZYD) can potentially improve pulmonary vascular remodeling; however, its mechanism requires further investigation.
Methods
Rat models of monocrotaline (MCT)-induced PH and chronic thromboembolic pulmonary hypertension (CTEPH) were employed to investigate whether XFZYD has the potential to improve pulmonary vascular remodeling. After 21 days of XFZYD administration, the right ventricular systolic pressure (RVSP), organ indices, and wall thickness of pulmonary arteries of the rats were measured. Considering the possibility of endothelial-to-mesenchymal transition (EndMT), the specific mechanism of XFZYD in improving pulmonary vascular remodeling was further explored. Immunofluorescence, immunohistochemistry, and western blotting were used to detect the expression of EndMT markers, transforming growth factor-β1 (TGF-β1)/Smad pathway-related proteins, hypoxia-inducible factor-1α (HIF-1α), and levels of reactive oxygen species (ROS) in the lung tissues.
Results
XFZYD demonstrated significant efficacy in treating PH, as evidenced by its effects in both the rat models of MCT-induced PH and CTEPH. XFZYD remarkably improved pulmonary vascular remodeling while reducing RVSP and right ventricular hypertrophy. XFZYD has the potential to improve pulmonary vascular remodeling by inhibiting EndMT in the pulmonary vasculature. The underlying mechanism may be closely associated with the inhibition of TGF-β1/Smad and HIF-1α signaling pathways and the reduction of ROS levels in lung tissue by XFZYD.
Conclusion
This study indicates that XFZYD may inhibit EndMT by modulating the ROS/HIF-1α/TGF-β1 signaling pathway, thereby improving pulmonary vascular remodeling. These findings provide a theoretical foundation for the clinical application of XFZYD in PH.
{"title":"Role of Xuefu Zhuyu decoction in improving pulmonary vascular remodeling by inhibiting endothelial-to-mesenchymal transition","authors":"Zuomei Zeng , Xinyue Wang , Hongjuan Wang , Leiyu Tian , Lidan Cui , Jian Guo , Yucai Chen","doi":"10.1016/j.vph.2025.107467","DOIUrl":"10.1016/j.vph.2025.107467","url":null,"abstract":"<div><h3>Background</h3><div>Pulmonary hypertension (PH) is a serious vascular disease characterized by pulmonary vascular remodeling. Xuefu Zhuyu decoction (XFZYD) can potentially improve pulmonary vascular remodeling; however, its mechanism requires further investigation.</div></div><div><h3>Methods</h3><div>Rat models of monocrotaline (MCT)-induced PH and chronic thromboembolic pulmonary hypertension (CTEPH) were employed to investigate whether XFZYD has the potential to improve pulmonary vascular remodeling. After 21 days of XFZYD administration, the right ventricular systolic pressure (RVSP), organ indices, and wall thickness of pulmonary arteries of the rats were measured. Considering the possibility of endothelial-to-mesenchymal transition (EndMT), the specific mechanism of XFZYD in improving pulmonary vascular remodeling was further explored. Immunofluorescence, immunohistochemistry, and western blotting were used to detect the expression of EndMT markers, transforming growth factor-β1 (TGF-β1)/Smad pathway-related proteins, hypoxia-inducible factor-1α (HIF-1α), and levels of reactive oxygen species (ROS) in the lung tissues.</div></div><div><h3>Results</h3><div>XFZYD demonstrated significant efficacy in treating PH, as evidenced by its effects in both the rat models of MCT-induced PH and CTEPH. XFZYD remarkably improved pulmonary vascular remodeling while reducing RVSP and right ventricular hypertrophy. XFZYD has the potential to improve pulmonary vascular remodeling by inhibiting EndMT in the pulmonary vasculature. The underlying mechanism may be closely associated with the inhibition of TGF-β1/Smad and HIF-1α signaling pathways and the reduction of ROS levels in lung tissue by XFZYD.</div></div><div><h3>Conclusion</h3><div>This study indicates that XFZYD may inhibit EndMT by modulating the ROS/HIF-1α/TGF-β1 signaling pathway, thereby improving pulmonary vascular remodeling. These findings provide a theoretical foundation for the clinical application of XFZYD in PH.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"158 ","pages":"Article 107467"},"PeriodicalIF":3.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081262","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 : 2025-01-23DOI: 10.1016/j.vph.2025.107465
Deivyd Vieira Silva Cavalcante , Mrinal Murali Krishna , Meghna Joseph , Ana Clara Felix de Farias Santos , Beatriz Ximenes Mendes , Nicole Asbeg , Wilton Francisco Gomes
Introduction
Aspirin is commonly recommended for individuals who have experienced stroke or myocardial infarction (MI). Indobufen, a cyclooxygenase-1 inhibitor, has been studied as a potential alternative. We conducted a meta-analysis and trial sequential analysis (TSA) to compare indobufen with aspirin in patients requiring antiplatelet therapy.
Methods
We searched PubMed, Scopus, and Cochrane Central for studies that compared indobufen and aspirin antiplatelet therapies. We focused on efficacy outcomes, such as composite vascular events, MI, and ischemic stroke, and safety outcomes, such as major bleeding and any bleeding. Heterogeneity was assessed using I2 statistics, and our analysis followed the PRISMA guidelines.
Results
The review included 5 studies with 11,943 patients (indobufen n = 5952, 49.84 %), three involving post-MI and two involving post-stroke patients. No significant differences were found between the groups in composite vascular events at 90 days (RR 0.84; 95 % CI 0.46–1.53; p = 0.560; I2 = 53 %) and 1-year (RR 1.13; 95 % CI 0.99–1.29; p = 0.08; I2 = 0 %). MI (RR 0.73; 95 % CI 0.43–1.22; p = 0.22; I2 = 0 %), ischemic stroke (RR 1.16; 95 % CI 0.99–1.37; p = 0.06; I2 = 0 %), and cardiovascular death (RR 1.35; 95 % CI 0.80–2.26; p = 0.257; I2 = 0 %) at 1-year also showed no significant differences. Major bleeding at 1 year (RR 0.73; 95 % CI 0.41–1.31; p = 0.297; I2 = 64 %) was comparable, but any bleeding at 1 year showed a significant difference (RR 0.65; 95 % CI 0.43–0.98; p = 0.03; I2 = 87 %) favoring indobufen. Subgroup analysis of RCTs showed marginally significant increased risk regarding ischemic stroke with indobufen (RR 1.18; 95 % CI 1.00–1.39; p = 0.05).
Conclusion
The efficacy and safety of antiplatelet therapy with indobufen were comparable to those of aspirin alone. Therefore, indobufen can be considered as a suitable alternative for patients who are intolerant or hypersensitive to aspirin. Nevertheless, additional trials involving larger populations are required to establish their clinical applicability.
简介：阿司匹林通常被推荐给经历过中风或心肌梗死（MI）的个体。吲哚布芬，一种环氧化酶-1抑制剂，已被研究作为潜在的替代品。我们进行了一项荟萃分析和试验序贯分析（TSA）来比较吲哚布芬和阿司匹林在需要抗血小板治疗的患者中的疗效。方法：我们检索PubMed、Scopus和Cochrane Central以比较吲哚布芬和阿司匹林抗血小板治疗的研究。我们关注疗效结局，如复合血管事件、心肌梗死和缺血性卒中，以及安全性结局，如大出血和任何出血。采用I2统计评估异质性，我们的分析遵循PRISMA指南。结果：本综述纳入5项研究，共11943例患者（吲哚布芬患者 = 5952 49.84 %），3项研究涉及心肌梗死后患者，2项研究涉及脑卒中后患者。90 天时，两组间复合血管事件无显著差异(RR 0.84；95 % ci 0.46-1.53；p = 0.560;I2 = 53 %)和1年(RR 1.13；95 % ci 0.99-1.29；p = 0.08;I2 = 0 %)。Mi (rr 0.73；95 % ci 0.43-1.22；p = 0.22;I2 = 0 %)，缺血性卒中(RR 1.16；95 % ci 0.99-1.37；p = 0.06;I2 = 0 %)和心血管死亡(RR 1.35；95 % ci 0.80-2.26；p = 0.257;I2 = 0 %)在1年后也无显著差异。1 年大出血(RR 0.73；95 % ci 0.41-1.31；p = 0.297;I2 = 64 %)具有可比性，但1 年的任何出血均具有显著性差异(RR 0.65；95 % ci 0.43-0.98；p = 0.03;I2 = 87 %)倾向于吲哚布芬。随机对照试验的亚组分析显示，吲哚布芬治疗缺血性卒中的风险略有增加(RR 1.18；95 % ci 1.00-1.39； = 0.05页)。结论：吲哚布芬联合抗血小板治疗的疗效和安全性与单用阿司匹林相当。因此，对于对阿司匹林不耐受或过敏的患者，吲哚布芬可以被认为是一种合适的替代药物。然而，需要更多的涉及更大人群的试验来确定其临床适用性。
{"title":"Indobufen versus aspirin in patients with indication for antiplatelet therapy: A systematic review and meta-analysis","authors":"Deivyd Vieira Silva Cavalcante , Mrinal Murali Krishna , Meghna Joseph , Ana Clara Felix de Farias Santos , Beatriz Ximenes Mendes , Nicole Asbeg , Wilton Francisco Gomes","doi":"10.1016/j.vph.2025.107465","DOIUrl":"10.1016/j.vph.2025.107465","url":null,"abstract":"<div><h3>Introduction</h3><div>Aspirin is commonly recommended for individuals who have experienced stroke or myocardial infarction (MI). Indobufen, a cyclooxygenase-1 inhibitor, has been studied as a potential alternative. We conducted a meta-analysis and trial sequential analysis (TSA) to compare indobufen with aspirin in patients requiring antiplatelet therapy.</div></div><div><h3>Methods</h3><div>We searched PubMed, Scopus, and Cochrane Central for studies that compared indobufen and aspirin antiplatelet therapies. We focused on efficacy outcomes, such as composite vascular events, MI, and ischemic stroke, and safety outcomes, such as major bleeding and any bleeding. Heterogeneity was assessed using I2 statistics, and our analysis followed the PRISMA guidelines.</div></div><div><h3>Results</h3><div>The review included 5 studies with 11,943 patients (indobufen <em>n</em> = 5952, 49.84 %), three involving post-MI and two involving post-stroke patients. No significant differences were found between the groups in composite vascular events at 90 days (RR 0.84; 95 % CI 0.46–1.53; <em>p</em> = 0.560; I2 = 53 %) and 1-year (RR 1.13; 95 % CI 0.99–1.29; <em>p</em> = 0.08; I2 = 0 %). MI (RR 0.73; 95 % CI 0.43–1.22; <em>p</em> = 0.22; I2 = 0 %), ischemic stroke (RR 1.16; 95 % CI 0.99–1.37; <em>p</em> = 0.06; I2 = 0 %), and cardiovascular death (RR 1.35; 95 % CI 0.80–2.26; <em>p</em> = 0.257; I2 = 0 %) at 1-year also showed no significant differences. Major bleeding at 1 year (RR 0.73; 95 % CI 0.41–1.31; <em>p</em> = 0.297; I2 = 64 %) was comparable, but any bleeding at 1 year showed a significant difference (RR 0.65; 95 % CI 0.43–0.98; <em>p</em> = 0.03; I2 = 87 %) favoring indobufen. Subgroup analysis of RCTs showed marginally significant increased risk regarding ischemic stroke with indobufen (RR 1.18; 95 % CI 1.00–1.39; <em>p</em> = 0.05).</div></div><div><h3>Conclusion</h3><div>The efficacy and safety of antiplatelet therapy with indobufen were comparable to those of aspirin alone. Therefore, indobufen can be considered as a suitable alternative for patients who are intolerant or hypersensitive to aspirin. Nevertheless, additional trials involving larger populations are required to establish their clinical applicability.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"158 ","pages":"Article 107465"},"PeriodicalIF":3.5,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143042498","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 : 2025-01-21DOI: 10.1016/j.vph.2025.107464
N. Bernardi , B.F. Neep , S. Garibaldi , E. Bianconi , J. Aman , A. Llucià-Valldeperas , D. Sirello , G. Zoppoli , F.S. de Man , P. Ameri
Long non-coding RNA (lncRNA) may be involved in dysfunction of pulmonary artery endothelial cells (PAEC) and, thus, in pulmonary arterial hypertension (PAH) pathobiology.
We screened the RNA expression profile of commercial human PAEC (hPAEC) exposed to increased hydrostatic pressure, and found that the lncRNA Down syndrome critical region 9 (DSCR9) was the most regulated transcript (log2FC 1.89 vs control). We confirmed by RT-qPCR that DSCR9 levels were higher in PAEC isolated from patients with idiopathic PAH (iPAH-PAEC), as well as in induced pluripotent stem cell-derived endothelial cells (iPSC-EC) from a patient with BMPR2-mutated PAH, than in relevant controls. Moreover, a re-analysis of the publicly available GSE117261 microarray dataset revealed that DSCR9 was upregulated in the lung tissue of PAH patients. In silico simulation indicated that DSCR9 would be mainly located in the nucleus and could interact with calcium/calmodulin-dependent protein kinase II beta (CAMK2B) and nitric oxide synthase 3 (NOS3, encoding eNOS). CAMK2B levels resulted 3.4-fold higher (p < 0.05) in iPAH-PAEC transfected with a DSCR9-GFP carrying plasmid than with a GFP-only-carrying one. A trend for higher NOS3 expression was also noted. GFP immunostaining was predominantly nuclear and cytoplasmic upon DSCR9-GFP or GFP-only transfection, respectively. CAMK2B and NOS3 mRNA were also higher in iPAH-PAEC than control-PAEC in basal conditions. Instead, variations in total and phosphorylated CAMK2B, eNOS, and NO synthesis were inconsistent. We conclude that DSCR9 is upregulated in PAH-related endothelial cell models and influences CAMK2B and NOS3 expression. Future studies are necessary to determine whether DSCR9 affects NO availability, including in PAH.
{"title":"The lncRNA DSCR9 is modulated in pulmonary arterial hypertension endothelial cell models and is associated with alterations in the nitric oxide pathway","authors":"N. Bernardi , B.F. Neep , S. Garibaldi , E. Bianconi , J. Aman , A. Llucià-Valldeperas , D. Sirello , G. Zoppoli , F.S. de Man , P. Ameri","doi":"10.1016/j.vph.2025.107464","DOIUrl":"10.1016/j.vph.2025.107464","url":null,"abstract":"<div><div>Long non-coding RNA (lncRNA) may be involved in dysfunction of pulmonary artery endothelial cells (PAEC) and, thus, in pulmonary arterial hypertension (PAH) pathobiology.</div><div>We screened the RNA expression profile of commercial human PAEC (hPAEC) exposed to increased hydrostatic pressure, and found that the lncRNA Down syndrome critical region 9 (DSCR9) was the most regulated transcript (log2FC 1.89 vs control). We confirmed by RT-qPCR that DSCR9 levels were higher in PAEC isolated from patients with idiopathic PAH (iPAH-PAEC), as well as in induced pluripotent stem cell-derived endothelial cells (iPSC-EC) from a patient with <em>BMPR2</em>-mutated PAH, than in relevant controls. Moreover, a re-analysis of the publicly available <span><span>GSE117261</span><svg><path></path></svg></span> microarray dataset revealed that DSCR9 was upregulated in the lung tissue of PAH patients. In silico simulation indicated that DSCR9 would be mainly located in the nucleus and could interact with calcium/calmodulin-dependent protein kinase II beta (<em>CAMK2B</em>) and nitric oxide synthase 3 (<em>NOS3</em>, encoding eNOS). <em>CAMK2B</em> levels resulted 3.4-fold higher (<em>p</em> < 0.05) in iPAH-PAEC transfected with a DSCR9-GFP carrying plasmid than with a GFP-only-carrying one. A trend for higher <em>NOS3</em> expression was also noted. GFP immunostaining was predominantly nuclear and cytoplasmic upon DSCR9-GFP or GFP-only transfection, respectively. <em>CAMK2B</em> and <em>NOS3</em> mRNA were also higher in iPAH-PAEC than control-PAEC in basal conditions. Instead, variations in total and phosphorylated CAMK2B, eNOS, and NO synthesis were inconsistent. We conclude that DSCR9 is upregulated in PAH-related endothelial cell models and influences <em>CAMK2B</em> and <em>NOS3</em> expression. Future studies are necessary to determine whether DSCR9 affects NO availability, including in PAH.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"158 ","pages":"Article 107464"},"PeriodicalIF":3.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The appropriate regulation of peripheral vascular tone is crucial for maintaining tissue perfusion. Myoendothelial junctions (MEJs), specialized connections between endothelial cells and vascular smooth muscle cells, are primarily located in peripheral resistance vessels. Therefore, these junctions, with their key membrane proteins, play a pivotal role in the physiological control of relaxation-contraction coupling in resistance arterioles, mainly mediated through endothelium-derived hyperpolarization (EDH). This review aims to illustrate the mechanisms involved in the initiation and propagation of EDH, emphasizing the role of membrane proteins involved in its generation (TRPV4, Piezo1, ASIC1a) and propagation (connexins, Notch). Finally, we discuss relevant studies on pathological events linked to EDH dysfunction and discuss novel approaches, including the effects of natural and dietary bioactive molecules, in modulating EDH-mediated vascular tone.
{"title":"Stay connected: The myoendothelial junction proteins in vascular function and dysfunction","authors":"Giulia Querio , Federica Geddo , Susanna Antoniotti , Saveria Femminò , Maria Pia Gallo , Claudia Penna , Pasquale Pagliaro","doi":"10.1016/j.vph.2025.107463","DOIUrl":"10.1016/j.vph.2025.107463","url":null,"abstract":"<div><div>The appropriate regulation of peripheral vascular tone is crucial for maintaining tissue perfusion. Myoendothelial junctions (MEJs), specialized connections between endothelial cells and vascular smooth muscle cells, are primarily located in peripheral resistance vessels. Therefore, these junctions, with their key membrane proteins, play a pivotal role in the physiological control of relaxation-contraction coupling in resistance arterioles, mainly mediated through endothelium-derived hyperpolarization (EDH). This review aims to illustrate the mechanisms involved in the initiation and propagation of EDH, emphasizing the role of membrane proteins involved in its generation (TRPV4, Piezo1, ASIC1a) and propagation (connexins, Notch). Finally, we discuss relevant studies on pathological events linked to EDH dysfunction and discuss novel approaches, including the effects of natural and dietary bioactive molecules, in modulating EDH-mediated vascular tone.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"158 ","pages":"Article 107463"},"PeriodicalIF":3.5,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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