Pub Date : 2024-11-19DOI: 10.1016/j.vph.2024.107442
Rosalinda Madonna, Filippo Biondi
Sotatercept (brand name WINREVAIR, developed by Merck) is an activin receptor type IIA-Fc (ActRIIA-Fc), working by sequestering free activins. Sotatercept restores the balance between the activin proliferative pathway and the bone morphogenic protein (BMP) antiproliferative pathway in the pulmonary arterial cirulation. Sotatercept recently received approval in the USA and in Europe for the treatment of adults with pulmonary arterial hypertension (PAH) Group 1, on top of background PAH therapy to increase exercise capacity, improve WHO functional class and reduce the risk of clinical worsening events. Nevertheless, several studies are ongoing to investigate the potential adverse reactions of the drug especially at the haematological level. We provide an overview of the clinical and preclinical evidence of the targeting the activing pathway through sotatercept on the treatment of PAH. We also discuss what other possibilities there are for the application of sotatercept in the setting of pulmonary hypertension other than PAH Group 1.
{"title":"Sotatercept: New drug on the horizon of pulmonary hypertension","authors":"Rosalinda Madonna, Filippo Biondi","doi":"10.1016/j.vph.2024.107442","DOIUrl":"10.1016/j.vph.2024.107442","url":null,"abstract":"<div><div>Sotatercept (brand name WINREVAIR, developed by Merck) is an activin receptor type IIA-Fc (ActRIIA-Fc), working by sequestering free activins. Sotatercept restores the balance between the activin proliferative pathway and the bone morphogenic protein (BMP) antiproliferative pathway in the pulmonary arterial cirulation. Sotatercept recently received approval in the USA and in Europe for the treatment of adults with pulmonary arterial hypertension (PAH) Group 1, on top of background PAH therapy to increase exercise capacity, improve WHO functional class and reduce the risk of clinical worsening events. Nevertheless, several studies are ongoing to investigate the potential adverse reactions of the drug especially at the haematological level. We provide an overview of the clinical and preclinical evidence of the targeting the activing pathway through sotatercept on the treatment of PAH. We also discuss what other possibilities there are for the application of sotatercept in the setting of pulmonary hypertension other than PAH Group 1.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"157 ","pages":"Article 107442"},"PeriodicalIF":3.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689032","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 : 2024-11-15DOI: 10.1016/j.vph.2024.107439
Yuan Chen , Yuan Li , Bin Leng , Chengrui Cao , Guifu Wu , Shugao Ye , Lin Deng
Background/objective
The pathogenesis and vascular remodeling during pulmonary hypertension (PH) have been associated with dysregulation of bone morphogenetic protein receptor type 2 (BMPR2) and transforming growth factor-β (TGF-β) signaling in pulmonary artery smooth muscle cells (PASMCs). Evidence suggests that the human-specific lncRNA MYOSLID is a transcriptional target of the TGF-β/SMAD pathway. In this study, we investigated the involvement of MYOSLID in the pathogenesis of PH.
Methods
Lung tissues from PH patients and rat PH models were analyzed to assess clinical relevance. RNA-Seq was performed to identify target genes. Pulmonary artery smooth muscle cells (PASMCs) were used to evaluate function and underlying mechanisms.
Results
RNA-Seq analysis of PASMCs stimulated by TGF-β1 revealed significantly dysregulated lncRNAs. MYOSLID expression was markedly elevated in lung tissues from PH patients and in PASMCs stimulated with TGF-β1. Mechanistically, loss of MYOSLID inhibited the TGF-β pathway by reducing SMAD2/3 PHosphorylation and activated the BMPR2 pathway by enhancing SMAD1/5/9 phosphorylation and increasing ID genes expression in PASMCs. DAZAP2, a target gene of MYOSLID, functions as an inhibitor of BMPR2 signaling. Moreover, DAZAP2 expression was significantly elevated in lung tissues from PH patients and rat PH models. Functionally, knockdown of MYOSLID and DAZAP2 reduced proliferation, migration, and apoptosis resistance in PASMCs.
Conclusion
The activation of the MYOSLID-DAZAP2-BMPR2 axis contributes to pulmonary vascular remodeling, and targeting MYOSLID and DAZAP2 may represent novel therapeutic strategies for PH treatment.
{"title":"LncRNA MYOSLID contributes to PH via targeting BMPR2 signaling in pulmonary artery smooth muscle cell","authors":"Yuan Chen , Yuan Li , Bin Leng , Chengrui Cao , Guifu Wu , Shugao Ye , Lin Deng","doi":"10.1016/j.vph.2024.107439","DOIUrl":"10.1016/j.vph.2024.107439","url":null,"abstract":"<div><h3>Background/objective</h3><div>The pathogenesis and vascular remodeling during pulmonary hypertension (PH) have been associated with dysregulation of bone morphogenetic protein receptor type 2 (BMPR2) and transforming growth factor-β (TGF-β) signaling in pulmonary artery smooth muscle cells (PASMCs). Evidence suggests that the human-specific lncRNA <em>MYOSLID</em> is a transcriptional target of the TGF-β/SMAD pathway. In this study, we investigated the involvement of <em>MYOSLID</em> in the pathogenesis of PH.</div></div><div><h3>Methods</h3><div>Lung tissues from PH patients and rat PH models were analyzed to assess clinical relevance. RNA-Seq was performed to identify target genes. Pulmonary artery smooth muscle cells (PASMCs) were used to evaluate function and underlying mechanisms.</div></div><div><h3>Results</h3><div>RNA-Seq analysis of PASMCs stimulated by TGF-β1 revealed significantly dysregulated lncRNAs. <em>MYOSLID</em> expression was markedly elevated in lung tissues from PH patients and in PASMCs stimulated with TGF-β1. Mechanistically, loss of <em>MYOSLID</em> inhibited the TGF-β pathway by reducing SMAD2/3 PHosphorylation and activated the BMPR2 pathway by enhancing SMAD1/5/9 phosphorylation and increasing ID genes expression in PASMCs. DAZAP2, a target gene of <em>MYOSLID</em>, functions as an inhibitor of BMPR2 signaling. Moreover, DAZAP2 expression was significantly elevated in lung tissues from PH patients and rat PH models. Functionally, knockdown of <em>MYOSLID</em> and DAZAP2 reduced proliferation, migration, and apoptosis resistance in PASMCs.</div></div><div><h3>Conclusion</h3><div>The activation of the <em>MYOSLID</em>-DAZAP2-BMPR2 axis contributes to pulmonary vascular remodeling, and targeting <em>MYOSLID</em> and DAZAP2 may represent novel therapeutic strategies for PH treatment.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"157 ","pages":"Article 107439"},"PeriodicalIF":3.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142645052","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 : 2024-11-12DOI: 10.1016/j.vph.2024.107440
Natalya S. Zinkevich , Kostiantyn Drachuk , David X. Zhang
The Ca2+ ionophore A23187 induces endothelium-dependent and non-receptor-mediated vasodilation in human adipose arterioles (HAAs). The purpose of this study was to determine the mechanism of A23187-induced dilation in HAAs from patients with and without coronary artery disease (CAD). HAAs were freshly isolated from adipose tissues obtained from non-CAD (n = 25) and CAD (n = 14) patients, and vascular reactivity was studied by videomicroscopy. No difference in baseline dose response to A23187 was observed between non-CAD and CAD subjects. However, acute (30 min) incubation with N(omega)-nitro-l-arginine methyl ester (L-NAME), NO synthase inhibitor strongly reduced A23187-induced dilation in non-CAD arterioles, while catalase, an H2O2 scavenger, largely abolished dilation in CAD. Surprising, prolonged (90 min) incubation with L-NAME restored A23187 response in non-CAD subjects, which was subsequently inhibited by catalase. The action of prolonged L-NAME exposure was not reversible after washing with Krebs while the effect of acute L-NAME exposure was largely reversible. To further determine the role of mitochondria-derived ROS in A23187-induced dilation, arterioles were treated with rotenone, an inhibitor of complex I of the electron transport chain. Rotenone abolished A23187 response in CAD patients and in non-CAD arterioles after prolonged L-NAME, but not in non-CAD controls. These data indicate that NO contributes to A23187-induced dilation in HAAs from non-CAD patients and H2O2 contributes to the dilation in CAD patients. Prolonged L-NAME exposure induces a NO-H2O2 switch in the mechanism of dilation in non-CAD subjects. Moreover, the effect of prolonged L-NAME exposure is not readily reversible, while the action of acute L-NAME exposure is reversible.
{"title":"Prolonged L-NAME exposure changes the vasodilator factor from NO to H2O2 in human arterioles in response to A23187","authors":"Natalya S. Zinkevich , Kostiantyn Drachuk , David X. Zhang","doi":"10.1016/j.vph.2024.107440","DOIUrl":"10.1016/j.vph.2024.107440","url":null,"abstract":"<div><div>The Ca<sup>2+</sup> ionophore A23187 induces endothelium-dependent and non-receptor-mediated vasodilation in human adipose arterioles (HAAs). The purpose of this study was to determine the mechanism of A23187-induced dilation in HAAs from patients with and without coronary artery disease (CAD). HAAs were freshly isolated from adipose tissues obtained from non-CAD (<em>n</em> = 25) and CAD (<em>n</em> = 14) patients, and vascular reactivity was studied by videomicroscopy. No difference in baseline dose response to A23187 was observed between non-CAD and CAD subjects. However, acute (30 min) incubation with N(omega)-nitro-l-arginine methyl ester (L-NAME), NO synthase inhibitor strongly reduced A23187-induced dilation in non-CAD arterioles, while catalase, an H<sub>2</sub>O<sub>2</sub> scavenger, largely abolished dilation in CAD. Surprising, prolonged (90 min) incubation with L-NAME restored A23187 response in non-CAD subjects, which was subsequently inhibited by catalase. The action of prolonged L-NAME exposure was not reversible after washing with Krebs while the effect of acute L-NAME exposure was largely reversible. To further determine the role of mitochondria-derived ROS in A23187-induced dilation, arterioles were treated with rotenone, an inhibitor of complex I of the electron transport chain. Rotenone abolished A23187 response in CAD patients and in non-CAD arterioles after prolonged L-NAME, but not in non-CAD controls. These data indicate that NO contributes to A23187-induced dilation in HAAs from non-CAD patients and H<sub>2</sub>O<sub>2</sub> contributes to the dilation in CAD patients. Prolonged L-NAME exposure induces a NO-H<sub>2</sub>O<sub>2</sub> switch in the mechanism of dilation in non-CAD subjects. Moreover, the effect of prolonged L-NAME exposure is not readily reversible, while the action of acute L-NAME exposure is reversible.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"157 ","pages":"Article 107440"},"PeriodicalIF":3.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629271","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 : 2024-10-30DOI: 10.1016/j.vph.2024.107438
Wei Zhang , Lihua Pan , Xiaoliang Wu , Orazio J. Slivano , Kunzhe Dong , Xiaochun Long
IL-8 (aka interleukin 8, CXCL8) is a prototypic cytokine that is highly expressed in the diseased vessel wall and its plasma concentration is strongly associated with cardiovascular events. However, whether IL-8 plays a causative role in cardiovascular diseases remains largely unknown. In this study we used a human IL-8 transgenic (Tg) mouse strain with a bacterial artificial chromosome (BAC) integrated into its genome. This BAC encompasses 166 kb of sequence encompassing the human IL-8 gene locus as well as upstream and downstream DNA sequences containing regulatory elements. This BAC ensured a pathophysiologically regulated, rather than forced constitutive, expression of human IL-8 in the mouse. Tg mice were subjected to complete carotid ligation injury. IL-8 was highly expressed in the ligation-injured carotid artery from 3 days until 2 weeks after injury. As a result, exacerbated neointimal hyperplasia and increased Mac2 and PCNA positive cells were observed in Tg mice. To further confirm its role in promoting neointimal formation, IL-8 was neutralized by anti-IL8 treatment at the ligation site. Consequently, the size of neointima was significantly reduced. Our results provided new insights into the regulation and function of IL-8 in response to vascular insult and during neointima formation.
{"title":"Functional characterization of human IL-8 in vascular stenosis using a novel humanized transgenic mouse model","authors":"Wei Zhang , Lihua Pan , Xiaoliang Wu , Orazio J. Slivano , Kunzhe Dong , Xiaochun Long","doi":"10.1016/j.vph.2024.107438","DOIUrl":"10.1016/j.vph.2024.107438","url":null,"abstract":"<div><div>IL-8 (aka interleukin 8, CXCL8) is a prototypic cytokine that is highly expressed in the diseased vessel wall and its plasma concentration is strongly associated with cardiovascular events. However, whether IL-8 plays a causative role in cardiovascular diseases remains largely unknown. In this study we used a human <em>IL-8</em> transgenic (Tg) mouse strain with a bacterial artificial chromosome (BAC) integrated into its genome. This BAC encompasses 166 kb of sequence encompassing the human <em>IL-8</em> gene locus as well as upstream and downstream DNA sequences containing regulatory elements. This BAC ensured a pathophysiologically regulated, rather than forced constitutive, expression of human <em>IL-8</em> in the mouse. Tg mice were subjected to complete carotid ligation injury. IL-8 was highly expressed in the ligation-injured carotid artery from 3 days until 2 weeks after injury. As a result, exacerbated neointimal hyperplasia and increased Mac2 and PCNA positive cells were observed in Tg mice. To further confirm its role in promoting neointimal formation, IL-8 was neutralized by anti-IL8 treatment at the ligation site. Consequently, the size of neointima was significantly reduced. Our results provided new insights into the regulation and function of IL-8 in response to vascular insult and during neointima formation.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"157 ","pages":"Article 107438"},"PeriodicalIF":3.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565027","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 : 2024-10-20DOI: 10.1016/j.vph.2024.107437
Abdmajid Hwej , Ali Al-Ferjani , Yazeed Alshuweishi , Abdullah Naji , Simon Kennedy , Ian P. Salt
Objective
Perivascular adipose tissue (PVAT) releases anti-contractile bioactive molecules including NO. PVAT anti-contractile activity is attenuated in mice lacking AMPKα1 (AMP-activated protein kinase-α1). As AMPK regulates endothelial NO synthase (eNOS) activity in cultured cells, NO synthesis was examined in PVAT from AMPKα1 knockout (KO) mice.
Methods and results
Endothelium-denuded thoracic or abdominal aortic rings were isolated from wild type (WT) and KO mice. NOS inhibition enhanced vasoconstriction in PVAT-intact thoracic aortic rings from mice of either genotype yet had no effect on abdominal rings as assessed by wire myography. Thoracic aorta PVAT exhibited increased NO production, NOS activity and levels of the brown adipose tissue marker uncoupling protein-1 (UCP1) compared to abdominal PVAT. In KO mice, NO production was significantly reduced in thoracic but not abdominal PVAT. Reduced NO production in KO thoracic PVAT was not due to altered levels or phosphorylation of eNOS but was associated with increased caveolin-1:eNOS association and caveolin-1 Tyr14 phosphorylation. A peptide that disrupts eNOS:caveolin-1 association increased NO synthesis and reduced vasoconstriction of PVAT-intact thoracic but not abdominal aortic rings. KO thoracic PVAT also exhibited reduced UCP1 levels.
Conclusions
Murine thoracic aorta PVAT exhibits higher NO synthesis and UCP1 levels than abdominal aortic PVAT. Downregulation of AMPK suppresses NO synthesis which may contribute to the reduced anticontractile activity and reduced brown adipose tissue phenotype of KO thoracic PVAT. The mechanism underlying the effect of AMPK downregulation likely results from increased caveolin-1:eNOS association associated with caveolin-1 Tyr14 phosphorylation.
目的血管周围脂肪组织（PVAT）释放包括 NO 在内的抗收缩生物活性分子。缺乏 AMPKα1 （AMP-活化蛋白激酶-α1）的小鼠的血管周围脂肪组织抗收缩活性减弱。由于 AMPK 在培养细胞中调节内皮 NO 合酶（eNOS）的活性，因此研究了 AMPKα1 基因敲除（KO）小鼠 PVAT 的 NO 合成情况：从野生型（WT）和 KO 小鼠体内分离出内皮剥离的胸主动脉环或腹主动脉环。抑制 NOS 可增强两种基因型小鼠与 PVAT 接触的胸主动脉环的血管收缩，但对腹主动脉环没有影响，这是由线性肌电图评估的。与腹主动脉皮下脂肪细胞相比，胸主动脉皮下脂肪细胞的 NO 产量、NOS 活性和棕色脂肪组织标志物解偶联蛋白-1（UCP1）水平均有所增加。在 KO 小鼠中，胸主动脉瓣的 NO 生成明显减少，而腹主动脉瓣则没有。KO 小鼠胸腔腹腔静脉血管内氮氧化物生成的减少不是由于 eNOS 水平或磷酸化的改变，而是与洞穴素-1:eNOS 结合和洞穴素-1 Tyr14 磷酸化的增加有关。一种能破坏 eNOS:caveolin-1 关联的多肽能增加 NO 的合成，并减少与 PVAT 接触的胸主动脉环的血管收缩，但不能减少腹主动脉环的血管收缩。KO 的胸主动脉瓣也显示出 UCP1 水平降低：结论：与腹主动脉 PVAT 相比，小鼠胸主动脉 PVAT 的 NO 合成和 UCP1 水平更高。AMPK的下调抑制了NO的合成，这可能是KO胸主动脉瓣抗收缩活性降低和棕色脂肪组织表型减少的原因。AMPK 下调的影响机制可能是与洞穴素-1 Tyr14 磷酸化相关的洞穴素-1:eNOS 关联增加所致。
{"title":"Lack of AMP-activated protein kinase-α1 reduces nitric oxide synthesis in thoracic aorta perivascular adipose tissue","authors":"Abdmajid Hwej , Ali Al-Ferjani , Yazeed Alshuweishi , Abdullah Naji , Simon Kennedy , Ian P. Salt","doi":"10.1016/j.vph.2024.107437","DOIUrl":"10.1016/j.vph.2024.107437","url":null,"abstract":"<div><h3>Objective</h3><div>Perivascular adipose tissue (PVAT) releases anti-contractile bioactive molecules including NO. PVAT anti-contractile activity is attenuated in mice lacking AMPKα1 (AMP-activated protein kinase-α1). As AMPK regulates endothelial NO synthase (eNOS) activity in cultured cells, NO synthesis was examined in PVAT from AMPKα1 knockout (KO) mice.</div></div><div><h3>Methods and results</h3><div>Endothelium-denuded thoracic or abdominal aortic rings were isolated from wild type (WT) and KO mice. NOS inhibition enhanced vasoconstriction in PVAT-intact thoracic aortic rings from mice of either genotype yet had no effect on abdominal rings as assessed by wire myography. Thoracic aorta PVAT exhibited increased NO production, NOS activity and levels of the brown adipose tissue marker uncoupling protein-1 (UCP1) compared to abdominal PVAT. In KO mice, NO production was significantly reduced in thoracic but not abdominal PVAT. Reduced NO production in KO thoracic PVAT was not due to altered levels or phosphorylation of eNOS but was associated with increased caveolin-1:eNOS association and caveolin-1 Tyr14 phosphorylation. A peptide that disrupts eNOS:caveolin-1 association increased NO synthesis and reduced vasoconstriction of PVAT-intact thoracic but not abdominal aortic rings. KO thoracic PVAT also exhibited reduced UCP1 levels.</div></div><div><h3>Conclusions</h3><div>Murine thoracic aorta PVAT exhibits higher NO synthesis and UCP1 levels than abdominal aortic PVAT. Downregulation of AMPK suppresses NO synthesis which may contribute to the reduced anticontractile activity and reduced brown adipose tissue phenotype of KO thoracic PVAT. The mechanism underlying the effect of AMPK downregulation likely results from increased caveolin-1:eNOS association associated with caveolin-1 Tyr14 phosphorylation.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"157 ","pages":"Article 107437"},"PeriodicalIF":3.5,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476165","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 : 2024-10-17DOI: 10.1016/j.vph.2024.107434
Yuyang Miao , Weihan Li , Marie Jeansson , Maarja Andaloussi Mäe , Lars Muhl , Liqun He
Aims
Pericytes in the brain play important roles for microvascular physiology and pathology and are affected in neurological disorders and neurodegenerative diseases. Mouse models are often utilized for pathophysiology studies of the role of pericytes in disease; however, the translatability is unclear as brain pericytes from mouse and human have not been systematically compared. In this study, we investigate the similarities and differences of brain pericyte gene expression between mouse and human. Our analysis provides a comprehensive resource for translational studies of brain pericytes.
Methods
We integrated and compared four mouse and human adult brain pericyte single-cell/nucleus RNA-sequencing datasets derived using two single-cell RNA sequencing platforms: Smart-seq and 10x. Gene expression abundance and specificity were analyzed. Pericyte-specific/enriched genes were assigned by comparison with endothelial cells present in the same datasets, and mouse and human pericyte transcriptomes were subsequently compared to identify species-specific genes.
Results
An overall concordance between pericyte transcriptomes was found in both Smart-seq and 10x data. 206 orthologous genes were consistently differentially expressed between human and mouse from both platforms, 91 genes were specific/up-regulated in human and 115 in mouse. Gene ontology analysis revealed differences in transporter categories in mouse and human brain pericytes. Importantly, several genes implicated in human disease were expressed in human but not in mouse brain pericytes, including SLC6A1, CACNA2D3, and SLC20A2.
Conclusions
This study provides a systematic illustration of the similarities and differences between mouse and human adult brain pericytes.
{"title":"Different gene expression patterns between mouse and human brain pericytes revealed by single-cell/nucleus RNA sequencing","authors":"Yuyang Miao , Weihan Li , Marie Jeansson , Maarja Andaloussi Mäe , Lars Muhl , Liqun He","doi":"10.1016/j.vph.2024.107434","DOIUrl":"10.1016/j.vph.2024.107434","url":null,"abstract":"<div><h3>Aims</h3><div>Pericytes in the brain play important roles for microvascular physiology and pathology and are affected in neurological disorders and neurodegenerative diseases. Mouse models are often utilized for pathophysiology studies of the role of pericytes in disease; however, the translatability is unclear as brain pericytes from mouse and human have not been systematically compared. In this study, we investigate the similarities and differences of brain pericyte gene expression between mouse and human. Our analysis provides a comprehensive resource for translational studies of brain pericytes.</div></div><div><h3>Methods</h3><div>We integrated and compared four mouse and human adult brain pericyte single-cell/nucleus RNA-sequencing datasets derived using two single-cell RNA sequencing platforms: Smart-seq and 10x. Gene expression abundance and specificity were analyzed. Pericyte-specific/enriched genes were assigned by comparison with endothelial cells present in the same datasets, and mouse and human pericyte transcriptomes were subsequently compared to identify species-specific genes.</div></div><div><h3>Results</h3><div>An overall concordance between pericyte transcriptomes was found in both Smart-seq and 10x data. 206 orthologous genes were consistently differentially expressed between human and mouse from both platforms, 91 genes were specific/up-regulated in human and 115 in mouse. Gene ontology analysis revealed differences in transporter categories in mouse and human brain pericytes. Importantly, several genes implicated in human disease were expressed in human but not in mouse brain pericytes, including <em>SLC6A1</em>, <em>CACNA2D3</em>, and <em>SLC20A2</em>.</div></div><div><h3>Conclusions</h3><div>This study provides a systematic illustration of the similarities and differences between mouse and human adult brain pericytes.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"157 ","pages":"Article 107434"},"PeriodicalIF":3.5,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476164","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 : 2024-10-15DOI: 10.1016/j.vph.2024.107436
Tao Fang, Ran Zhang, Yanmei Li
Background
Venous thromboembolism (VTE) is a significant concern in vascular surgery due to its potentially severe consequences. Effective prophylactic measures are essential to minimize the risks associated with VTE. However, considerable controversy remains regarding the optimal strategies for VTE prevention in patients undergoing vascular procedures.
Methods
This review critically analyzes key clinical research, guidelines, and expert opinions to explore the advantages and limitations of various VTE prophylaxis approaches. The pharmacological and mechanical methods are explored, with a focus on balancing the risk of VTE against the potential for bleeding complications, particularly in high-risk patients.
Results
The review addresses controversial issues such as the choice of anticoagulants, dosage, timing, and duration of prophylaxis. The lack of consensus in existing guidelines and the variability in clinical practice regarding VTE prevention in vascular surgery patients is highlighted. The role of patient-specific risk factors, including the use of intraoperative anticoagulation and bleeding risks, is also examined.
Conclusion
This review provides a comprehensive evaluation of VTE prophylaxis strategies in vascular surgery, emphasizing the need for individualized, evidence-based approaches. Clarifying these controversies is crucial for optimizing patient outcomes and minimizing both thrombotic and hemorrhagic complications.
{"title":"Examining the controversies in venous thromboembolism prophylaxis for vascular surgery patients: A critical review","authors":"Tao Fang, Ran Zhang, Yanmei Li","doi":"10.1016/j.vph.2024.107436","DOIUrl":"10.1016/j.vph.2024.107436","url":null,"abstract":"<div><h3>Background</h3><div>Venous thromboembolism (VTE) is a significant concern in vascular surgery due to its potentially severe consequences. Effective prophylactic measures are essential to minimize the risks associated with VTE. However, considerable controversy remains regarding the optimal strategies for VTE prevention in patients undergoing vascular procedures.</div></div><div><h3>Methods</h3><div>This review critically analyzes key clinical research, guidelines, and expert opinions to explore the advantages and limitations of various VTE prophylaxis approaches. The pharmacological and mechanical methods are explored, with a focus on balancing the risk of VTE against the potential for bleeding complications, particularly in high-risk patients.</div></div><div><h3>Results</h3><div>The review addresses controversial issues such as the choice of anticoagulants, dosage, timing, and duration of prophylaxis. The lack of consensus in existing guidelines and the variability in clinical practice regarding VTE prevention in vascular surgery patients is highlighted. The role of patient-specific risk factors, including the use of intraoperative anticoagulation and bleeding risks, is also examined.</div></div><div><h3>Conclusion</h3><div>This review provides a comprehensive evaluation of VTE prophylaxis strategies in vascular surgery, emphasizing the need for individualized, evidence-based approaches. Clarifying these controversies is crucial for optimizing patient outcomes and minimizing both thrombotic and hemorrhagic complications.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"157 ","pages":"Article 107436"},"PeriodicalIF":3.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476208","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 : 2024-10-15DOI: 10.1016/j.vph.2024.107435
Ali Khattib , Manar Shmet , Achinoam Levi , Tony Hayek , Majdi Halabi , Soliman Khatib
Background
Atherosclerotic cardiovascular disease (CVD) remains a leading cause of vascular disease worldwide. Atherosclerosis is characterized by the accumulation of lipids and oxidized lipids on the blood vessel walls. Coronary artery disease (CAD) is the most common display of atherosclerotic CVD.
Objectives
We investigated the effects of the bioactive lipids as lyso-diacylglyceryltrimethylhomoserine (lyso-DGTS (20,5,0)) and its derivative oleoyl-N-trimethyl homoserine amide (oleoyl amide-MHS) on the properties and functionality of HDL and paraoxonase 1 (PON1) activities in the serum of individuals who exhibited arterial plaque as observed by coronary CT angiography (CCTA).
Methods
The study included two independent groups comprising 40 patients who had undergone arterial CCTA scans at Ziv Medical Center for various medical indications. The CAD group included 20 patients with coronary artery plaques with luminal stenosis of more than 50 % in a major coronary vessel. The control group consisted of 20 healthy patients (patients without artery plaques).
Results
Serum samples from CAD patients exhibited lower serum PON1 and cholesterol efflux activities and higher pro-inflammatory than the control group. HDL isolated from CAD patients contains elevated levels of oxidizing lipids (specifically lyso- phosphatidyl ethanolamines and lyso-phosphocholines(compared to the control. However, incubation of the CAD patients' serum with lyso-DGTS and oleoyl amide-MHS restored the antiatherogenic activities of HDL. The lipids increased serum PON1 activities, enhanced apoB-depleted serum cholesterol-efflux activity, and elevated the serum's anti-inflammatory properties.
Conclusions
The results of the present study suggest the potential of the bioactive lipids lyso-DGTS and oleoyl amide-MHS to attenuate atherosclerosis via the improvement of dysfunctional HDL properties and PON1 activities. Further, in-vivo experiments are needed to assess the athero-protective effect of the lipids.
{"title":"Bioactive lipids improve serum HDL and PON1 activities in coronary artery disease patients: Ex-vivo study","authors":"Ali Khattib , Manar Shmet , Achinoam Levi , Tony Hayek , Majdi Halabi , Soliman Khatib","doi":"10.1016/j.vph.2024.107435","DOIUrl":"10.1016/j.vph.2024.107435","url":null,"abstract":"<div><h3>Background</h3><div>Atherosclerotic cardiovascular disease (CVD) remains a leading cause of vascular disease worldwide. Atherosclerosis is characterized by the accumulation of lipids and oxidized lipids on the blood vessel walls. Coronary artery disease (CAD) is the most common display of atherosclerotic CVD.</div></div><div><h3>Objectives</h3><div>We investigated the effects of the bioactive lipids as lyso-diacylglyceryltrimethylhomoserine (lyso-DGTS (20,5,0)) and its derivative oleoyl-<em>N</em>-trimethyl homoserine amide (oleoyl amide-MHS) on the properties and functionality of HDL and paraoxonase 1 (PON1) activities in the serum of individuals who exhibited arterial plaque as observed by coronary CT angiography (CCTA).</div></div><div><h3>Methods</h3><div>The study included two independent groups comprising 40 patients who had undergone arterial CCTA scans at Ziv Medical Center for various medical indications. The CAD group included 20 patients with coronary artery plaques with luminal stenosis of more than 50 % in a major coronary vessel. The control group consisted of 20 healthy patients (patients without artery plaques).</div></div><div><h3>Results</h3><div>Serum samples from CAD patients exhibited lower serum PON1 and cholesterol efflux activities and higher pro-inflammatory than the control group. HDL isolated from CAD patients contains elevated levels of oxidizing lipids (specifically lyso- phosphatidyl ethanolamines and lyso-phosphocholines(compared to the control. However, incubation of the CAD patients' serum with lyso-DGTS and oleoyl amide-MHS restored the antiatherogenic activities of HDL. The lipids increased serum PON1 activities, enhanced apoB-depleted serum cholesterol-efflux activity, and elevated the serum's anti-inflammatory properties.</div></div><div><h3>Conclusions</h3><div>The results of the present study suggest the potential of the bioactive lipids lyso-DGTS and oleoyl amide-MHS to attenuate atherosclerosis via the improvement of dysfunctional HDL properties and PON1 activities. Further, in-vivo experiments are needed to assess the athero-protective effect of the lipids.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"157 ","pages":"Article 107435"},"PeriodicalIF":3.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476166","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 : 2024-09-22DOI: 10.1016/j.vph.2024.107433
Md. Selim Hossain , Archita Das , Ashiq M. Rafiq , Ferenc Deák , Zsolt Bagi , Rashelle Outlaw , Varadarajan Sudhahar , Mai Yamamoto , Jack H. Kaplan , Masuko Ushio-Fukai , Tohru Fukai
Oxidative stress and blood-brain barrier (BBB) disruption due to brain endothelial barrier dysfunction contribute to Alzheimer's Disease (AD), which is characterized by beta-amyloid (Aβ) accumulation in senile plaques. Copper (Cu) is implicated in AD pathology and its levels are tightly controlled by several Cu transport proteins. However, their expression and role in AD, particularly in relation to brain endothelial barrier function remains unclear. In this study, we examined the expression of Cu transport proteins in the brains of AD mouse models as well as their involvement in Aβ42-induced brain endothelial barrier dysfunction. We found that the Cu uptake transporter CTR1 was upregulated, while the Cu exporter ATP7A was downregulated in the hippocampus of AD mouse models and in Aβ42-treated human brain microvascular endothelial cells (hBMECs). In the 5xFAD AD mouse model, Cu levels (assessed by ICP-MS) were elevated in the hippocampus. Moreover, in cultured hBMECs, Aβ42-induced reactive oxygen species (ROS) production, ROS-dependent loss in barrier function (measured by transendothelial electrical resistance), and tyrosine phosphorylation of CDH5 were all inhibited by either a membrane permeable Cu chelator or by knocking down CTR1 expression. These findings suggest that dysregulated expression of Cu transport proteins may lead to intracellular Cu accumulation in the AD brain, and that Aβ42 promotes ROS-dependent brain endothelial barrier dysfunction and CDH5 phosphorylation in a CTR1-Cu-dependent manner. Our study uncovers the critical role of Cu transport proteins in oxidative stress-related loss of BBB integrity in AD.
{"title":"Altered copper transport in oxidative stress-dependent brain endothelial barrier dysfunction associated with Alzheimer's disease","authors":"Md. Selim Hossain , Archita Das , Ashiq M. Rafiq , Ferenc Deák , Zsolt Bagi , Rashelle Outlaw , Varadarajan Sudhahar , Mai Yamamoto , Jack H. Kaplan , Masuko Ushio-Fukai , Tohru Fukai","doi":"10.1016/j.vph.2024.107433","DOIUrl":"10.1016/j.vph.2024.107433","url":null,"abstract":"<div><div>Oxidative stress and blood-brain barrier (BBB) disruption due to brain endothelial barrier dysfunction contribute to Alzheimer's Disease (AD), which is characterized by beta-amyloid (Aβ) accumulation in senile plaques. Copper (Cu) is implicated in AD pathology and its levels are tightly controlled by several Cu transport proteins. However, their expression and role in AD, particularly in relation to brain endothelial barrier function remains unclear. In this study, we examined the expression of Cu transport proteins in the brains of AD mouse models as well as their involvement in Aβ42-induced brain endothelial barrier dysfunction. We found that the Cu uptake transporter CTR1 was upregulated, while the Cu exporter ATP7A was downregulated in the hippocampus of AD mouse models and in Aβ42-treated human brain microvascular endothelial cells (hBMECs). In the 5xFAD AD mouse model, Cu levels (assessed by ICP-MS) were elevated in the hippocampus. Moreover, in cultured hBMECs, Aβ42-induced reactive oxygen species (ROS) production, ROS-dependent loss in barrier function (measured by transendothelial electrical resistance), and tyrosine phosphorylation of CDH5 were all inhibited by either a membrane permeable Cu chelator or by knocking down CTR1 expression. These findings suggest that dysregulated expression of Cu transport proteins may lead to intracellular Cu accumulation in the AD brain, and that Aβ42 promotes ROS-dependent brain endothelial barrier dysfunction and CDH5 phosphorylation in a CTR1-Cu-dependent manner. Our study uncovers the critical role of Cu transport proteins in oxidative stress-related loss of BBB integrity in AD.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"157 ","pages":"Article 107433"},"PeriodicalIF":3.5,"publicationDate":"2024-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142322361","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 : 2024-09-10DOI: 10.1016/j.vph.2024.107432
Giovanna Manzi , Raymond L. Benza , Paola Argiento , Gavino Casu , Marco Corda , Michele Correale , Michele D'Alto , Giuseppe Galgano , Andrea Garascia , Stefano Ghio , Mardi Gomberg-Maitland , Massimiliano Mulé , Giuseppe Paciocco , Silvia Papa , Daniele Prati , Ioana R. Preston , Claudia Raineri , Emanuele Romeo , Laura Scelsi , Davide Stolfo , Carmine Dario Vizza
Despite the innovations introduced in the 2022 European Society of Cardiology/European Respiratory Society Guidelines on Pulmonary Hypertension, risk discrimination and management of pulmonary arterial hypertension (PAH) patients at intermediate risk still represents a grey zone. Additionally, clinical evidence derived from currently available studies is limited. This expert panel survey intends to aid physicians in choosing the best therapeutic strategy for patients at intermediate risk despite ongoing oral therapy. An expert panel of 24 physicians, specialized in cardiology and/or pulmonology with expertise in handling all drugs available for the treatment of PAH participated in the survey. All potential therapeutic options for patients at intermediate risk were explored and analyzed to produce graded consensus statements regarding: the switch from endothelin receptor antagonist (ERA) or phosphodiesterase 5 inhibitor (PDE5i) to another oral drug of the same class; the addition of a drug targeting the prostacyclin pathway administered by different routes; the switch from PDE5i to riociguat.
{"title":"Gaps in evidence in the treatment of prevalent patients with pulmonary arterial hypertension at intermediate risk: An expert consensus","authors":"Giovanna Manzi , Raymond L. Benza , Paola Argiento , Gavino Casu , Marco Corda , Michele Correale , Michele D'Alto , Giuseppe Galgano , Andrea Garascia , Stefano Ghio , Mardi Gomberg-Maitland , Massimiliano Mulé , Giuseppe Paciocco , Silvia Papa , Daniele Prati , Ioana R. Preston , Claudia Raineri , Emanuele Romeo , Laura Scelsi , Davide Stolfo , Carmine Dario Vizza","doi":"10.1016/j.vph.2024.107432","DOIUrl":"10.1016/j.vph.2024.107432","url":null,"abstract":"<div><p>Despite the innovations introduced in the 2022 European Society of Cardiology/European Respiratory Society Guidelines on Pulmonary Hypertension, risk discrimination and management of pulmonary arterial hypertension (PAH) patients at intermediate risk still represents a grey zone. Additionally, clinical evidence derived from currently available studies is limited. This expert panel survey intends to aid physicians in choosing the best therapeutic strategy for patients at intermediate risk despite ongoing oral therapy. An expert panel of 24 physicians, specialized in cardiology and/or pulmonology with expertise in handling all drugs available for the treatment of PAH participated in the survey. All potential therapeutic options for patients at intermediate risk were explored and analyzed to produce graded consensus statements regarding: the switch from endothelin receptor antagonist (ERA) or phosphodiesterase 5 inhibitor (PDE5i) to another oral drug of the same class; the addition of a drug targeting the prostacyclin pathway administered by different routes; the switch from PDE5i to riociguat.</p></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"157 ","pages":"Article 107432"},"PeriodicalIF":3.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142241183","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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