Chronic venous disease (CVD) is a prevalent vascular disorder with a poorly characterized genetic basis. In this study, we employed an integrative omics strategy combining genome-wide association studies (GWAS), expression quantitative trait loci (eQTL) mapping, endothelial cell functional assays, and transcriptomic correlation analysis to elucidate the molecular architecture of CVD. A GWAS conducted in a Taiwanese population identified two CVD-associated single nucleotide polymorphisms: VSTM2L rs1998049 and DPYSL2 rs1442887. Through eQTL analysis and endothelial functional assays, four QTLs (VSTM2L, RPRD1B, SAMHD1, and PNMA2) were found to significantly affect VEGF consumption, vWF expression, and endothelial tube formation. Co-expression and correlation analyses further linked these QTLs to key vascular effector genes, including VEGF, vWF, MMP9, and CCM2. A logistic regression model based on QTL expression profiles demonstrated high diagnostic performance (area under the curve, AUC = 0.898), highlighting their translational potential. These findings offer novel insights into the functional genomics of CVD, particularly in relation to vascular remodeling, endothelial dysfunction, and inflammation. They also demonstrate the utility of multi-omics integration for biomarker discovery in complex vascular disorders.
{"title":"Multi-omics identification of quantitative trait loci associated with vascular pathogenesis and diagnostic potential in chronic venous disease","authors":"Cheng-Hsun Chuang , Hsiao-Hsuan Huang , Yi-Syuan Wu , Nien-Che Ho , Chi-Ting Huang , Yi-Chen Huang , Hsien-Da Huang , Shun-Long Weng , Meng-Lin Lee , Kuang-Wen Liao","doi":"10.1016/j.vph.2025.107532","DOIUrl":"10.1016/j.vph.2025.107532","url":null,"abstract":"<div><div>Chronic venous disease (CVD) is a prevalent vascular disorder with a poorly characterized genetic basis. In this study, we employed an integrative omics strategy combining genome-wide association studies (GWAS), expression quantitative trait loci (eQTL) mapping, endothelial cell functional assays, and transcriptomic correlation analysis to elucidate the molecular architecture of CVD. A GWAS conducted in a Taiwanese population identified two CVD-associated single nucleotide polymorphisms: VSTM2L rs1998049 and DPYSL2 rs1442887. Through eQTL analysis and endothelial functional assays, four QTLs (<em>VSTM2L</em>, <em>RPRD1B</em>, <em>SAMHD1</em>, and <em>PNMA2</em>) were found to significantly affect VEGF consumption, vWF expression, and endothelial tube formation. Co-expression and correlation analyses further linked these QTLs to key vascular effector genes, including <em>VEGF</em>, <em>vWF</em>, <em>MMP9</em>, and <em>CCM2</em>. A logistic regression model based on QTL expression profiles demonstrated high diagnostic performance (area under the curve, AUC = 0.898), highlighting their translational potential. These findings offer novel insights into the functional genomics of CVD, particularly in relation to vascular remodeling, endothelial dysfunction, and inflammation. They also demonstrate the utility of multi-omics integration for biomarker discovery in complex vascular disorders.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107532"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925368","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 : 2025-09-01Epub Date: 2025-08-07DOI: 10.1016/j.vph.2025.107527
Masharh Lipscomb, Ignacia Salfate Del Rio, Maya Eid, Allison Rahtes, Grace Martino, Sudeshna Sadhu, Sayeed Khan, Katherine C MacNamara, Gabrielle Fredman
Atherosclerosis is a non-resolving inflammatory disease, and mechanisms to promote inflammation resolution, reduce vascular injury and promote repair in atherosclerosis are unmet needs. Specialized pro-resolving mediators (SPMs) like Resolvins, in part, mediate inflammation resolution and limit atherosclerosis progression. Uncovering processes associated with their protective actions are of interest. Senescent cells are maladaptive in atherosclerosis, and their accumulation promotes necrotic core formation in plaques. The SPM Resolvin D2 (RvD2) reduces plaque necrosis in part through its G-protein coupled receptor (GPCR), called GPR18. Here, we show how RvD2 can limit senescent cell accumulation in vivo and in vitro. Loss of myeloid GPR18 in Ldlr-/- mice led to increased accumulation of senescent cells, and RvD2 treatment in Ldlr-/- mice led to decreased accumulation of senescent cells in plaques. We found that senescent macrophages are not readily efferocytozed due to elevated "don't eat me" signals called CD24 and CD47. Knockdown or blockade of these signals improved senescent macrophage clearance, but not as efficient as efferocytosis of apoptotic cells in vitro. RvD2 treatment to senescent macrophages in vitro increased Cleaved Caspase-3 (an apoptosis marker) but did not impact the levels of CD24 or CD47. RvD2 enhanced the clearance of senescent macrophages but knockdown or blockade of CD24 and CD47 were also required for efficient clearance. Our work provides a cellular mechanism in which RvD2 treatment may limit plaque necrosis through decreasing senescent macrophages in plaques.
{"title":"Resolvin D2 limits senescent cell accumulation in atherosclerotic plaques.","authors":"Masharh Lipscomb, Ignacia Salfate Del Rio, Maya Eid, Allison Rahtes, Grace Martino, Sudeshna Sadhu, Sayeed Khan, Katherine C MacNamara, Gabrielle Fredman","doi":"10.1016/j.vph.2025.107527","DOIUrl":"10.1016/j.vph.2025.107527","url":null,"abstract":"<p><p>Atherosclerosis is a non-resolving inflammatory disease, and mechanisms to promote inflammation resolution, reduce vascular injury and promote repair in atherosclerosis are unmet needs. Specialized pro-resolving mediators (SPMs) like Resolvins, in part, mediate inflammation resolution and limit atherosclerosis progression. Uncovering processes associated with their protective actions are of interest. Senescent cells are maladaptive in atherosclerosis, and their accumulation promotes necrotic core formation in plaques. The SPM Resolvin D2 (RvD2) reduces plaque necrosis in part through its G-protein coupled receptor (GPCR), called GPR18. Here, we show how RvD2 can limit senescent cell accumulation in vivo and in vitro. Loss of myeloid GPR18 in Ldlr<sup>-/-</sup> mice led to increased accumulation of senescent cells, and RvD2 treatment in Ldlr<sup>-/-</sup> mice led to decreased accumulation of senescent cells in plaques. We found that senescent macrophages are not readily efferocytozed due to elevated \"don't eat me\" signals called CD24 and CD47. Knockdown or blockade of these signals improved senescent macrophage clearance, but not as efficient as efferocytosis of apoptotic cells in vitro. RvD2 treatment to senescent macrophages in vitro increased Cleaved Caspase-3 (an apoptosis marker) but did not impact the levels of CD24 or CD47. RvD2 enhanced the clearance of senescent macrophages but knockdown or blockade of CD24 and CD47 were also required for efficient clearance. Our work provides a cellular mechanism in which RvD2 treatment may limit plaque necrosis through decreasing senescent macrophages in plaques.</p>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":" ","pages":"107527"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144785361","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 : 2025-09-01DOI: 10.1016/j.vph.2025.107525
Rosalinda Madonna , Vincenzo Lionetti
{"title":"Exploring new cardiovascular frontiers: The Italian cardiovascular research landscape","authors":"Rosalinda Madonna , Vincenzo Lionetti","doi":"10.1016/j.vph.2025.107525","DOIUrl":"10.1016/j.vph.2025.107525","url":null,"abstract":"","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107525"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144709174","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 : 2025-08-21DOI: 10.1016/j.vph.2025.107530
Jad Hamze , Christopher Stone , Dwight Douglas Harris , Kelsey Muir , Keertana Yalamanchili , Nicholas C. Sellke , Frank W. Sellke
Objective
This study evaluates the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition on testicular microvascular function and vascular signaling pathways in a swine model of metabolic syndrome (MetS) and ischemic cardiomyopathy (ICM).
Methods
Eleven male Yorkshire swine were fed a high-fat diet to induce MetS. At 11 weeks, ICM was induced by placing an ameroid constrictor around the left circumflex artery. After a two-week stabilization period, swine were randomized into a high-fat control (HFC) or canagliflozin-treated (HCAN, 300 mg/day) group for five weeks. Terminal harvests were performed to assess testicular perfusion, endothelial function markers, and pro-apoptotic signaling.
Results
Canagliflozin (CAN) significantly improved testicular perfusion (p = 0.0134). Molecular analysis showed a significant increase in p-AMPK/AMPK ratio (p = 0.0483), indicating enhanced metabolic and endothelial signaling, and a significant reduction in BAD/BCL2 ratio (p = 0.0095), consistent with a shift toward anti-apoptotic signaling. The p-eNOS/eNOS ratio trended upward in treated animals (p = 0.1007), suggesting potential augmentation of nitric oxide–mediated vasodilation. Total ERK expression was also increased (p = 0.0201), supporting engagement of MAPK pathways.
Conclusion
SGLT2 inhibition improved testicular microvascular perfusion and modulated key signaling ratios, including increased p-AMPK/AMPK and reduced BAD/BCL2, with a trend toward higher p-eNOS/eNOS. These findings demonstrate that canagliflozin promotes vascular survival pathways in peripheral tissues, underscoring its vasculoprotective potential beyond the myocardium.
{"title":"Sodium-glucose cotransporter 2 inhibition restores testicular microvascular perfusion via endothelial signaling in a large animal model of metabolic syndrome and heart failure","authors":"Jad Hamze , Christopher Stone , Dwight Douglas Harris , Kelsey Muir , Keertana Yalamanchili , Nicholas C. Sellke , Frank W. Sellke","doi":"10.1016/j.vph.2025.107530","DOIUrl":"10.1016/j.vph.2025.107530","url":null,"abstract":"<div><h3>Objective</h3><div>This study evaluates the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition on testicular microvascular function and vascular signaling pathways in a swine model of metabolic syndrome (MetS) and ischemic cardiomyopathy (ICM).</div></div><div><h3>Methods</h3><div>Eleven male Yorkshire swine were fed a high-fat diet to induce MetS. At 11 weeks, ICM was induced by placing an ameroid constrictor around the left circumflex artery. After a two-week stabilization period, swine were randomized into a high-fat control (HFC) or canagliflozin-treated (HCAN, 300 mg/day) group for five weeks. Terminal harvests were performed to assess testicular perfusion, endothelial function markers, and pro-apoptotic signaling.</div></div><div><h3>Results</h3><div>Canagliflozin (CAN) significantly improved testicular perfusion (p = 0.0134). Molecular analysis showed a significant increase in p-AMPK/AMPK ratio (p = 0.0483), indicating enhanced metabolic and endothelial signaling, and a significant reduction in BAD/BCL2 ratio (p = 0.0095), consistent with a shift toward anti-apoptotic signaling. The p-eNOS/eNOS ratio trended upward in treated animals (p = 0.1007), suggesting potential augmentation of nitric oxide–mediated vasodilation. Total ERK expression was also increased (p = 0.0201), supporting engagement of MAPK pathways.</div></div><div><h3>Conclusion</h3><div>SGLT2 inhibition improved testicular microvascular perfusion and modulated key signaling ratios, including increased p-AMPK/AMPK and reduced BAD/BCL2, with a trend toward higher p-eNOS/eNOS. These findings demonstrate that canagliflozin promotes vascular survival pathways in peripheral tissues, underscoring its vasculoprotective potential beyond the myocardium.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107530"},"PeriodicalIF":3.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144912202","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}
The heart is an organ that depends significantly on mitochondria to operate, since it requires a lot of energy, which mitochondria create, making them essential for the efficient functioning of the heart. The term “mitochondrial dynamics” refers to extremely dynamic organelles known as mitochondria that undergo cycles of fusion and fission to modify their appearance, distribution, and function. Drp1 or Dynamin-related protein 1, a primary fission protein, strictly regulates the elimination of damaged mitochondria by mitophagy. This ensures that the complex processes of organ and cellular dynamics in the heart are strictly managed. Phosphorylation, SUMOylation, palmitoylation, ubiquitination, S-nitrosylation, and O-GlcNAcylation are some of the posttranslational modifications (PTMs) of Drp1 that contribute to the regulation of mitochondrial dynamics. While abnormalities in mitochondrial dynamics are a crucial component of the pathophysiology of a number of cardiovascular diseases (CVDs), the heart requires an effective mitochondrial balance to sustain cardiomyocyte metabolism along with contractile activity. This review summarizes the current knowledge of the crucial function of Drp1 inhibitors in the pathophysiology of cardiovascular diseases, including myocardial ischemia–reperfusion, dysfunction of endothelial cells, smooth muscle remodelling, hypertrophy of the heart, high blood pressure, and myocardial infarction. We further highlighted the possible advantages of treating CVDs by specifically targeting Drp1.
{"title":"Balancing act: Drp1 inhibition and mitochondrial homeostasis in cardiovascular diseases","authors":"Nandini Dubey , Ahsas Goyal , Neeraj Parakh , Rajiv Narang , Sudhir Kumar Arava , Arvind Kumar , Mayank Yadav , Harlokesh Narayan Yadav","doi":"10.1016/j.vph.2025.107531","DOIUrl":"10.1016/j.vph.2025.107531","url":null,"abstract":"<div><div>The heart is an organ that depends significantly on mitochondria to operate, since it requires a lot of energy, which mitochondria create, making them essential for the efficient functioning of the heart. The term “mitochondrial dynamics” refers to extremely dynamic organelles known as mitochondria that undergo cycles of fusion and fission to modify their appearance, distribution, and function. Drp1 or Dynamin-related protein 1, a primary fission protein, strictly regulates the elimination of damaged mitochondria by mitophagy. This ensures that the complex processes of organ and cellular dynamics in the heart are strictly managed. Phosphorylation, SUMOylation, palmitoylation, ubiquitination, S-nitrosylation, and O-GlcNAcylation are some of the posttranslational modifications (PTMs) of Drp1 that contribute to the regulation of mitochondrial dynamics. While abnormalities in mitochondrial dynamics are a crucial component of the pathophysiology of a number of cardiovascular diseases (CVDs), the heart requires an effective mitochondrial balance to sustain cardiomyocyte metabolism along with contractile activity. This review summarizes the current knowledge of the crucial function of Drp1 inhibitors in the pathophysiology of cardiovascular diseases, including myocardial ischemia–reperfusion, dysfunction of endothelial cells, smooth muscle remodelling, hypertrophy of the heart, high blood pressure, and myocardial infarction. We further highlighted the possible advantages of treating CVDs by specifically targeting Drp1.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107531"},"PeriodicalIF":3.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144890903","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 : 2025-08-19DOI: 10.1016/j.vph.2025.107529
Livio Giuliani , Michele D'Alto , Emma Di Poi , Lorenzo Dagna , Federico Guerra , Marco Corda , Gian Piero Perna , Andrea Doria , Roberto Badagliacca , Marco Vicenzi , Edoardo Airò , Matteo Toma , Laura Scelsi , Cristina Piccinino , Natale Daniele Brunetti , Carlo Mario Lombardi , Fabiana Baldi , Matteo Biancospino , Alessia Uglietti , Stefano De Santis
Background
Connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) is a progressive, high-risk subtype of PAH characterized by immune-mediated vascular remodeling, poor treatment response, and reduced survival. Real-world data on therapeutic response and risk evolution in this population remain limited.
Methods
This post hoc analysis of the multicenter, prospective INSPECTIO study evaluated the CTD-PAH subpopulation treated with macitentan and/or selexipag. The primary endpoint was the change in the number of non-invasive low-risk criteria (World Health Organization functional class I–II, 6-min walk distance >440 m, BNP <50 ng/L or NT-proBNP <300 ng/L) from baseline to 12 months. Secondary endpoints included changes in risk stratification, 6MWD, BNP/NT-proBNP levels, echocardiographic and hemodynamic parameters, a comparison with the non-CTD PAH population of the study was also conducted.
Results
Among a total of 176 patients enrolled in the INSPECTIO study, 64 (36.4 %) had CTD-PAH. The CTD group, with a larger prevalence of systemic sclerosis (SSc) patients, was predominantly female (93.8 %) and older than the non-CTD group (66.4 vs. 59.6 years, p = 0.0005). The mean number of non-invasive low-risk criteria increased significantly from baseline to Month 12 (+0.20; p = 0.0389), with 10.9 % of CTD patients achieving three low-risk criteria at Month 12. Secondary endpoints (Investigator's risk assessment, 6MWD, BNP, NT-proBNP, echocardiographic and hemodynamic parameters, baseline therapeutic strategy, vital signs) remained collectively stable.
Conclusions
CTD-PAH patients showed improvement in non-invasive risk criteria and stabilization of functional, echocardiographic, and hemodynamic parameters under macitentan and/or selexipag therapy. Despite the observational nature and small sample size, this real-world analysis supports the use of risk-based treatment strategies and close monitoring in this patient population.
{"title":"Evaluation of non-invasive low-risk criteria in patients with connective tissue disease-associated pulmonary arterial hypertension: A 12-months analysis from the INSPECTIO study","authors":"Livio Giuliani , Michele D'Alto , Emma Di Poi , Lorenzo Dagna , Federico Guerra , Marco Corda , Gian Piero Perna , Andrea Doria , Roberto Badagliacca , Marco Vicenzi , Edoardo Airò , Matteo Toma , Laura Scelsi , Cristina Piccinino , Natale Daniele Brunetti , Carlo Mario Lombardi , Fabiana Baldi , Matteo Biancospino , Alessia Uglietti , Stefano De Santis","doi":"10.1016/j.vph.2025.107529","DOIUrl":"10.1016/j.vph.2025.107529","url":null,"abstract":"<div><h3>Background</h3><div>Connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) is a progressive, high-risk subtype of PAH characterized by immune-mediated vascular remodeling, poor treatment response, and reduced survival. Real-world data on therapeutic response and risk evolution in this population remain limited.</div></div><div><h3>Methods</h3><div>This post hoc analysis of the multicenter, prospective INSPECTIO study evaluated the CTD-PAH subpopulation treated with macitentan and/or selexipag. The primary endpoint was the change in the number of non-invasive low-risk criteria (World Health Organization functional class I–II, 6-min walk distance >440 m, BNP <50 ng/L or NT-proBNP <300 ng/L) from baseline to 12 months. Secondary endpoints included changes in risk stratification, 6MWD, BNP/NT-proBNP levels, echocardiographic and hemodynamic parameters, a comparison with the non-CTD PAH population of the study was also conducted.</div></div><div><h3>Results</h3><div>Among a total of 176 patients enrolled in the INSPECTIO study, 64 (36.4 %) had CTD-PAH. The CTD group, with a larger prevalence of systemic sclerosis (SSc) patients, was predominantly female (93.8 %) and older than the non-CTD group (66.4 vs. 59.6 years, <em>p</em> = 0.0005). The mean number of non-invasive low-risk criteria increased significantly from baseline to Month 12 (+0.20; <em>p</em> = 0.0389), with 10.9 % of CTD patients achieving three low-risk criteria at Month 12. Secondary endpoints (Investigator's risk assessment, 6MWD, BNP, NT-proBNP, echocardiographic and hemodynamic parameters, baseline therapeutic strategy, vital signs) remained collectively stable.</div></div><div><h3>Conclusions</h3><div>CTD-PAH patients showed improvement in non-invasive risk criteria and stabilization of functional, echocardiographic, and hemodynamic parameters under macitentan and/or selexipag therapy. Despite the observational nature and small sample size, this real-world analysis supports the use of risk-based treatment strategies and close monitoring in this patient population.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107529"},"PeriodicalIF":3.5,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144890902","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 : 2025-08-11DOI: 10.1016/j.vph.2025.107528
Yihui Chen , Baoxing Wu , Shichai Hong
Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disorder with no effective drug treatment. Inflammation and macrophage infiltration in the abdominal aorta play a pivotal role in AAA development, progression, and rupture. However, the precise molecular mechanisms driving these processes remain unclear. To address this, we analyzed single-cell RNA sequencing datasets from three AAA mouse models and two healthy controls. Our findings revealed that AAA samples showed a marked increase in macrophage populations, with a shift toward pro-inflammatory M1 polarization compared to the predominantly M2 phenotype in controls. CellChat analysis revealed that the STAT1 pathway may mediate the enhanced intercellular communication between M1 and M2 macrophages. SCENIC analysis further identified STAT1 as a central transcriptional regulator in macrophages. We also developed a ten-gene inflammatory signature predictive of AAA prognosis, validated with external datasets, and confirmed STAT1's involvement via Western blotting and real-time PCR. These findings highlight the importance of macrophage polarization and STAT1-driven signaling in AAA pathogenesis. The identified gene signature offers potential for risk stratification and therapeutic targeting, advancing both mechanistic understanding and clinical management of AAA.
{"title":"Unveiling the role of STAT1-activated macrophages in abdominal aortic aneurysm: Insights from scRNA-seq and prognostic signature development","authors":"Yihui Chen , Baoxing Wu , Shichai Hong","doi":"10.1016/j.vph.2025.107528","DOIUrl":"10.1016/j.vph.2025.107528","url":null,"abstract":"<div><div>Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disorder with no effective drug treatment. Inflammation and macrophage infiltration in the abdominal aorta play a pivotal role in AAA development, progression, and rupture. However, the precise molecular mechanisms driving these processes remain unclear. To address this, we analyzed single-cell RNA sequencing datasets from three AAA mouse models and two healthy controls. Our findings revealed that AAA samples showed a marked increase in macrophage populations, with a shift toward pro-inflammatory M1 polarization compared to the predominantly M2 phenotype in controls. CellChat analysis revealed that the STAT1 pathway may mediate the enhanced intercellular communication between M1 and M2 macrophages. SCENIC analysis further identified STAT1 as a central transcriptional regulator in macrophages. We also developed a ten-gene inflammatory signature predictive of AAA prognosis, validated with external datasets, and confirmed STAT1's involvement via Western blotting and real-time PCR. These findings highlight the importance of macrophage polarization and STAT1-driven signaling in AAA pathogenesis. The identified gene signature offers potential for risk stratification and therapeutic targeting, advancing both mechanistic understanding and clinical management of AAA.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107528"},"PeriodicalIF":3.5,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144849192","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}
Anthracyclines remain the cornerstone of treatment for malignancies with dose-dependent cardiac damage, ranging from oxidative stress and mitochondrial dysfunction to DNA damage and ferroptosis, and continue to compromise patient outcome.
Animal models, encompassing rodents, rabbits, pigs, and nonhuman primates, are essential for investigating doxorubicin (DOX)-induced cardiovascular toxicity. Acute models facilitate rapid evaluation of cardiac injury; however, they frequently fail to replicate chronic human cardiomyopathy. In contrast, chronic models represent clinical scenarios more accurately but encounter logistical challenges. Species-specific variations in drug metabolism, cardiac physiology, and compensatory mechanisms further complicate the extrapolation. The primary limitations of existing models include the absence of comorbid conditions, lack of combination chemotherapy protocols, and underrepresentation of sex- and age-specific responses. Addressing these challenges is crucial for the development of effective and personalized cardioprotective strategies in cardio-oncology.
This review explores the translational challenges of DOX-induced cardiotoxicity, a critical limitation in the development of new cardioprotective strategies in cardio-oncology despite decades of research. We will elucidate the underlying factors that contribute to the difficulties in translating experimental in vivo results into clinical applications.
{"title":"Translational aspects of doxorubicin-induced cardiotoxicity: What we have omitted for the past decades?","authors":"Ashot Avagimyan , Rosalinda Madonna , Mohammad Sheibani , Nana Pogosova , Artem Trofimenko , Olga Urazova , Laura Iop , Zinaida Jndoyan , Hasmik Yeranosyan , Anahit Aznauryan , Karmen Sahakyan , Anna Petrosyan , Ruzanna Petrosyan , Marina Tatoyan , Gayane Mkrtchyan , Elina Sulemaniayants , Goarik Meltonyan , Aleh Kuzniatsou , Rupak Mukherjee , Aysa Rezabakhsh , Nizal Sarrafzadegan","doi":"10.1016/j.vph.2025.107526","DOIUrl":"10.1016/j.vph.2025.107526","url":null,"abstract":"<div><div>Anthracyclines remain the cornerstone of treatment for malignancies with dose-dependent cardiac damage, ranging from oxidative stress and mitochondrial dysfunction to DNA damage and ferroptosis, and continue to compromise patient outcome.</div><div>Animal models, encompassing rodents, rabbits, pigs, and nonhuman primates, are essential for investigating doxorubicin (DOX)-induced cardiovascular toxicity. Acute models facilitate rapid evaluation of cardiac injury; however, they frequently fail to replicate chronic human cardiomyopathy. In contrast, chronic models represent clinical scenarios more accurately but encounter logistical challenges. Species-specific variations in drug metabolism, cardiac physiology, and compensatory mechanisms further complicate the extrapolation. The primary limitations of existing models include the absence of comorbid conditions, lack of combination chemotherapy protocols, and underrepresentation of sex- and age-specific responses. Addressing these challenges is crucial for the development of effective and personalized cardioprotective strategies in cardio-oncology.</div><div>This review explores the translational challenges of DOX-induced cardiotoxicity, a critical limitation in the development of new cardioprotective strategies in cardio-oncology despite decades of research. We will elucidate the underlying factors that contribute to the difficulties in translating experimental in vivo results into clinical applications.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107526"},"PeriodicalIF":3.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144711467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-18DOI: 10.1016/j.vph.2025.107523
Luan Victor Resque Ramos, Marcela M. Blascke de Mello, Bruno Marcel Silva de Melo, José Teles de Oliveira Neto, Evellin Karina Pires Bueno, José Carlos Farias Alves Filho, Rita Tostes, Michele M. Castro
Angiotensin II (Ang II) increases C3a effects through its receptors, promoting aortic oxidative stress and upregulating matrix metalloproteinase (MMP)-2. MMP-2 is implicated in hypertrophic arterial remodeling in hypertension. This study investigated whether C3a receptor activation contributes to oxidative stress and increased MMP-2 activity in aortas of Ang II treated mice, ultimately leading to maladaptive vascular changes. Hypertension was induced in C57BL/6 mice via subcutaneous implantation of osmotic mini pumps delivering Ang II (1000 ng/kg/min) for 14 days. Mice were administered the C3aR antagonist, SB290157 (1 mg/kg/day, intraperitoneally) every other day for 14 days. Systolic blood pressure (SBP) and vascular function were assessed via direct blood pressure measurements and contraction and relaxation analysis in a wire myography. Aortic MMP-2 activity was analyzed by gel and in situ zymography. SB290157 did not decrease SBP, aortic hypertrophy or increased aortic reactivity to phenylephrine in Ang II treated mice. Ang II exhibited higher levels of C3a in the plasma and increased tumor necrose factor (TNF)-α and interleukin (IL)-6 in the kidneys (*p < 0.05). SB290157 did not alter C3a, but reduced TNF-α and IL-6 in hypertension (#p < 0.05 vs. Ang II). SB290157 also decreased aortic oxidative stress and p65 factor nuclear kappa B (NFkB) in Ang II treated mice (*p < 0.05). MMP-2 activity was increased in the aortas of Ang II (*p < 0.05) and SB290157 decreased it (*p < 0.05). Pharmacological antagonism of C3a receptor attenuates oxidative stress and MMP-2 activity in the aortas of Ang II treated mice.
{"title":"Antagonism of the complement receptor reduces oxidative stress and matrix metalloproteinase (MMP)-2 activity in the aortas of mice with angiotensin-II-induced hypertension","authors":"Luan Victor Resque Ramos, Marcela M. Blascke de Mello, Bruno Marcel Silva de Melo, José Teles de Oliveira Neto, Evellin Karina Pires Bueno, José Carlos Farias Alves Filho, Rita Tostes, Michele M. Castro","doi":"10.1016/j.vph.2025.107523","DOIUrl":"10.1016/j.vph.2025.107523","url":null,"abstract":"<div><div>Angiotensin II (Ang II) increases C3a effects through its receptors, promoting aortic oxidative stress and upregulating matrix metalloproteinase (MMP)-2. MMP-2 is implicated in hypertrophic arterial remodeling in hypertension. This study investigated whether C3a receptor activation contributes to oxidative stress and increased MMP-2 activity in aortas of Ang II treated mice, ultimately leading to maladaptive vascular changes. Hypertension was induced in C57BL/6 mice via subcutaneous implantation of osmotic mini pumps delivering Ang II (1000 ng/kg/min) for 14 days. Mice were administered the C3aR antagonist, SB290157 (1 mg/kg/day, intraperitoneally) every other day for 14 days. Systolic blood pressure (SBP) and vascular function were assessed via direct blood pressure measurements and contraction and relaxation analysis in a wire myography. Aortic MMP-2 activity was analyzed by gel and in situ zymography. SB290157 did not decrease SBP, aortic hypertrophy or increased aortic reactivity to phenylephrine in Ang II treated mice. Ang II exhibited higher levels of C3a in the plasma and increased tumor necrose factor (TNF)-α and interleukin (IL)-6 in the kidneys (*<em>p</em> < 0.05). SB290157 did not alter C3a, but reduced TNF-α and IL-6 in hypertension (#<em>p</em> < 0.05 vs. Ang II). SB290157 also decreased aortic oxidative stress and p65 factor nuclear kappa B (NFkB) in Ang II treated mice (*<em>p</em> < 0.05). MMP-2 activity was increased in the aortas of Ang II (*<em>p</em> < 0.05) and SB290157 decreased it (*<em>p</em> < 0.05). Pharmacological antagonism of C3a receptor attenuates oxidative stress and MMP-2 activity in the aortas of Ang II treated mice.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107523"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-18DOI: 10.1016/j.vph.2025.107524
Peter Muiruri Kamau , Yang Chen , Xiaopei Yang , Jinglin Li , Rebecca Caroline Thuku , Dawit Tadese , Hao Zhang , Haiying Wu , Lei Luo , Qiumin Lu
Renal hypertension, a common form of secondary hypertension, results from kidney disease. It arises due to the narrowing of arteries connected to the kidneys, often caused by atherosclerosis. Over time, this condition can lead to kidney failure. Therapeutics for kidney protection are currently limited, prompting continual search for new renoprotective agents in the context of hypertension. Dual blockage of both L-type and T-type calcium channels has shown promise in the treatment of hypertension when compared to selective calcium channel blockers. Toddaculin has been proven to be a potent inhibitor of the T-type channel. Conserved amino acid sequence comparison, electrophysiological recordings, and Flex Station were used to evaluate and compare toddaculin effect on the CaV3.1 and CaV1.2 channels and their respective residues, transiently expressed in HEK293T cells. Intracellular Ca2+ was assessed using the molecular probe fluo-4-AM. They specifically investigated the impact of toddaculin on vascular smooth muscle cells (VSMCs). Toddaculin's myogenic effects were assessed using aortic rings isolated from rats within an organ bath system. In an in vivo context, a mouse model with L-NAME-induced hypertension was employed to investigate toddaculin's anti-hypertensive and renoprotective properties. We found that L1047A in CaV1.2, and L1456A in CaV3.1 are potential key binding sites for toddaculin, and that toddaculin inhibited CaV3.1 and CaV1.2 equally and dose-dependently. Toddaculin-induced decline of [Ca2+]i cultured VSMCs under a laser scanning confocal microscopy. Aortic rings exposed to toddaculin demonstrated dose-dependent relaxation following KCl-induced contraction. Moreover, toddaculin exhibited significant blood pressure reduction and renoprotective effects against L-NAME-induced renal injury in mice. This finding provides an evident therapeutic potential of toddaculin as an antihypertensive drug candidate with a renoprotective effect.
{"title":"Dual L/T calcium channel blocker exerts both antihypertensive and renoprotective effects in L-NAME-induced hypertension model","authors":"Peter Muiruri Kamau , Yang Chen , Xiaopei Yang , Jinglin Li , Rebecca Caroline Thuku , Dawit Tadese , Hao Zhang , Haiying Wu , Lei Luo , Qiumin Lu","doi":"10.1016/j.vph.2025.107524","DOIUrl":"10.1016/j.vph.2025.107524","url":null,"abstract":"<div><div>Renal hypertension, a common form of secondary hypertension, results from kidney disease. It arises due to the narrowing of arteries connected to the kidneys, often caused by atherosclerosis. Over time, this condition can lead to kidney failure. Therapeutics for kidney protection are currently limited, prompting continual search for new renoprotective agents in the context of hypertension. Dual blockage of both L-type and T-type calcium channels has shown promise in the treatment of hypertension when compared to selective calcium channel blockers. Toddaculin has been proven to be a potent inhibitor of the T-type channel. Conserved amino acid sequence comparison, electrophysiological recordings, and Flex Station were used to evaluate and compare toddaculin effect on the Ca<sub>V</sub>3.1 and Ca<sub>V</sub>1.2 channels and their respective residues, transiently expressed in HEK293T cells. Intracellular Ca<sup>2+</sup> was assessed using the molecular probe fluo-4-AM. They specifically investigated the impact of toddaculin on vascular smooth muscle cells (VSMCs). Toddaculin's myogenic effects were assessed using aortic rings isolated from rats within an organ bath system. In an in vivo context, a mouse model with L-NAME-induced hypertension was employed to investigate toddaculin's anti-hypertensive and renoprotective properties. We found that L1047A in Ca<sub>V</sub>1.2, and L1456A in Ca<sub>V</sub>3.1 are potential key binding sites for toddaculin, and that toddaculin inhibited Ca<sub>V</sub>3.1 and Ca<sub>V</sub>1.2 equally and dose-dependently. Toddaculin-induced decline of [Ca<sup>2+</sup>]<sub>i</sub> cultured VSMCs under a laser scanning confocal microscopy. Aortic rings exposed to toddaculin demonstrated dose-dependent relaxation following KCl-induced contraction. Moreover, toddaculin exhibited significant blood pressure reduction and renoprotective effects against L-NAME-induced renal injury in mice. This finding provides an evident therapeutic potential of toddaculin as an antihypertensive drug candidate with a renoprotective effect.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107524"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675954","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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