Pub Date : 2026-02-02DOI: 10.1016/j.vph.2026.107585
Michele D'Alto, Laura Scelsi, Livio Giuliani, Gian Piero Perna, Fabiana Baldi, Federico Guerra, Emma Di Poi, Marco Vicenzi, Roberto Badagliacca, Marco Corda, Edoardo Airò, Paolo Ferrero, Pietro Ameri, Francesca Bux, Piergiuseppe Agostoni, Carlo D'Agostino, Gavino Casu, Matteo Biancospino, Alessia Uglietti, Stefano De Santis
Background: Pulmonary arterial hypertension (PAH) is a progressive disease associated with significant morbidity and mortality. Combination therapy targeting multiple pathways has been shown to improve clinical outcomes.
Methods: The INSPECTIO study was a prospective, multicenter, observational study conducted across 29 Italian centers specializing in PAH management. The study sought to explore the impact of combination therapy on disease progression and quality of life, by assessing non-invasive risk parameters, echocardiographic and hemodynamic conditions, and patient-reported outcomes (PROs). Patients with PAH at low or intermediate mortality risk, treated with macitentan and/or selexipag (as monotherapy or in combination), were enrolled. Data on non-invasive low-risk criteria (WHO Functional Class, 6-min walk distance [6MWD], and NT-proBNP), REVEAL risk scores, echocardiographic and hemodynamic parameters, and patient-reported outcomes (emPHasis-10) were collected at baseline and 12 months. A Narrative Medicine analysis complemented quantitative findings by exploring patients' experiences.
Results: Among 176 patients with follow-up data, the number of non-invasive low-risk criteria increased by an average of 0.15 at 12 months (p = 0.0167). REVEAL 2.0 and REVEAL Lite 2 scores showed significant reductions (mean changes: -1.0, p = 0.0142; -0.8, p = 0.0111, respectively). Modest changes were observed in echocardiographic and hemodynamic parameters. Narrative analysis highlighted strengthened patient-provider relationships and improved coping strategies. Safety outcomes aligned with known profiles.
Conclusions: The INSPECTIO study supports the effectiveness of guideline-directed therapy and regular risk assessment to optimize treatment strategies in PAH. The increase in non-invasive low-risk criteria suggests a stabilization of disease over 12 months.
{"title":"Real-world observational study on pulmonary arterial hypertension: Italian cohort treated with macitentan and/or selexipag as a part of a combination treatment (INSPECTIO).","authors":"Michele D'Alto, Laura Scelsi, Livio Giuliani, Gian Piero Perna, Fabiana Baldi, Federico Guerra, Emma Di Poi, Marco Vicenzi, Roberto Badagliacca, Marco Corda, Edoardo Airò, Paolo Ferrero, Pietro Ameri, Francesca Bux, Piergiuseppe Agostoni, Carlo D'Agostino, Gavino Casu, Matteo Biancospino, Alessia Uglietti, Stefano De Santis","doi":"10.1016/j.vph.2026.107585","DOIUrl":"https://doi.org/10.1016/j.vph.2026.107585","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary arterial hypertension (PAH) is a progressive disease associated with significant morbidity and mortality. Combination therapy targeting multiple pathways has been shown to improve clinical outcomes.</p><p><strong>Methods: </strong>The INSPECTIO study was a prospective, multicenter, observational study conducted across 29 Italian centers specializing in PAH management. The study sought to explore the impact of combination therapy on disease progression and quality of life, by assessing non-invasive risk parameters, echocardiographic and hemodynamic conditions, and patient-reported outcomes (PROs). Patients with PAH at low or intermediate mortality risk, treated with macitentan and/or selexipag (as monotherapy or in combination), were enrolled. Data on non-invasive low-risk criteria (WHO Functional Class, 6-min walk distance [6MWD], and NT-proBNP), REVEAL risk scores, echocardiographic and hemodynamic parameters, and patient-reported outcomes (emPHasis-10) were collected at baseline and 12 months. A Narrative Medicine analysis complemented quantitative findings by exploring patients' experiences.</p><p><strong>Results: </strong>Among 176 patients with follow-up data, the number of non-invasive low-risk criteria increased by an average of 0.15 at 12 months (p = 0.0167). REVEAL 2.0 and REVEAL Lite 2 scores showed significant reductions (mean changes: -1.0, p = 0.0142; -0.8, p = 0.0111, respectively). Modest changes were observed in echocardiographic and hemodynamic parameters. Narrative analysis highlighted strengthened patient-provider relationships and improved coping strategies. Safety outcomes aligned with known profiles.</p><p><strong>Conclusions: </strong>The INSPECTIO study supports the effectiveness of guideline-directed therapy and regular risk assessment to optimize treatment strategies in PAH. The increase in non-invasive low-risk criteria suggests a stabilization of disease over 12 months.</p>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":" ","pages":"107585"},"PeriodicalIF":3.5,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146120326","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 : 2026-02-02DOI: 10.1016/j.vph.2026.107582
Geoffrey E Woodard
The human heart exhibits remarkable chamber-specific ion channel expression patterns that underlie the distinct electrophysiological properties of atrial versus ventricular myocardium. This comprehensive review examines the molecular architecture, biophysical properties, and functional roles of 79 ion channel subunits and related proteins across all four cardiac chambers based on quantitative transcriptomic data from non-diseased donor hearts. Understanding chamber-specific expression profiles is essential for comprehending cardiac electrophysiology, arrhythmia mechanisms, and the development of chamber-selective therapeutic strategies.
{"title":"Ion channels of the human heart: A comprehensive four-chamber analysis.","authors":"Geoffrey E Woodard","doi":"10.1016/j.vph.2026.107582","DOIUrl":"https://doi.org/10.1016/j.vph.2026.107582","url":null,"abstract":"<p><p>The human heart exhibits remarkable chamber-specific ion channel expression patterns that underlie the distinct electrophysiological properties of atrial versus ventricular myocardium. This comprehensive review examines the molecular architecture, biophysical properties, and functional roles of 79 ion channel subunits and related proteins across all four cardiac chambers based on quantitative transcriptomic data from non-diseased donor hearts. Understanding chamber-specific expression profiles is essential for comprehending cardiac electrophysiology, arrhythmia mechanisms, and the development of chamber-selective therapeutic strategies.</p>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":" ","pages":"107582"},"PeriodicalIF":3.5,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146120270","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 : 2026-02-01DOI: 10.1016/j.vph.2026.107583
Anass M Abbas, Hayder M Al-Kuraishy, Thabat Jumaah Al-Maiahy, Ali I Al-Gareeb, Waheeb Alharbi, Mohamed N Fawzy, Gaber El-Saber Batiha
Preeclampsia (PE), a major hypertensive disorder of pregnancy, is increasingly recognized as a significant risk factor for cognitive decline and Alzheimer's disease (AD). Placental ischemia in PE leads to an anti-angiogenic state, characterized by elevated soluble FMS-like tyrosine kinase-1 (sFlt-1) and reduced placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), causing systemic endothelial dysfunction. These alterations may persist during the postpartum period, promoting cerebrovascular impairment, blood-brain barrier (BBB) disruption, and neuroinflammation. Furthermore, PE is associated with the release of AD-related proteins, including amyloid-beta (Aβ) and hyperphosphorylated tau protein. However, the potential link between AD and PE regarding the angiogenic and anti-angiogenic factors is not fully elucidated. This review aims to explore the shared pathophysiological pathways, focusing on the angiogenic and anti-angiogenic factors. The manuscript also evaluates the potential for repurposing pharmacological agents to mitigate the long-term risk of AD in women with a history of PE.
{"title":"Angiogenic and anti-angiogenic factors are the shared mechanistic pathways between preeclampsia and Alzheimer's disease: Perspective and take-away.","authors":"Anass M Abbas, Hayder M Al-Kuraishy, Thabat Jumaah Al-Maiahy, Ali I Al-Gareeb, Waheeb Alharbi, Mohamed N Fawzy, Gaber El-Saber Batiha","doi":"10.1016/j.vph.2026.107583","DOIUrl":"10.1016/j.vph.2026.107583","url":null,"abstract":"<p><p>Preeclampsia (PE), a major hypertensive disorder of pregnancy, is increasingly recognized as a significant risk factor for cognitive decline and Alzheimer's disease (AD). Placental ischemia in PE leads to an anti-angiogenic state, characterized by elevated soluble FMS-like tyrosine kinase-1 (sFlt-1) and reduced placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), causing systemic endothelial dysfunction. These alterations may persist during the postpartum period, promoting cerebrovascular impairment, blood-brain barrier (BBB) disruption, and neuroinflammation. Furthermore, PE is associated with the release of AD-related proteins, including amyloid-beta (Aβ) and hyperphosphorylated tau protein. However, the potential link between AD and PE regarding the angiogenic and anti-angiogenic factors is not fully elucidated. This review aims to explore the shared pathophysiological pathways, focusing on the angiogenic and anti-angiogenic factors. The manuscript also evaluates the potential for repurposing pharmacological agents to mitigate the long-term risk of AD in women with a history of PE.</p>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":" ","pages":"107583"},"PeriodicalIF":3.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146114391","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 : 2026-01-27DOI: 10.1016/j.vph.2026.107581
Liao Tan, Jie Liu, Ruizheng Shi, Yubo Liu
Background: Thoracic aortic aneurysm and dissection (TAAD) is a kind of life-threatening cardiovascular condition with a poor prognosis, currently lacking effective drug therapies that can halt the progression of TAAD. Tirzepatide, a dual GIP and GLP-1 receptor agonist used for type 2 diabetes and weight management, has shown cardioprotective potential, yet its effect on TAAD remains unknown.
Methods: A TAAD model in mice was developed by providing 0.5% β-aminopropionitrile (BAPN) for 28 days.Mice were categorized into control, tirzepatide-only, BAPN, and BAPN combined with tirzepatide.Tirzepatide (10 nmol/kg) was administered daily via intraperitoneal injection. Aortic morphology, incidence of TAAD, medial degeneration, inflammation, elastin integrity, and proteoglycan deposition were assessed by gross examination and histological analyses. Inflammatory cells infiltration and signaling pathways were evaluated by immunostaining and western blotting. In parallel, platelet-derived growth factor-BB (PDGF-BB) stimulated human aortic smooth muscle cells (HASMCs) were used as an in vitro model to examine the direct effects of TZP on VSMC phenotypic modulation.
Results: Treatment with tirzepatide led to a significant reduction in both the formation of TAAD (from 88.9% to 50.0%) and related deaths (from 83.3% to 38.9%). It also effectively suppressed the pathological expansion of the aortic diameter in the ascending, arch, and descending regions. Histological analysis revealed improved elastic fiber integrity and reduced degradation. Tirzepatide prevented VSMC phenotypic switching, reduced inflammatory cells infiltration, and lowered IL-1β, IL-6, and MCP-1 levels. It also downregulated NLRP3 and caspase-1 expression. In vitro, TZP directly reversed PDGF-BB-induced downregulation of VSMC contractile markers (MYH11, SMA, SM22, and CNN1) and mitigated cytoskeletal and morphological changes associated with phenotypic switching.
Conclusion: Our findings indicate that tirzepatide curbs the development of TAAD in mice. The underlying mechanism likely involves the suppression of the NLRP3 inflammasome priming, a consequent reduction in vascular inflammation, and the preservation of the contractile state of VSMC. These findings highlight its potential as a novel therapeutic strategy for TAAD.
{"title":"Tirzepatide mitigates thoracic aortic aneurysm and dissection by alleviating the loss of the contractile phenotype in vascular smooth muscle cells and reducing vascular inflammation.","authors":"Liao Tan, Jie Liu, Ruizheng Shi, Yubo Liu","doi":"10.1016/j.vph.2026.107581","DOIUrl":"10.1016/j.vph.2026.107581","url":null,"abstract":"<p><strong>Background: </strong>Thoracic aortic aneurysm and dissection (TAAD) is a kind of life-threatening cardiovascular condition with a poor prognosis, currently lacking effective drug therapies that can halt the progression of TAAD. Tirzepatide, a dual GIP and GLP-1 receptor agonist used for type 2 diabetes and weight management, has shown cardioprotective potential, yet its effect on TAAD remains unknown.</p><p><strong>Methods: </strong>A TAAD model in mice was developed by providing 0.5% β-aminopropionitrile (BAPN) for 28 days.Mice were categorized into control, tirzepatide-only, BAPN, and BAPN combined with tirzepatide.Tirzepatide (10 nmol/kg) was administered daily via intraperitoneal injection. Aortic morphology, incidence of TAAD, medial degeneration, inflammation, elastin integrity, and proteoglycan deposition were assessed by gross examination and histological analyses. Inflammatory cells infiltration and signaling pathways were evaluated by immunostaining and western blotting. In parallel, platelet-derived growth factor-BB (PDGF-BB) stimulated human aortic smooth muscle cells (HASMCs) were used as an in vitro model to examine the direct effects of TZP on VSMC phenotypic modulation.</p><p><strong>Results: </strong>Treatment with tirzepatide led to a significant reduction in both the formation of TAAD (from 88.9% to 50.0%) and related deaths (from 83.3% to 38.9%). It also effectively suppressed the pathological expansion of the aortic diameter in the ascending, arch, and descending regions. Histological analysis revealed improved elastic fiber integrity and reduced degradation. Tirzepatide prevented VSMC phenotypic switching, reduced inflammatory cells infiltration, and lowered IL-1β, IL-6, and MCP-1 levels. It also downregulated NLRP3 and caspase-1 expression. In vitro, TZP directly reversed PDGF-BB-induced downregulation of VSMC contractile markers (MYH11, SMA, SM22, and CNN1) and mitigated cytoskeletal and morphological changes associated with phenotypic switching.</p><p><strong>Conclusion: </strong>Our findings indicate that tirzepatide curbs the development of TAAD in mice. The underlying mechanism likely involves the suppression of the NLRP3 inflammasome priming, a consequent reduction in vascular inflammation, and the preservation of the contractile state of VSMC. These findings highlight its potential as a novel therapeutic strategy for TAAD.</p>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":" ","pages":"107581"},"PeriodicalIF":3.5,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146086859","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 : 2026-01-20DOI: 10.1016/j.vph.2025.107580
Filippo Biondi , Sandra Ghelardoni , Doralisa Morrone , Raffaele De Caterina , Rosalinda Madonna
Exercise pulmonary hypertension (exPH) is currently defined as a mean pulmonary artery pressure to cardiac output slope (mPAP/CO slope) greater than 3 mmHg/L/min during the transition from rest to end-exercise, and a normal mPAP at rest. ExPH may represent an early marker of vascular dysfunction in patients with chronic thromboembolic pulmonary disease (CTEPD) without resting pulmonary hypertension (pH). This is one of the possible complications of pulmonary embolism and is characterized by a variable degree of exercise intolerance. Its natural history is largely unknown and its clinical management is constrained by the lack of validated prognostic markers.
We conducted a systematic review and meta-analysis to evaluate the prevalence of exPH and its prognostic role in CTEPD without resting PH. Secondary aims were to ascertain the prevalence of mPAP/CO and PAWP/CO slopes in CTEPD without resting pulmonary hypertension and in patients with post-capillary PH. Upon identification and screening, 12 studies satisfied the criteria for eligibility and were included in the systematic review, with a total of 373 patients. This data base consisted of studies with different designs. Quantitative data were meta-analyzed for each of the aims when provided by at least 5 studies. Approximately 50% of patients suffered from exPH, with a pooled prevalence of 0.50 as per random effect model and 0.44 as per fixed effect model with high heterogeneity. Mean mPAP/CO slope was 4.10 and 3.51 mmHg/L/min as per random effect meta-analysis or common effects model, respectively. The studies included did not provide evidence on the prognostic role in CTEPD without resting PH. Only a few data were reported on PAWP/CO slope and post capillary exPH. In conclusion, our systematic review indicates that ExPH is highly prevalent in CTEPD without resting PH, but its prognostic value is still to be defined.
{"title":"Exercise pulmonary hypertension in chronic thromboembolic pulmonary disease without resting pulmonary hypertension: A systematic review and meta-analysis","authors":"Filippo Biondi , Sandra Ghelardoni , Doralisa Morrone , Raffaele De Caterina , Rosalinda Madonna","doi":"10.1016/j.vph.2025.107580","DOIUrl":"10.1016/j.vph.2025.107580","url":null,"abstract":"<div><div>Exercise pulmonary hypertension (exPH) is currently defined as a mean pulmonary artery pressure to cardiac output slope (mPAP/CO slope) greater than 3 mmHg/L/min during the transition from rest to end-exercise, and a normal mPAP at rest. ExPH may represent an early marker of vascular dysfunction in patients with chronic thromboembolic pulmonary disease (CTEPD) without resting pulmonary hypertension (pH). This is one of the possible complications of pulmonary embolism and is characterized by a variable degree of exercise intolerance. Its natural history is largely unknown and its clinical management is constrained by the lack of validated prognostic markers.</div><div>We conducted a systematic review and meta-analysis to evaluate the prevalence of exPH and its prognostic role in CTEPD without resting PH. Secondary aims were to ascertain the prevalence of mPAP/CO and PAWP/CO slopes in CTEPD without resting pulmonary hypertension and in patients with post-capillary PH. Upon identification and screening, 12 studies satisfied the criteria for eligibility and were included in the systematic review, with a total of 373 patients. This data base consisted of studies with different designs. Quantitative data were meta-analyzed for each of the aims when provided by at least 5 studies. Approximately 50% of patients suffered from exPH, with a pooled prevalence of 0.50 as per random effect model and 0.44 as per fixed effect model with high heterogeneity. Mean mPAP/CO slope was 4.10 and 3.51 mmHg/L/min as per random effect meta-analysis or common effects model, respectively. The studies included did not provide evidence on the prognostic role in CTEPD without resting PH. Only a few data were reported on PAWP/CO slope and post capillary exPH. In conclusion, our systematic review indicates that ExPH is highly prevalent in CTEPD without resting PH, but its prognostic value is still to be defined.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"162 ","pages":"Article 107580"},"PeriodicalIF":3.5,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030968","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 : 2025-12-29DOI: 10.1016/j.vph.2025.107579
Franceska Kishta , Ignacio Fernando Hall , Guanliang Li , Tanushree Tripathi , Matthieu Vermeren , Justyna Cholewa-Waclaw , Fiona Rossi , Bruno M. Péault , Julie Rodor , Abdelaziz Beqqali , Judith C. Sluimer , Mihaela Crisan , Andrew H. Baker
Endothelial-to-mesenchymal transition (EndMT), in which endothelial cells (ECs) lose their endothelial identity and acquire mesenchymal-like features, contributes to vascular dysfunction and remodeling in atherosclerosis. However, the fate and function of these cells remain unclear. Here, we investigated their differentiation potential and functional properties to define how EndMT contributes to vascular dysfunction.
Human umbilical vein ECs (HUVECs) were treated with transforming growth factor-β2 (TGF-β2) and interleukin-1β (IL-1β) for seven days to induce EndMT. Mesenchymal stem/stromal cell (MSC) identity was assessed by flow cytometry for canonical markers (CD44, CD73, CD105, CD90). Differentiation states were evaluated using published single-cell RNA sequencing (scRNA-seq) data of EndMT-treated HUVECs and validated under lineage-specific culture environments. In vivo analysis was performed using scRNA-seq data from EC lineage reporter mice in atherosclerosis models.
EndMT-treated HUVECs displayed an intermediate mesenchymal phenotype, expressing CD44, CD73 and CD105 but lacking CD90, failing to meet MSC criteria. Potency analysis showed that 77 % of EndMT-treated HUVECs remained oligopotent, while 19 % acquired osteogenic and chondrogenic potential, accompanied by activation of lineage-associated transcriptional programs (RUNX2, BMPR1A, NOTCH2, WNT5A; CD151, ANXA6, DCN). In vivo, endothelial lineage-traced cells in atherosclerotic mice formed an EndMT cluster enriched for osteogenic and chondrogenic gene programs, including ossification and cartilage development pathways.
We define a primed oligopotent state of EndMT-derived cells both in vitro and in vivo, marked by transition toward osteogenic and chondrogenic fates. These findings suggest that EndMT contributes to atherosclerosis by generating osteogenic- and chondrogenic-like cells, linking endothelial dysfunction to vascular calcification in disease.
{"title":"Endothelial-to-mesenchymal transition primes vascular endothelial cells toward an osteochondrogenic fate","authors":"Franceska Kishta , Ignacio Fernando Hall , Guanliang Li , Tanushree Tripathi , Matthieu Vermeren , Justyna Cholewa-Waclaw , Fiona Rossi , Bruno M. Péault , Julie Rodor , Abdelaziz Beqqali , Judith C. Sluimer , Mihaela Crisan , Andrew H. Baker","doi":"10.1016/j.vph.2025.107579","DOIUrl":"10.1016/j.vph.2025.107579","url":null,"abstract":"<div><div>Endothelial-to-mesenchymal transition (EndMT), in which endothelial cells (ECs) lose their endothelial identity and acquire mesenchymal-like features, contributes to vascular dysfunction and remodeling in atherosclerosis. However, the fate and function of these cells remain unclear. Here, we investigated their differentiation potential and functional properties to define how EndMT contributes to vascular dysfunction.</div><div>Human umbilical vein ECs (HUVECs) were treated with transforming growth factor-β2 (TGF-β2) and interleukin-1β (IL-1β) for seven days to induce EndMT. Mesenchymal stem/stromal cell (MSC) identity was assessed by flow cytometry for canonical markers (CD44, CD73, CD105, CD90). Differentiation states were evaluated using published single-cell RNA sequencing (scRNA-seq) data of EndMT-treated HUVECs and validated under lineage-specific culture environments. <em>In vivo</em> analysis was performed using scRNA-seq data from EC lineage reporter mice in atherosclerosis models.</div><div>EndMT-treated HUVECs displayed an intermediate mesenchymal phenotype, expressing CD44, CD73 and CD105 but lacking CD90, failing to meet MSC criteria. Potency analysis showed that 77 % of EndMT-treated HUVECs remained oligopotent, while 19 % acquired osteogenic and chondrogenic potential, accompanied by activation of lineage-associated transcriptional programs (<em>RUNX2</em>, <em>BMPR1A</em>, <em>NOTCH2</em>, <em>WNT5A</em>; <em>CD151</em>, <em>ANXA6</em>, <em>DCN</em>). <em>In vivo</em>, endothelial lineage-traced cells in atherosclerotic mice formed an EndMT cluster enriched for osteogenic and chondrogenic gene programs, including ossification and cartilage development pathways.</div><div>We define a primed oligopotent state of EndMT-derived cells both <em>in vitro</em> and <em>in vivo</em>, marked by transition toward osteogenic and chondrogenic fates. These findings suggest that EndMT contributes to atherosclerosis by generating osteogenic- and chondrogenic-like cells, linking endothelial dysfunction to vascular calcification in disease.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"162 ","pages":"Article 107579"},"PeriodicalIF":3.5,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145879118","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 : 2025-12-25DOI: 10.1016/j.vph.2025.107578
Reza Bozorgpour
Predicting which intracranial aneurysms will progress to rupture remains a major unmet need in neurosurgical practice. Conventional imaging provides limited insight into the hemodynamic forces acting on the aneurysm wall, yet these forces play a central role in its long-term stability. To address this limitation, we developed a patient-specific computational pipeline capable of converting routine MRA data into detailed maps of aneurysmal blood-flow dynamics. The tool reconstructs vascular geometry directly from imaging and quantifies hemodynamic biomarkers associated with rupture risk, enabling clinicians to access physiologically meaningful information that is not visible on structural imaging alone.
Using this framework, we analyzed six aneurysm cases with known longitudinal outcomes to determine whether baseline flow conditions differed between lesions that later ruptured and those that remained stable. High-resolution CFD simulations were used to compute wall shear stress (WSS), time-averaged WSS (TAWSS), oscillatory shear index (OSI), relative residence time (RRT), and endothelial cell activation potential (ECAP). Distinct hemodynamic patterns emerged: aneurysms that remained stable showed higher WSS/TAWSS and lower OSI/RRT, whereas aneurysms that ultimately ruptured exhibited low shear environments, stronger oscillatory flow, and greater endothelial activation. Regions with elevated OSI and RRT frequently coincide with vortex cores, suggesting localized flow disturbances that may serve as early indicators of wall vulnerability.
These results demonstrate that clinically acquired MRA, when paired with a dedicated computational tool, can reveal baseline hemodynamic signatures predictive of future aneurysm behavior. This approach offers a noninvasive, imaging-driven method to support clinical decision-making, refine surveillance strategies, and improve individualized management of patients with intracranial aneurysms.
{"title":"Hemodynamic markers: CFD-based prediction of cerebral aneurysm rupture risk","authors":"Reza Bozorgpour","doi":"10.1016/j.vph.2025.107578","DOIUrl":"10.1016/j.vph.2025.107578","url":null,"abstract":"<div><div>Predicting which intracranial aneurysms will progress to rupture remains a major unmet need in neurosurgical practice. Conventional imaging provides limited insight into the hemodynamic forces acting on the aneurysm wall, yet these forces play a central role in its long-term stability. To address this limitation, we developed a patient-specific computational pipeline capable of converting routine MRA data into detailed maps of aneurysmal blood-flow dynamics. The tool reconstructs vascular geometry directly from imaging and quantifies hemodynamic biomarkers associated with rupture risk, enabling clinicians to access physiologically meaningful information that is not visible on structural imaging alone.</div><div>Using this framework, we analyzed six aneurysm cases with known longitudinal outcomes to determine whether baseline flow conditions differed between lesions that later ruptured and those that remained stable. High-resolution CFD simulations were used to compute wall shear stress (WSS), time-averaged WSS (TAWSS), oscillatory shear index (OSI), relative residence time (RRT), and endothelial cell activation potential (ECAP). Distinct hemodynamic patterns emerged: aneurysms that remained stable showed higher WSS/TAWSS and lower OSI/RRT, whereas aneurysms that ultimately ruptured exhibited low shear environments, stronger oscillatory flow, and greater endothelial activation. Regions with elevated OSI and RRT frequently coincide with vortex cores, suggesting localized flow disturbances that may serve as early indicators of wall vulnerability.</div><div>These results demonstrate that clinically acquired MRA, when paired with a dedicated computational tool, can reveal baseline hemodynamic signatures predictive of future aneurysm behavior. This approach offers a noninvasive, imaging-driven method to support clinical decision-making, refine surveillance strategies, and improve individualized management of patients with intracranial aneurysms.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"162 ","pages":"Article 107578"},"PeriodicalIF":3.5,"publicationDate":"2025-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145840600","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}
Recent randomized clinical trials (RCTs) have demonstrated the efficacy of sotatercept in the treatment of pulmonary arterial hypertension (PAH), leading to its approval by both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This novel first-in-class fusion protein acts as a ligand trap for select members of the transforming growth factor-beta (TGF-β) superfamily, thereby exerting a broad spectrum of biological effects. These include vascular remodeling (via Activin A and B inhibition), enhancement of angiogenesis (through modulation of BMP-9), stimulation of erythropoiesis (by targeting GDF-11), and, to a lesser extent, modulation of skeletal muscle homeostasis (through GDF-8/myostatin inhibition). This review focuses on the pleiotropic effects of sotatercept, with the aim of encouraging the reader to delve deeper into the drug's multifaceted mechanisms.
{"title":"The pleiotropic effects of sotatercept","authors":"Giovanna Manzi, Enrico Maggio, Tommaso Recchioni, Francesca Ileana Adamo, Annalisa Caputo, Alexandra Mihai, Silvia Papa, Giorgia Serino, Gianmarco Scoccia, Roberto Badagliacca, Carmine Dario Vizza","doi":"10.1016/j.vph.2025.107577","DOIUrl":"10.1016/j.vph.2025.107577","url":null,"abstract":"<div><div>Recent randomized clinical trials (RCTs) have demonstrated the efficacy of sotatercept in the treatment of pulmonary arterial hypertension (PAH), leading to its approval by both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This novel first-in-class fusion protein acts as a ligand trap for select members of the transforming growth factor-beta (TGF-β) superfamily, thereby exerting a broad spectrum of biological effects. These include vascular remodeling (via Activin A and B inhibition), enhancement of angiogenesis (through modulation of BMP-9), stimulation of erythropoiesis (by targeting GDF-11), and, to a lesser extent, modulation of skeletal muscle homeostasis (through GDF-8/myostatin inhibition). This review focuses on the pleiotropic effects of sotatercept, with the aim of encouraging the reader to delve deeper into the drug's multifaceted mechanisms.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"162 ","pages":"Article 107577"},"PeriodicalIF":3.5,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145811549","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 : 2025-12-04DOI: 10.1016/j.vph.2025.107571
Chuyan Long , Mouwen Lin , Wenjie Wang , Yang Liu , Zixi Huang , Zhenyan Xu
Pulmonary hypertension (PH) is a life-threatening condition characterized by progressive pulmonary vascular remodeling, and endothelial-mesenchymal transition (EndMT) is recognized as a critical pathogenic process driving this remodeling. This study investigated the role of microplastics (MPs) in promoting EndMT in human pulmonary artery endothelial cells (HPAECs) and its underlying regulatory mechanism. We demonstrated that MPs were internalized by HPAECs, leading to significant downregulation of endothelial markers (CD31 and VE-cadherin) and upregulation of mesenchymal markers (α-SMA and vimentin), thereby promoting EndMT. In a rat model of PH induced by monocrotaline, intratracheal instillation of MPs further increased right ventricular and pulmonary arterial pressures, exacerbated vascular remodeling, and enhanced inflammatory infiltration. RNA-seq analysis revealed that MPs activated inflammatory pathways and enhanced glycolysis in HPAECs, with significant upregulation of glycolytic genes such as HK2. Knockdown of HK2 attenuated the cell viability and migratory ability of HPAECs and counteracted MP-induced EndMT. Additionally, MPs increased lactate production and histone lactylation, which were reversed by HK2 interference. ChIP-seq further confirmed the altered histone lactylation by MPs in HPAECs, including 603 genes with hyper-lactylation and 1292 genes with hypo-lactylation. Genes with hyper-lactylation were related to inflammation, and genes with hypo-lactylation were associated with epithelial/endothelial cell migration, angiogenesis, and vascular endothelial growth factor signaling pathway. Integrative analysis of the RNA-seq and ChIP-seq data identified four PH- and inflammation-associated differentially expressed genes exhibiting hyper-lactylation (FOXO3, RUNX1, TNFRSF11B, and SGK1). Among them, RT-PCR and ChIP-qPCR confirmed the upregulation and increased histone lactylation of TNFRSF11B and SGK1. These findings highlight the critical role of MPs in modulating metabolic and histone lactylation in PH and suggest potential therapeutic targets for mitigating PH progression.
{"title":"RNA-seq and ChIP-seq reveal microplastics induce endothelial-mesenchymal transition via HK2-mediated histone lactylation in pulmonary hypertension","authors":"Chuyan Long , Mouwen Lin , Wenjie Wang , Yang Liu , Zixi Huang , Zhenyan Xu","doi":"10.1016/j.vph.2025.107571","DOIUrl":"10.1016/j.vph.2025.107571","url":null,"abstract":"<div><div>Pulmonary hypertension (PH) is a life-threatening condition characterized by progressive pulmonary vascular remodeling, and endothelial-mesenchymal transition (EndMT) is recognized as a critical pathogenic process driving this remodeling. This study investigated the role of microplastics (MPs) in promoting EndMT in human pulmonary artery endothelial cells (HPAECs) and its underlying regulatory mechanism. We demonstrated that MPs were internalized by HPAECs, leading to significant downregulation of endothelial markers (CD31 and VE-cadherin) and upregulation of mesenchymal markers (α-SMA and vimentin), thereby promoting EndMT. In a rat model of PH induced by monocrotaline, intratracheal instillation of MPs further increased right ventricular and pulmonary arterial pressures, exacerbated vascular remodeling, and enhanced inflammatory infiltration. RNA-seq analysis revealed that MPs activated inflammatory pathways and enhanced glycolysis in HPAECs, with significant upregulation of glycolytic genes such as HK2. Knockdown of HK2 attenuated the cell viability and migratory ability of HPAECs and counteracted MP-induced EndMT. Additionally, MPs increased lactate production and histone lactylation, which were reversed by HK2 interference. ChIP-seq further confirmed the altered histone lactylation by MPs in HPAECs, including 603 genes with hyper-lactylation and 1292 genes with hypo-lactylation. Genes with hyper-lactylation were related to inflammation, and genes with hypo-lactylation were associated with epithelial/endothelial cell migration, angiogenesis, and vascular endothelial growth factor signaling pathway. Integrative analysis of the RNA-seq and ChIP-seq data identified four PH- and inflammation-associated differentially expressed genes exhibiting hyper-lactylation (FOXO3, RUNX1, TNFRSF11B, and SGK1). Among them, RT-PCR and ChIP-qPCR confirmed the upregulation and increased histone lactylation of TNFRSF11B and SGK1. These findings highlight the critical role of MPs in modulating metabolic and histone lactylation in PH and suggest potential therapeutic targets for mitigating PH progression.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"162 ","pages":"Article 107571"},"PeriodicalIF":3.5,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696411","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 : 2025-12-03DOI: 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}
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