Pub Date : 2025-12-03DOI: 10.1016/j.vph.2025.107570
Louise Frausto , Matthew L. Scott , A. Wayne Orr , Arif Yurdagul Jr
Vascular smooth muscle cells (vSMCs) play a central role in atherosclerotic plaque development and stability through their remarkable phenotypic plasticity. In healthy vessels, contractile vSMCs maintain vascular tone and structural integrity. During atherogenesis, lipid accumulation, inflammatory cues, growth factors, and mechanical stress drive vSMC dedifferentiation, proliferation, and migration into the intima. This transition involves downregulation of contractile genes regulated by SRF-myocardin and induction of synthetic, proliferative, inflammatory, macrophage-like, or osteogenic phenotypes, mediated in part by KLF4, PDGF, TNFα, oxidized lipids, and TGFβ signaling. Mechanotransduction through integrins and ECM remodeling reinforces these phenotypic shifts, with pathological stretch, matrix stiffening, and provisional matrix deposition promoting plasticity via RhoA/ROCK, FAK, and YAP/TAZ pathways. Clonal expansion of select medial vSMCs further shapes plaque architecture, while non-coding RNAs fine-tune phenotypic modulation at the post-transcriptional level. Collectively, these processes contribute to fibrous cap thinning, impaired efferocytosis, necrotic core expansion, and vascular calcification – features of vulnerable plaques. Here, we review the molecular, mechanical, and post-transcriptional mechanisms driving vSMC phenotypic modulation in atherosclerosis, highlighting their contributions to plaque progression and instability, and discussing emerging areas that may inform future therapeutic strategies.
{"title":"Smooth muscle cell phenotypic modulation during atherosclerosis","authors":"Louise Frausto , Matthew L. Scott , A. Wayne Orr , Arif Yurdagul Jr","doi":"10.1016/j.vph.2025.107570","DOIUrl":"10.1016/j.vph.2025.107570","url":null,"abstract":"<div><div>Vascular smooth muscle cells (vSMCs) play a central role in atherosclerotic plaque development and stability through their remarkable phenotypic plasticity. In healthy vessels, contractile vSMCs maintain vascular tone and structural integrity. During atherogenesis, lipid accumulation, inflammatory cues, growth factors, and mechanical stress drive vSMC dedifferentiation, proliferation, and migration into the intima. This transition involves downregulation of contractile genes regulated by SRF-myocardin and induction of synthetic, proliferative, inflammatory, macrophage-like, or osteogenic phenotypes, mediated in part by KLF4, PDGF, TNFα, oxidized lipids, and TGFβ signaling. Mechanotransduction through integrins and ECM remodeling reinforces these phenotypic shifts, with pathological stretch, matrix stiffening, and provisional matrix deposition promoting plasticity via RhoA/ROCK, FAK, and YAP/TAZ pathways. Clonal expansion of select medial vSMCs further shapes plaque architecture, while non-coding RNAs fine-tune phenotypic modulation at the post-transcriptional level. Collectively, these processes contribute to fibrous cap thinning, impaired efferocytosis, necrotic core expansion, and vascular calcification – features of vulnerable plaques. Here, we review the molecular, mechanical, and post-transcriptional mechanisms driving vSMC phenotypic modulation in atherosclerosis, highlighting their contributions to plaque progression and instability, and discussing emerging areas that may inform future therapeutic strategies.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"162 ","pages":"Article 107570"},"PeriodicalIF":3.5,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145688374","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 : 2025-12-02DOI: 10.1016/j.vph.2025.107562
Edoardo Roberto Ginghina , Giuseppe Biondi-Zoccai , Andrea Vitali , Lucia Fatima Di Napoli , Giacomo Frati
Heart failure (HF) remains a major global health challenge, marked by clinical heterogeneity and high morbidity, especially among elderly and comorbid patients. While β-blockers are central to HF management, conventional agents often present tolerability limitations, particularly in populations with preserved ejection fraction (HFpEF) or impaired vascular function. Nebivolol, a third-generation β-blocker characterized by high β₁-selectivity and nitric oxide-mediated vasodilation, offers a differentiated therapeutic profile with potential advantages in these subgroups.
This review synthesizes current evidence on nebivolol's pharmacologic mechanisms, including its dual action on adrenergic and endothelial pathways, as well as its antioxidant and anti-inflammatory effects. Preclinical studies and translational biomarkers support their vascular and myocardial protective actions, while the SENIORS trial provides pivotal clinical evidence demonstrating efficacy across ejection fraction spectrums in elderly HF patients. Comparative data further reinforces its tolerability and favorable metabolic impact relative to traditional β-blockers.
Nebivolol's role is also explored in guideline contexts and its potential utility in special populations such as those with renal impairment, diabetes, or cancer therapy–related cardiac dysfunction. Looking ahead, advances in pharmacogenomics, digital phenotyping, and adaptive trial designs may help personalize nebivolol therapy. This review underscores nebivolol's emerging position in the evolving landscape of HF treatment.
{"title":"Nebivolol in the therapeutic landscape of heart failure: Mechanisms and clinical outcomes","authors":"Edoardo Roberto Ginghina , Giuseppe Biondi-Zoccai , Andrea Vitali , Lucia Fatima Di Napoli , Giacomo Frati","doi":"10.1016/j.vph.2025.107562","DOIUrl":"10.1016/j.vph.2025.107562","url":null,"abstract":"<div><div>Heart failure (HF) remains a major global health challenge, marked by clinical heterogeneity and high morbidity, especially among elderly and comorbid patients. While β-blockers are central to HF management, conventional agents often present tolerability limitations, particularly in populations with preserved ejection fraction (HFpEF) or impaired vascular function. Nebivolol, a third-generation β-blocker characterized by high β₁-selectivity and nitric oxide-mediated vasodilation, offers a differentiated therapeutic profile with potential advantages in these subgroups.</div><div>This review synthesizes current evidence on nebivolol's pharmacologic mechanisms, including its dual action on adrenergic and endothelial pathways, as well as its antioxidant and anti-inflammatory effects. Preclinical studies and translational biomarkers support their vascular and myocardial protective actions, while the SENIORS trial provides pivotal clinical evidence demonstrating efficacy across ejection fraction spectrums in elderly HF patients. Comparative data further reinforces its tolerability and favorable metabolic impact relative to traditional β-blockers.</div><div>Nebivolol's role is also explored in guideline contexts and its potential utility in special populations such as those with renal impairment, diabetes, or cancer therapy–related cardiac dysfunction. Looking ahead, advances in pharmacogenomics, digital phenotyping, and adaptive trial designs may help personalize nebivolol therapy. This review underscores nebivolol's emerging position in the evolving landscape of HF treatment.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"162 ","pages":"Article 107562"},"PeriodicalIF":3.5,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145665316","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}
Obesity is a chronic, relapsing metabolic disorder driven by complex genetic and environmental factors, leading to an imbalance in energy regulation. Despite the presence of GLP-1 receptor agonists with induced mild weight loss, there are significant unmet clinical needs with poor efficacy and tolerability problems. Amylin, a neuroendocrine hormone co-released with insulin, controls hunger, gastric motility, glucagon secretion, and energy metabolism via divergent amylin receptor (AMYR) subtypes (1–3), namely the calcitonin receptor (CTR) and the receptor activity-modifying proteins (RAMPs). Novel insight into the molecular make-up of AMYRs and central signaling reinforces its key function in modulating homeostatic and hedonic feeding mechanisms. The article is a review of the emerging preclinical and clinical data regarding the application of peptide-based amylin receptor agonists (AMYRAs), including pramlintide and cagrilintide, KBP-series DACRAs, and investigational drugs, including ZP8396 and amycretin. The agents show enhanced pharmacokinetics, synergy with GLP-1 receptor agonist, and favorable impact on weight regulation and metabolic plasticity. Genetic CALCR and RAMP mutations, new delivery approaches, and dual therapy by digital health technologies and bariatric surgery are also discussed in this review. Of particular interest, amylin-derived medications can have advantages over weight loss but definite disease-modifying action remains to be determined. Taken together, AMYRAs represent a potential category of therapeutics with promising disease-modifying effects that goes beyond weight loss, providing fresh perspectives for precision obesity management by 2030.
{"title":"Amylin receptors as therapeutic targets in obesity: Emerging peptide-based strategies","authors":"Mokhtar Rejili , Md Sadique Hussain , Yumna Khan , Faouzi Haouala , Subbulakshmi Ganesan , Samir Sahoo , Amrita Pal , Vimal Arora","doi":"10.1016/j.vph.2025.107563","DOIUrl":"10.1016/j.vph.2025.107563","url":null,"abstract":"<div><div>Obesity is a chronic, relapsing metabolic disorder driven by complex genetic and environmental factors, leading to an imbalance in energy regulation. Despite the presence of GLP-1 receptor agonists with induced mild weight loss, there are significant unmet clinical needs with poor efficacy and tolerability problems. Amylin, a neuroendocrine hormone co-released with insulin, controls hunger, gastric motility, glucagon secretion, and energy metabolism via divergent amylin receptor (AMYR) subtypes (1–3), namely the calcitonin receptor (CTR) and the receptor activity-modifying proteins (RAMPs). Novel insight into the molecular make-up of AMYRs and central signaling reinforces its key function in modulating homeostatic and hedonic feeding mechanisms. The article is a review of the emerging preclinical and clinical data regarding the application of peptide-based amylin receptor agonists (AMYRAs), including pramlintide and cagrilintide, KBP-series DACRAs, and investigational drugs, including ZP8396 and amycretin. The agents show enhanced pharmacokinetics, synergy with GLP-1 receptor agonist, and favorable impact on weight regulation and metabolic plasticity. Genetic CALCR and RAMP mutations, new delivery approaches, and dual therapy by digital health technologies and bariatric surgery are also discussed in this review. Of particular interest, amylin-derived medications can have advantages over weight loss but definite disease-modifying action remains to be determined. Taken together, AMYRAs represent a potential category of therapeutics with promising disease-modifying effects that goes beyond weight loss, providing fresh perspectives for precision obesity management by 2030.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"162 ","pages":"Article 107563"},"PeriodicalIF":3.5,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145679105","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 : 2025-11-29DOI: 10.1016/j.vph.2025.107561
Silvia Papa , Michele D'Alto , Laura Scelsi , Mauro Acquaro , Francesca Adamo , Carlo Albera , Pietro Ameri , Paola Argiento , Roberto Badagliacca , Renato Carignola , Gavino Casu , Marco Confalonieri , Marco Corda , Michele Correale , Chiara Cresci , Francesca D'Alessandro , Carlo D'Agostino , Raffaele De Caterina , Lucrezia De Michele , Elisabetta De Tommasi , Stefano Ghio
Background
Our understanding of pulmonary arterial hypertension (PAH) pathophysiology and treatment has significantly improved over time. Within this scenario we established the Italian Network on Pulmonary Arterial Hypertension (IPHNET), promoting a national prospective registry (ASPYRE-1) to collect data on contemporary PAH patients and to define the baseline features of Italian PAH patients.
The aim of our study is to show the clinical characteristics of the Italian PAH patients. This cohort of patients will be followed in the ongoing registry to provide important insight into risk stratification and mode of death.
Methods
Twenty-six PAH centers were initially involved in the registry. Data were collected on anthropometric measurements, medical history, vital signs, clinical signs of heart failure, physical examination, laboratory tests (hematology and clinical chemistry), WHO functional class evaluation, non-encouraged 6-min walk test (6MWT), echocardiographic imaging and right heart catheterization (RHC) of outpatients and inpatients with PAH (Group 1) diagnosis. All the centers shared a common database for the prospective follow-up of the patients.
Results
between May 2014 and January 2023, a total of 500 prevalent patients with clinical diagnosis of PAH were enrolled: idiopathic (40.6 %), heritable (4.6 %), associated with drug or toxins (0.8 %), associated with connective tissue disease (26.4 %), associated with HIV infection (4.8 %), associated with portal hypertension (3.8 %), associated with congenital heart disease (16,4 %), with features of venous/capillary involvement (1.4 %), others (1.2 %) were enrolled. According to the ERS/ESC guidelines risk assessment, 207 (41.4 %) patients were at low risk, and 286 (57.2 %) were at intermediate risk. According to the REVEAL 2.0 score, 352 (70.4 %) patients were at low risk (score < 7), 93 (18.6 %) were at intermediate risk (score 7–8), and 55 (11 %) were at high risk (score > 8),
Of the total patient population, 177 (35.4 %) received monotherapy, 222 (44.4 %) received double combination therapy, and 101 (20.2 %) received triple combination therapy.
Conclusion
Built as a collaborative registry of centers treating PAH patients in Italy, it holds significant promise for addressing several critical needs within the field, including patients' clinical trajectory and risk stratification.
{"title":"ASPYRE-1 study: An Italian multicenter prospective study on pulmonary hypertension modality of death and validation of REVEAL risk score","authors":"Silvia Papa , Michele D'Alto , Laura Scelsi , Mauro Acquaro , Francesca Adamo , Carlo Albera , Pietro Ameri , Paola Argiento , Roberto Badagliacca , Renato Carignola , Gavino Casu , Marco Confalonieri , Marco Corda , Michele Correale , Chiara Cresci , Francesca D'Alessandro , Carlo D'Agostino , Raffaele De Caterina , Lucrezia De Michele , Elisabetta De Tommasi , Stefano Ghio","doi":"10.1016/j.vph.2025.107561","DOIUrl":"10.1016/j.vph.2025.107561","url":null,"abstract":"<div><h3>Background</h3><div>Our understanding of pulmonary arterial hypertension (PAH) pathophysiology and treatment has significantly improved over time. Within this scenario we established the Italian Network on Pulmonary Arterial Hypertension (IPHNET), promoting a national prospective registry (ASPYRE-1) to collect data on contemporary PAH patients and to define the baseline features of Italian PAH patients.</div><div>The aim of our study is to show the clinical characteristics of the Italian PAH patients. This cohort of patients will be followed in the ongoing registry to provide important insight into risk stratification and mode of death.</div></div><div><h3>Methods</h3><div>Twenty-six PAH centers were initially involved in the registry. Data were collected on anthropometric measurements, medical history, vital signs, clinical signs of heart failure, physical examination, laboratory tests (hematology and clinical chemistry), WHO functional class evaluation, non-encouraged 6-min walk test (6MWT), echocardiographic imaging and right heart catheterization (RHC) of outpatients and inpatients with PAH (Group 1) diagnosis. All the centers shared a common database for the prospective follow-up of the patients.</div></div><div><h3>Results</h3><div>between May 2014 and January 2023, a total of 500 prevalent patients with clinical diagnosis of PAH were enrolled: idiopathic (40.6 %), heritable (4.6 %), associated with drug or toxins (0.8 %), associated with connective tissue disease (26.4 %), associated with HIV infection (4.8 %), associated with portal hypertension (3.8 %), associated with congenital heart disease (16,4 %), with features of venous/capillary involvement (1.4 %), others (1.2 %) were enrolled. According to the ERS/ESC guidelines risk assessment, 207 (41.4 %) patients were at low risk, and 286 (57.2 %) were at intermediate risk. According to the REVEAL 2.0 score, 352 (70.4 %) patients were at low risk (score < 7), 93 (18.6 %) were at intermediate risk (score 7–8), and 55 (11 %) were at high risk (score > 8),</div><div>Of the total patient population, 177 (35.4 %) received monotherapy, 222 (44.4 %) received double combination therapy, and 101 (20.2 %) received triple combination therapy.</div></div><div><h3>Conclusion</h3><div>Built as a collaborative registry of centers treating PAH patients in Italy, it holds significant promise for addressing several critical needs within the field, including patients' clinical trajectory and risk stratification.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"162 ","pages":"Article 107561"},"PeriodicalIF":3.5,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145655841","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 : 2025-11-08DOI: 10.1016/j.vph.2025.107559
Basant Elsaid , Irakli Kopaliani , Birgit Zatschler , Ansam Seif , Stephan Speier , Andreas Deussen
Estrogen's role in cardiovascular health remains inconsistent. This study investigates the non-genomic vasorelaxant effects of 17β-estradiol, focusing on sex-specific differences in estrogen receptor (ER) subtypes (ERα, ERβ and GPER), endothelial function, and phosphoinositide 3-kinase (PI3K) pathway.
Ex vivo experiments using thoracic aorta from male and female wild-type mice assessed ER expression by immunofluorescence and vascular reactivity by wire myography. Vasorelaxant responses to 17β-estradiol and ER-selective agonists (PPT, DPN and G1) were examined. Some experiments were conducted in the presence of pharmacological inhibitors targeting endothelium-dependent relaxation pathways (L-NMMA, indomethacin and apamin/charybdotoxin), as well as PI3K inhibitor LY294002. In vitro, primary mouse aortic smooth muscle cells (MASMCs) were used to assess acute effects of 17β-estradiol on myosin light chain (MLC) and Akt phosphorylation via western blot.
ER subtypes were observed in the endothelial and medial regions of the vessel wall. 17β-estradiol induced similar vasorelaxation in both sexes, with subtle differences in endothelial ERβ and GPER. Nitric oxide synthase (NOS) inhibition attenuated vasorelaxation, with modest sex-specific differences in ERβ. PI3K inhibition augmented vasorelaxation regardless of endothelial integrity, exhibiting slight sex variability across ER subtypes. MASMCs showed a near-significant increase in MLC phosphorylation with 17β-estradiol, without significant Akt activation.
In conclusion, estrogen induces NOS dependent vasorelaxation in mouse aorta, with no sex differences. However, subtle sex differences among ER subtypes were observed in the contribution of endothelium, NOS and PI3K pathways. The PI3K pathway may attenuate vasorelaxation by promoting MLC phosphorylation in vascular smooth muscle, and its inhibition unmasks the vasorelaxant potential of 17β-estradiol.
雌激素在心血管健康中的作用仍然不一致。本研究探讨了17β-雌二醇的非基因组性血管松弛作用，重点研究了雌激素受体（ER）亚型（ERα、ERβ、GPER）、内皮功能和磷酸肌苷激酶（PI3K）信号通路的性别差异。利用雄性和雌性野生型小鼠胸主动脉进行离体实验，免疫荧光法检测ER表达，钢丝肌图检测血管反应性。观察17β-雌二醇和er选择性激动剂（PPT、DPN、G1）的血管松弛反应。一些实验是在针对内皮依赖性松弛途径的药物抑制剂- l - nmma、吲哚美辛和apamin/charybdotoxin-以及PI3K途径抑制剂LY294002 hydrochloride存在的情况下进行的。在体外，采用小鼠主动脉平滑肌细胞（MASMCs），通过western blot评估17β-雌二醇对肌球蛋白轻链（MLC）和Akt磷酸化的短期剂量依赖性影响。内皮和血管平滑肌层均检测到ER亚型。17β-雌二醇诱导血管松弛，性别差异不显著。一氧化氮合酶（NOS）的抑制降低了血管舒张，内质网亚型之间存在适度的性别特异性差异。PI3K抑制增强了这种血管松弛，无论内皮完整性如何，在不同的ER亚型中表现出轻微的性别特异性差异。17β-雌二醇对MASMCs的MLC磷酸化有增加的趋势，但没有明显的Akt激活。综上所述，雌激素诱导小鼠主动脉NOS依赖性血管松弛，性别差异不显著。然而，内质网亚型对NOS和PI3K通路的贡献存在细微的性别差异。PI3K通路可能通过促进血管平滑肌中MLC的磷酸化而减弱血管松弛作用，其抑制作用揭示了雌激素的血管松弛潜能。
{"title":"Endothelial and non-endothelial actions of estrogen receptor subtypes in male and female mouse Aorta","authors":"Basant Elsaid , Irakli Kopaliani , Birgit Zatschler , Ansam Seif , Stephan Speier , Andreas Deussen","doi":"10.1016/j.vph.2025.107559","DOIUrl":"10.1016/j.vph.2025.107559","url":null,"abstract":"<div><div>Estrogen's role in cardiovascular health remains inconsistent. This study investigates the non-genomic vasorelaxant effects of 17β-estradiol, focusing on sex-specific differences in estrogen receptor (ER) subtypes (ERα, ERβ and GPER), endothelial function, and phosphoinositide 3-kinase (PI3K) pathway.</div><div>Ex vivo experiments using thoracic aorta from male and female wild-type mice assessed ER expression by immunofluorescence and vascular reactivity by wire myography. Vasorelaxant responses to 17β-estradiol and ER-selective agonists (PPT, DPN and G1) were examined. Some experiments were conducted in the presence of pharmacological inhibitors targeting endothelium-dependent relaxation pathways (L-NMMA, indomethacin and apamin/charybdotoxin), as well as PI3K inhibitor LY294002. In vitro, primary mouse aortic smooth muscle cells (MASMCs) were used to assess acute effects of 17β-estradiol on myosin light chain (MLC) and Akt phosphorylation via western blot.</div><div>ER subtypes were observed in the endothelial and medial regions of the vessel wall. 17β-estradiol induced similar vasorelaxation in both sexes, with subtle differences in endothelial ERβ and GPER. Nitric oxide synthase (NOS) inhibition attenuated vasorelaxation, with modest sex-specific differences in ERβ. PI3K inhibition augmented vasorelaxation regardless of endothelial integrity, exhibiting slight sex variability across ER subtypes. MASMCs showed a near-significant increase in MLC phosphorylation with 17β-estradiol, without significant Akt activation.</div><div>In conclusion, estrogen induces NOS dependent vasorelaxation in mouse aorta, with no sex differences. However, subtle sex differences among ER subtypes were observed in the contribution of endothelium, NOS and PI3K pathways. The PI3K pathway may attenuate vasorelaxation by promoting MLC phosphorylation in vascular smooth muscle, and its inhibition unmasks the vasorelaxant potential of 17β-estradiol.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"161 ","pages":"Article 107559"},"PeriodicalIF":3.5,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145490176","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 : 2025-11-07DOI: 10.1016/j.vph.2025.107558
Yan-Ni Hu , Mi Wang , Zheng Zhang
Aortic aneurysm and dissection (AAD) is a critical aortic disease with high mortality. AAD is characterized by aortic inflammation, which manifests as the infiltration of immune cells and the accumulation of inflammatory mediators. Studies have predominantly focused on the innate immune response, while the role of adaptive immunity in AAD remains poorly characterized. Given the substantial knowledge gaps, this review systematically outlines the development of the adaptive immune response in AAD - from antigen initiation and lymphocyte activation to its ultimate effects on the aortic wall. Additionally, promising immunomodulatory therapies, such as biologic agents and cell-based treatments, are discussed. This review underscores the need for a deeper understanding of the contributions of adaptive immunity to AAD, as elucidating these mechanisms could inform precise therapeutic strategies for this serious condition.
{"title":"Emerging role of the adaptive immunity in aortic aneurysm and dissection","authors":"Yan-Ni Hu , Mi Wang , Zheng Zhang","doi":"10.1016/j.vph.2025.107558","DOIUrl":"10.1016/j.vph.2025.107558","url":null,"abstract":"<div><div>Aortic aneurysm and dissection (AAD) is a critical aortic disease with high mortality. AAD is characterized by aortic inflammation, which manifests as the infiltration of immune cells and the accumulation of inflammatory mediators. Studies have predominantly focused on the innate immune response, while the role of adaptive immunity in AAD remains poorly characterized. Given the substantial knowledge gaps, this review systematically outlines the development of the adaptive immune response in AAD - from antigen initiation and lymphocyte activation to its ultimate effects on the aortic wall. Additionally, promising immunomodulatory therapies, such as biologic agents and cell-based treatments, are discussed. This review underscores the need for a deeper understanding of the contributions of adaptive immunity to AAD, as elucidating these mechanisms could inform precise therapeutic strategies for this serious condition.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"161 ","pages":"Article 107558"},"PeriodicalIF":3.5,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145483046","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 : 2025-11-02DOI: 10.1016/j.vph.2025.107557
Fabiola Mestriner , Vinicius Flora Dugaich , Pedro Brüch Dantas , Henrique Z. Kovacs , Marcela M. Blascke de Mello , Carina A. Pedersoli , Rafael Menezes da Costa , Maria Cecilia Jordani , Leandra N.Z. Ramalho , Michele M. de Castro , Júlio A. Silva-Neto , Rita C.A. Tostes Passaglia , Mauricio Serra Ribeiro , Christiane Becari
Abdominal aortic aneurysm (AAA) involves the remodeling of the aortic wall extracellular matrix (ECM), compromising biomechanical support and increasing the risk of aortic dissection and rupture. Activation of the renin-angiotensin system (RAS), particularly the synthesis of angiotensin II (Ang II), plays a fundamental role in AAA initiation and progression. Elastase-2 (ELA-2), a chymotrypsin-like serine protease, contributes to tissue Ang II generation and may be a key player in AAA pathophysiology. This study investigated the effects of ELA-2 deletion in a murine model of angiotensin II-induced AAA, with particular focus on determining whether ELA-2 modulates vascular contractility and aortic relaxation in wild-type mice and whether these effects are absent in ELA-2 knockout mice. We additionally examined the cellular alterations within the aortic wall that contribute to increased reactive oxygen species generation during AAA development. Male C57BL/6 J (wild-type, WT) and ELA-2 knockout (ELA-2KO) mice, aged 10 to 15 weeks, were infused with Ang II (1500 ng/kg/min) for 28 days to induce AAA formation. Wild-type (WT) mice developed AAA, as evidenced by aortic dilation, structural remodeling, fibrosis, and inflammation. In contrast, ELA-2KO mice showed markedly reduced pathological changes following Ang II-induced AAA. Histological and biochemical analyses of the abdominal aorta revealed enhanced gelatinolytic activity, macrophage infiltration, and oxidative stress in WT mice, all of which were significantly attenuated in ELA-2KO mice. Furthermore, transcriptional profiling demonstrated that ELA-2 deletion maintained a contractile VSMC phenotype, suggesting a protective effect against maladaptive vascular remodeling. In summary, ELA-2 deficiency prevented Ang II- induced AAA formation and pathological vascular remodeling, highlighting its potential as a therapeutic target to mitigate AAA progression.
{"title":"Elastase-2 deletion prevents vascular remodeling and abdominal aortic aneurysm development in a mice model induced by angiotensin II","authors":"Fabiola Mestriner , Vinicius Flora Dugaich , Pedro Brüch Dantas , Henrique Z. Kovacs , Marcela M. Blascke de Mello , Carina A. Pedersoli , Rafael Menezes da Costa , Maria Cecilia Jordani , Leandra N.Z. Ramalho , Michele M. de Castro , Júlio A. Silva-Neto , Rita C.A. Tostes Passaglia , Mauricio Serra Ribeiro , Christiane Becari","doi":"10.1016/j.vph.2025.107557","DOIUrl":"10.1016/j.vph.2025.107557","url":null,"abstract":"<div><div>Abdominal aortic aneurysm (AAA) involves the remodeling of the aortic wall extracellular matrix (ECM), compromising biomechanical support and increasing the risk of aortic dissection and rupture. Activation of the renin-angiotensin system (RAS), particularly the synthesis of angiotensin II (Ang II), plays a fundamental role in AAA initiation and progression. Elastase-2 (ELA-2), a chymotrypsin-like serine protease, contributes to tissue Ang II generation and may be a key player in AAA pathophysiology. This study investigated the effects of ELA-2 deletion in a murine model of angiotensin II-induced AAA, with particular focus on determining whether ELA-2 modulates vascular contractility and aortic relaxation in wild-type mice and whether these effects are absent in ELA-2 knockout mice. We additionally examined the cellular alterations within the aortic wall that contribute to increased reactive oxygen species generation during AAA development. Male C57BL/6 J (wild-type, WT) and ELA-2 knockout (ELA-2KO) mice, aged 10 to 15 weeks, were infused with Ang II (1500 ng/kg/min) for 28 days to induce AAA formation. Wild-type (WT) mice developed AAA, as evidenced by aortic dilation, structural remodeling, fibrosis, and inflammation. In contrast, ELA-2KO mice showed markedly reduced pathological changes following Ang II-induced AAA. Histological and biochemical analyses of the abdominal aorta revealed enhanced gelatinolytic activity, macrophage infiltration, and oxidative stress in WT mice, all of which were significantly attenuated in ELA-2KO mice. Furthermore, transcriptional profiling demonstrated that ELA-2 deletion maintained a contractile VSMC phenotype, suggesting a protective effect against maladaptive vascular remodeling. In summary, ELA-2 deficiency prevented Ang II- induced AAA formation and pathological vascular remodeling, highlighting its potential as a therapeutic target to mitigate AAA progression.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"161 ","pages":"Article 107557"},"PeriodicalIF":3.5,"publicationDate":"2025-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145445995","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 : 2025-10-25DOI: 10.1016/j.vph.2025.107556
M.S. Josef
{"title":"Comment on “Vascular diameter determines sensitivity to soluble guanylate cyclase activation in human mesenteric and renal arteries” [Lubomirov et al., Vascular pharmacology 160 (2025) 107515]","authors":"M.S. Josef","doi":"10.1016/j.vph.2025.107556","DOIUrl":"10.1016/j.vph.2025.107556","url":null,"abstract":"","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"161 ","pages":"Article 107556"},"PeriodicalIF":3.5,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145525795","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 : 2025-10-24DOI: 10.1016/j.vph.2025.107555
Sara A. Wennersten, Hongxia Wang, J. Lee Franklin, Vivek Nanda
The transition of smooth muscle cells (SMCs) from a contractile to a synthetic phenotype is a key contributor to cardiovascular disease (CVD) pathologies, such as atherosclerosis and in-stent restenosis. We previously reported that loss of leiomodin 1 (LMOD1), a coronary artery disease risk gene highly expressed in SMCs, promotes SMC phenotypic switching in vitro. However, the in vivo role of LMOD1 and the molecular mechanisms driving this transition remain unknown. In this study, we found that Lmod1 heterozygous mice subjected to carotid artery ligation developed larger neointimal lesions. Histopathological analyses attributed this phenotype to increased SMC proliferation. RNA sequencing studies of LMOD1-deficient SMCs revealed a significant upregulation of genes associated with increased cell proliferation, particularly those involved in the G1/S phase transition. Further analysis identified cyclin-dependent kinase 6 (CDK6) as a potential mediator of this hyperproliferative response. Notably, the knockdown of CDK6 in LMOD1-deficient cultured SMCs restored SMC proliferation to near baseline levels, indicating that the observed phenotype is reversible in vitro. Collectively, these findings indicate that LMOD1 deficiency promotes SMC proliferation by upregulating CDK6 expression and provide mechanistic insight into how reduced LMOD1 expression may contribute to increased neointimal lesion size and vascular remodeling.
{"title":"Leiomodin 1 haploinsufficiency promotes smooth muscle cell proliferation and increases neointimal lesion size","authors":"Sara A. Wennersten, Hongxia Wang, J. Lee Franklin, Vivek Nanda","doi":"10.1016/j.vph.2025.107555","DOIUrl":"10.1016/j.vph.2025.107555","url":null,"abstract":"<div><div>The transition of smooth muscle cells (SMCs) from a contractile to a synthetic phenotype is a key contributor to cardiovascular disease (CVD) pathologies, such as atherosclerosis and in-stent restenosis. We previously reported that loss of leiomodin 1 (<em>LMOD1</em>), a coronary artery disease risk gene highly expressed in SMCs, promotes SMC phenotypic switching <em>in vitro</em>. However, the <em>in vivo</em> role of LMOD1 and the molecular mechanisms driving this transition remain unknown. In this study, we found that <em>Lmod1</em> heterozygous mice subjected to carotid artery ligation developed larger neointimal lesions. Histopathological analyses attributed this phenotype to increased SMC proliferation. RNA sequencing studies of <em>LMOD1</em>-deficient SMCs revealed a significant upregulation of genes associated with increased cell proliferation, particularly those involved in the G1/S phase transition. Further analysis identified cyclin-dependent kinase 6 (CDK6) as a potential mediator of this hyperproliferative response. Notably, the knockdown of <em>CDK6</em> in <em>LMOD1</em>-deficient cultured SMCs restored SMC proliferation to near baseline levels, indicating that the observed phenotype is reversible <em>in vitro</em>. Collectively, these findings indicate that LMOD1 deficiency promotes SMC proliferation by upregulating CDK6 expression and provide mechanistic insight into how reduced LMOD1 expression may contribute to increased neointimal lesion size and vascular remodeling.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"161 ","pages":"Article 107555"},"PeriodicalIF":3.5,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145474216","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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