Pub Date : 2025-01-01Epub Date: 2025-03-28DOI: 10.1016/j.jvssci.2025.100285
Sean M. Carr PhD, Ottis Scrivner PhD, Katherine Elizabeth Hekman MD, PhD
Objective
Several decades of medical research have shown an intricate and definitive connection between dysfunctional endothelium and cardiovascular disorders, including atherosclerosis and peripheral artery disease (PAD). Initial investigations into endothelial cell (EC) physiology highlighted excretion of protein-based growth factors and their signaling pathways with highly specific targets. However, more recent research has focused on nonprotein metabolic signaling.
Methods
A narrative review methodology was used. The review involved keyword searches of electronic databases, including Medline and ScienceDirect, conducted in March through October 2022. Review search terms included “endothelial cell metabolism,” “peripheral artery disease metabolism,” “angiogenesis metabolism,” and “endothelial cell metabolic regulation.” The search included primary research articles and subject matter narrative reviews. Abstracts were reviewed for English-language articles published between 2003 and 2022 and supplemented with targeted reference tracing.
Results
Small-molecular-weight metabolites have been found to regulate key EC functions such as angiogenesis directly. More specifically, they impact EC behavior through control of energy production, de novo biomass synthesis, redox homeostasis, and production of gases like nitric oxide and hydrogen sulfide. Recent investigations targeting these metabolic pathways have yielded preliminary success in correcting undesirable endothelial dysfunction in atherosclerosis and PAD.
Conclusions
Further investigations into therapeutic targeting of EC metabolism may yield novel approaches for treating PAD.
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Pub Date : 2025-01-01Epub Date: 2025-08-28DOI: 10.1016/j.jvssci.2025.100393
Pierce L. Massie MD , Marcus A. Garcia PharmD , Daniel Gallego MD , Christopher Schlosser PA , Aerlin Decker BSPS , Rui Liu PhD , Milad MazloumiBakhshayesh MPharm , Deepali Kulkarni MD , Matthew P. Justus MS , Carolyn Pace BS , Rowza T. Rumma MD , Matthew J. Campen PhD , Ross M. Clark MD, MBA, FSVS
<div><h3>Objective</h3><div>As plastic production continues to accelerate, the byproducts increasingly fill the environment. Once degraded into micronanoplastics (MNPs), particles may circulate into food, drinking water, or air. Nascent literature has demonstrated MNP bioaccumulation within human tissues, such as the blood, brain, and solid organs. Only recently have MNPs been identified within thrombi and atherosclerotic plaques of diseased blood vessels, and these findings have been associated with adverse clinical outcomes. Data on MNP content in infrainguinal arterial occlusive disease is currently lacking, however. We investigated MNP presence within femoral artery plaques and examined patient clinical variables to characterize their associations in a territory commonly affected by peripheral arterial disease.</div></div><div><h3>Methods</h3><div>Common femoral artery plaques were collected from patients undergoing common femoral endarterectomy for medically refractory lower extremity peripheral arterial disease. These samples were then sectioned, frozen, and analyzed using pyrolysis gas chromatography/mass spectrometry for MNP content by polymer. A total of 12 polymers were investigated in triplicate. A group of decedent patients without clinical atherosclerosis served as control with whole carotid artery tissue used for a similar analysis.</div></div><div><h3>Results</h3><div>A total of 10 plaques from 8 patients were collected for the plaque group, and 30 whole carotids were gathered from decedents and age matched to the plaque group. The total MNP concentration was 80-fold higher in femoral plaque compared with the control group 3234 μg/g tissue vs 40.68 μg/g tissue for control arteries (<em>P</em> = .0001). By polymer, polyethylene, polystyrene, acrylonitrile butadiene styrene, styrene-butadiene, polyvinylchloride, polyethylene terephthalate, poly(methyl methacrylate), polycarbonate, nylon 66, and nylon 6 were all significantly elevated compared with control tissue. No differences in sex were detected in either group. Polypropylene content was positively correlated with age (<em>P</em> = .011). Within the plaque group, patients undergoing revascularization for chronic limb-threatening ischemia had a greater than three-fold concentration of PP (247 ± 113.6 μg/g vs 71.9 ± 73.5 μg/g) and 10-fold concentration of polyurethane (17.4 ± 12.1 μg/g vs 1.69 ± 2.9 μg/g) compared with those with claudication (<em>P</em> = .0381 and <em>P</em> = .0238, respectively).</div></div><div><h3>Conclusions</h3><div>This study demonstrates a greater accumulation of MNPs in common femoral artery plaques compared with nonatherosclerotic artery tissue. This finding further supports the premise that, despite similarities in age between groups, MNPs tend to be represented heavily in atherosclerotic tissues. Patients with chronic limb-threatening ischemia showed a greater concentration of some polymers compared with those with claudication, raising the question of
随着塑料生产的不断加速，其副产品越来越多地填满环境。一旦降解为微塑料（MNPs），颗粒可能会循环进入食物、饮用水或空气中。早期文献已经证明MNP在人体组织（如血液、大脑和实体器官）中具有生物蓄积性。直到最近才在病变血管的血栓和动脉粥样硬化斑块中发现MNPs，这些发现与不良临床结果有关。然而，腹股沟下动脉闭塞性疾病中MNP含量的数据目前缺乏。我们研究了MNP在股动脉斑块中的存在，并检查了患者的临床变量，以表征它们在通常受外周动脉疾病影响的区域中的关联。方法对难治性下肢外周动脉疾病行股总动脉内膜切除术的患者收集股总动脉斑块。然后对这些样品进行切片、冷冻，并使用热解气相色谱/质谱法分析聚合物的MNP含量。共研究了12种聚合物，一式三次。一组没有临床动脉粥样硬化的死亡患者作为对照组，用整个颈动脉组织进行类似的分析。结果斑块组共收集了8例患者的10个斑块，斑块组收集了与斑块组年龄匹配的死者的30个完整的颈动脉。与对照组相比，股骨斑块中MNP总浓度高80倍（3234 μg/g），对照组为40.68 μg/g （P = 0.0001）。经聚合物处理后，聚乙烯、聚苯乙烯、丙烯腈-丁二烯、苯乙烯-丁二烯、聚氯乙烯、聚对苯二甲酸乙二醇酯、聚甲基丙烯酸甲酯、聚碳酸酯、尼龙66和尼龙6均显著高于对照组织。在两组中均未发现性别差异。聚丙烯含量与年龄呈正相关（P = 0.011）。在斑块组中，慢性肢体缺血血运重建患者的PP浓度（247±113.6 μg/g vs 71.9±73.5 μg/g）和聚氨酯浓度（17.4±12.1 μg vs 1.69±2.9 μg/g）分别是跛行组的3倍和10倍（P = 0.0381和0.0238）。结论：本研究表明，与非动脉粥样硬化组织相比，MNPs在股动脉总斑块中的积累更多。这一发现进一步支持了一个前提，即尽管组间年龄相似，但MNPs往往在动脉粥样硬化组织中大量存在。与跛行患者相比，慢性肢体威胁缺血患者的某些聚合物浓度更高，这就提出了不同个体聚合物与不同疾病严重程度相关的问题。这项研究表明，与健康的、未患病的人颈动脉相比，人股动脉粥样硬化斑块中微塑料（MNPs）水平较高。在肢体缺血或对照患者中，年龄和MNP水平之间没有明显的关联。与跛行相比，一些单独的聚合物与晚期动脉粥样硬化疾病（慢性肢体威胁缺血）有关。这些数据增加了越来越多的文献，表明MNP颗粒在动脉粥样硬化病变中积聚。未来的工作应该研究MNPs在血管粥样硬化疾病的病理生理中可能发挥的机制作用，如果有的话。
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Pub Date : 2025-01-01Epub Date: 2024-12-28DOI: 10.1016/j.jvssci.2024.100279
Marcos Vinícius Melo de Oliveira MD, PhD , Alexandre Malta Brandão MD, PhD , Gina Camillo Rocha Silvestre BS , Alexandre Queiroz Silva BS , Michele Alberto Marques BS , Marcia Martins Reis PhD , Maria de Lourdes Higuchi MD, PhD , Erasmo Simão da Silva MD, PhD
Objective
Infrarenal abdominal aortic aneurysm (AAA) and popliteal artery aneurysm (PAA) are localized arterial dilatations with distinct clinical outcomes. This study aimed to comprehensively compare these two types of aneurysms' biomechanical, histological, and immunohistochemical characteristics.
Methods
This study included 180 patients with AAA and 18 with PAA. Medical history and imaging data were collected. Biomechanical testing assessed arterial wall mechanical strength and elasticity, and histological and immunohistochemical analyses examined tissue composition and inflammatory markers.
Results
PAA wall fragments demonstrate higher failure strain energy (13.36 N/m2 vs 9.95 N/m2; P = .023), a measure of mechanical strength. Regarding immunohistochemical markers, AAA exhibited more B lymphocyte cells in the adventitia (CD20 1475.50 vs 320; P = .003) compared with PAA. Additionally, AAA demonstrated more adipogenic differentiation in the adventitia (PPARgamma 4854.50 vs 778; P = .009), whereas PAA showed more adipogenic differentiation in the intima (KLF5 283.50 vs 77.50; P = .039).
Conclusions
PAA wall fragments demonstrate greater mechanical strength compared with AAA wall fragments. In contrast, AAA walls contain a greater number of B lymphocytes within the adventitia compared with PAA walls. Adipogenic differentiation is more pronounced in the adventitia of AAA than in PAA, whereas in PAA, it is more prominent in the intima compared with AAA.
Clinical Relevance
The clinical significance of this study lies in its potential to enhance our understanding of the distinct pathophysiological mechanisms underlying abdominal aortic aneurysms, which is often associated with rupture, and popliteal artery aneurysms, which are more prone to thrombosis and distal embolization. By comprehensively comparing the biomechanical, histological, and immunohistochemical aspects of these two aneurysm types, the study aims to illuminate the factors contributing to their differing clinical presentations and outcomes.
目的：肾下腹主动脉瘤（AAA）和腘动脉动脉瘤（PAA）是两种具有不同临床结局的局限性动脉扩张。本研究旨在全面比较这两种动脉瘤的生物力学、组织学和免疫组织化学特征。方法本研究纳入AAA患者180例，PAA患者18例。收集病史和影像学资料。生物力学测试评估了动脉壁的机械强度和弹性，组织学和免疫组织化学分析检查了组织成分和炎症标志物。结果spaa壁片具有较高的破坏应变能（13.36 N/m2 vs 9.95 N/m2）；P = .023)，是机械强度的量度。在免疫组织化学标志物方面，AAA在外膜中显示更多的B淋巴细胞(CD20 1475.50 vs 320；P = .003)。此外，AAA表现出更多的外膜脂肪分化(PPARgamma 4854.50 vs 778；P = 0.009)，而PAA在内膜中显示更多的脂肪分化(KLF5 283.50 vs 77.50；p = .039)。结论spaa壁片比AAA壁片具有更高的机械强度。相反，与PAA壁相比，AAA壁在外膜内含有更多的B淋巴细胞。AAA的外膜比PAA的脂肪分化更明显，而PAA的内膜比AAA的脂肪分化更突出。临床意义本研究的临床意义在于，它有可能加深我们对腹主动脉瘤不同的病理生理机制的理解，腹主动脉瘤常伴有破裂，腘动脉动脉瘤更容易形成血栓和远端栓塞。通过全面比较这两种动脉瘤类型的生物力学、组织学和免疫组织化学方面，本研究旨在阐明导致其不同临床表现和结果的因素。
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Pub Date : 2025-01-01Epub Date: 2025-01-17DOI: 10.1016/j.jvssci.2025.100280
Paul Cyréus MSc , Katarina Wadén MD , Sofie Hellberg MSc , Otto Bergman PhD , Mariette Lengquist MSc , Eva Karlöf MD, PhD , Andrew Buckler PhD , Ljubica Matic PhD , Joy Roy MD, PhD , David Marlevi PhD , Melody Chemaly PhD , Ulf Hedin MD, PhD
<div><h3>Objective</h3><div>Carotid endarterectomy for symptomatic carotid stenosis is recommended for patients with >70% stenosis, but not in those with <50%. Because non-significant, low-degree stenoses may still cause strokes, refined risk stratification is necessary, which could be improved by assessing biological features of plaque instability. To challenge risk-stratification based on luminal narrowing, we compared biological features of carotid plaques from symptomatic patients with low-degree (<50%) vs high-degree (>70%) stenosis and explored potential mechanisms behind plaque instability in low-degree stenoses.</div></div><div><h3>Methods</h3><div>Endarterectomy specimens were taken from symptomatic patients with high-degree (n = 204) and low-degree (n = 34) stenosis, all part of the Biobank of Karolinska Endarterectomies. Patient demographics, image-derived plaque morphology, and gene expression analyses of extracted lesions were used for comparisons. Plaque biology was assessed by transcriptomics using dimensionality reduction, differential gene expression, and gene-set enrichment analyses. Immunohistochemistry was used to study proteins corresponding to upregulated genes.</div></div><div><h3>Results</h3><div>The demographics of the two groups were statistically similar. Calcification, lipid-rich necrotic core, intraplaque hemorrhage, plaque burden, and fibrous cap thickness were similar in both groups, whereas the sum of lipid-rich necrotic core and intraplaque hemorrhage was higher (<em>P</em> = .033) in the high-degree stenosis group. Dimensionality reduction analysis indicated poor clustering separation of plaque gene expression in low-compared with high-degree stenosis lesions, whereas differential gene expression showed upregulation of hypoxia-inducible factor 3A (log<sub>2</sub> fold change, 0.7212; <em>P</em> = .0003), and gene-set enrichment analyses identified pathways related to tissue hypoxia and angiogenesis in low-degree stenoses. Hypoxia-inducible factor 3-alpha protein was associated with smooth muscle cells in neo-vascularized plaque regions.</div></div><div><h3>Conclusions</h3><div>Plaques from symptomatic patients with non-significant low-degree carotid stenoses showed morphologic and biological features of atherosclerotic plaque instability that were comparable to plaques from patients with high-degree stenoses, emphasizing the need for improved stroke risk stratification for intervention in all patients with symptomatic carotid stenosis irrespective of luminal narrowing. An increased expression of hypoxia-inducible factor 3A in low-degree stenotic lesions suggested mechanisms of plaque instability associated with tissue hypoxia and plaque angiogenesis, but the exact role of hypoxia-inducible factor 3A in this process remains to be determined.</div></div><div><h3>Clinical relevance</h3><div>Carotid plaques from symptomatic patients with <50% stenosis show morphologic and biological features of plaque
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Pub Date : 2025-01-01Epub Date: 2025-05-08DOI: 10.1016/j.jvssci.2025.100290
Samuel Khodursky PhD , Shuai Yuan PhD , Joshua M. Spin MD, PhD , Philip S. Tsao PhD , Michael G. Levin MD , Scott M. Damrauer MD
Objective
Abdominal aortic aneurysm (AAA) is a common and life-threatening vascular disease. Genetic studies have identified numerous risk loci, many potentially encoding plasma proteins. However, the causal effects of plasma proteins on AAAs have not been thoroughly studied. We used genetic causal inference approaches to identify plasma proteins that have a potential causal impact on AAAs.
Methods
Causal inference was performed using two-sample Mendelian randomization (MR). For AAAs, we utilized recently published summary statistics from a multi-population genome-wide association meta-analysis including 39,221 individuals with and 1,086,107 individuals without AAAs from 14 cohorts. We used protein quantitative trait loci (protein quantitative trait loci) identified in two large-scale plasma-proteomics studies (deCODE and UKB-PPP) to generate genetic instruments. We tested 2783 plasma proteins for possible causal effects on AAAs using two-sample MR with inverse variance weighting with common sensitivity analyses.
Results
MR identified 90 plasma proteins associated with AAAs at a false discovery rate <0.05, with 25 supported by colocalization analysis. Among those supported by both MR and colocalization were proteins such as PCSK9 (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.2-1.4; P < 1e-10), LTBP4 (OR, 3.4; 95% CI, 2.6-4.6; P < 1e-10), and COL6A3 (OR, 0.6; 95% CI, 0.5-0.7; P < 1e-6). Gene Ontology analysis revealed enrichment of proteins (extracellular matrix; OR, 7.8; P < 1e-4), some with maximal mRNA levels in aortic tissue. Bi-directional MR suggested plasma level changes were not caused by liability to AAA itself. Colocalization analysis showed that an aortic expression quantitative trait locus for COL6A3, and a splicing quantitative trait locus for LTBP4 colocalized with their respective plasma pQTLs and AAA signals.
Conclusions
Our results highlight proteins and pathways with potential causal effects on AAAs, providing a foundation for future functional experiments. These findings suggest a possible causal pathway whereby genetic variation affecting extracellular matrix proteins expressed in the aortic wall cause their levels to change in blood plasma, influencing development of AAAs.
{"title":"Plasma proteome-wide Mendelian randomization reveals the association of extracellular matrix proteins with abdominal aortic aneurysm","authors":"Samuel Khodursky PhD , Shuai Yuan PhD , Joshua M. Spin MD, PhD , Philip S. Tsao PhD , Michael G. Levin MD , Scott M. Damrauer MD","doi":"10.1016/j.jvssci.2025.100290","DOIUrl":"10.1016/j.jvssci.2025.100290","url":null,"abstract":"<div><h3>Objective</h3><div>Abdominal aortic aneurysm (AAA) is a common and life-threatening vascular disease. Genetic studies have identified numerous risk loci, many potentially encoding plasma proteins. However, the causal effects of plasma proteins on AAAs have not been thoroughly studied. We used genetic causal inference approaches to identify plasma proteins that have a potential causal impact on AAAs.</div></div><div><h3>Methods</h3><div>Causal inference was performed using two-sample Mendelian randomization (MR). For AAAs, we utilized recently published summary statistics from a multi-population genome-wide association meta-analysis including 39,221 individuals with and 1,086,107 individuals without AAAs from 14 cohorts. We used protein quantitative trait loci (protein quantitative trait loci) identified in two large-scale plasma-proteomics studies (deCODE and UKB-PPP) to generate genetic instruments. We tested 2783 plasma proteins for possible causal effects on AAAs using two-sample MR with inverse variance weighting with common sensitivity analyses.</div></div><div><h3>Results</h3><div>MR identified 90 plasma proteins associated with AAAs at a false discovery rate <0.05, with 25 supported by colocalization analysis. Among those supported by both MR and colocalization were proteins such as PCSK9 (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.2-1.4; <em>P</em> < 1e-10), LTBP4 (OR, 3.4; 95% CI, 2.6-4.6; <em>P</em> < 1e-10), and COL6A3 (OR, 0.6; 95% CI, 0.5-0.7; <em>P</em> < 1e-6). Gene Ontology analysis revealed enrichment of proteins (extracellular matrix; OR, 7.8; <em>P</em> < 1e-4), some with maximal mRNA levels in aortic tissue. Bi-directional MR suggested plasma level changes were not caused by liability to AAA itself. Colocalization analysis showed that an aortic expression quantitative trait locus for COL6A3, and a splicing quantitative trait locus for LTBP4 colocalized with their respective plasma pQTLs and AAA signals.</div></div><div><h3>Conclusions</h3><div>Our results highlight proteins and pathways with potential causal effects on AAAs, providing a foundation for future functional experiments. These findings suggest a possible causal pathway whereby genetic variation affecting extracellular matrix proteins expressed in the aortic wall cause their levels to change in blood plasma, influencing development of AAAs.</div></div>","PeriodicalId":74035,"journal":{"name":"JVS-vascular science","volume":"6 ","pages":"Article 100290"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144306431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-12-30DOI: 10.1016/j.jvssci.2024.100278
Leela Morena MD , Isabella Ferlini Cieri MD , Daniel Marconi Mendes PhD , Sasha P. Suarez Ferreira MD , Shiv Patel BS , Samir Ghandour MD , Maria Fernanda Andrade BS , Mohit Manchella BS , Adriana A. Rodriguez MD , Henry Davies MBBS, MD, MRSC , Shruti Sharma PhD , Anahita Dua MD, MS, MBA
Objective
To investigate the mechanisms through which platelets and antiplatelet therapies modulate the immune response and propose directions for future research in this field, with a particular emphasis on their impact on treatment efficacy and surgical outcomes.
Methods
A comprehensive review of recent studies investigating the role of platelets in immune modulation, specifically highlighting their involvement in pathogen recognition, leukocyte recruitment, and lymphocyte activation. Additionally, the review evaluates the impact of antiplatelet therapies, such as aspirin, P2Y12 inhibitors, and glycoprotein IIb/IIIa inhibitors, on immune responses.
Results
Recent studies have emphasized the critical role of platelets in immune-driven applications, namely, atherosclerosis, cancer, viral infections, and sepsis. These studies also suggest that antiplatelet therapies may alter immune responses. However, the precise mechanisms through which platelets and antiplatelet drugs influence immune responses, as well as their effects on post-treatment and surgical outcomes, are not yet fully elucidated.
Conclusions
Recent studies highlight the important role of platelets in immune processes, such as in atherosclerosis, cancer, viral infections, and sepsis, and suggest that antiplatelet therapies can influence immune responses. However, the exact mechanisms by which platelets and antiplatelet drugs modulate these responses remain unclear. This area presents valuable opportunities for future research to uncover these mechanisms, which could lead to novel therapeutic strategies and better clinical outcomes for patients.
{"title":"The impact of platelets and antiplatelets medications on immune mediation","authors":"Leela Morena MD , Isabella Ferlini Cieri MD , Daniel Marconi Mendes PhD , Sasha P. Suarez Ferreira MD , Shiv Patel BS , Samir Ghandour MD , Maria Fernanda Andrade BS , Mohit Manchella BS , Adriana A. Rodriguez MD , Henry Davies MBBS, MD, MRSC , Shruti Sharma PhD , Anahita Dua MD, MS, MBA","doi":"10.1016/j.jvssci.2024.100278","DOIUrl":"10.1016/j.jvssci.2024.100278","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate the mechanisms through which platelets and antiplatelet therapies modulate the immune response and propose directions for future research in this field, with a particular emphasis on their impact on treatment efficacy and surgical outcomes.</div></div><div><h3>Methods</h3><div>A comprehensive review of recent studies investigating the role of platelets in immune modulation, specifically highlighting their involvement in pathogen recognition, leukocyte recruitment, and lymphocyte activation. Additionally, the review evaluates the impact of antiplatelet therapies, such as aspirin, P2Y12 inhibitors, and glycoprotein IIb/IIIa inhibitors, on immune responses.</div></div><div><h3>Results</h3><div>Recent studies have emphasized the critical role of platelets in immune-driven applications, namely, atherosclerosis, cancer, viral infections, and sepsis. These studies also suggest that antiplatelet therapies may alter immune responses. However, the precise mechanisms through which platelets and antiplatelet drugs influence immune responses, as well as their effects on post-treatment and surgical outcomes, are not yet fully elucidated.</div></div><div><h3>Conclusions</h3><div>Recent studies highlight the important role of platelets in immune processes, such as in atherosclerosis, cancer, viral infections, and sepsis, and suggest that antiplatelet therapies can influence immune responses. However, the exact mechanisms by which platelets and antiplatelet drugs modulate these responses remain unclear. This area presents valuable opportunities for future research to uncover these mechanisms, which could lead to novel therapeutic strategies and better clinical outcomes for patients.</div></div>","PeriodicalId":74035,"journal":{"name":"JVS-vascular science","volume":"6 ","pages":"Article 100278"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143937845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-10-10DOI: 10.1016/j.jvssci.2025.100394
Fujie Zhao MD, PhD , Feifei Li MD, PhD , Farbod Sedaghati PhD , Hai Dong PhD , Sandeep Kumar PhD , Dennis Gene Foster MD , Jim Otto PhD , Dana Giangiacomo BS , Lucas H. Timmins PhD , Maiko Sasaki MS, MPH , Gloriani Sanchez Marrero BS , Kyung In Baek PhD , Michael Tu BS , Sandra Peprah MD , Xiangqin Cui PhD , Jeffrey H. Lawson MD, PhD , Rudolph L. Gleason PhD , Hanjoong Jo PhD , Luke Brewster MD, PhD
Objective
The objectives of this work are to: define murine femoral artery stiffening with age and the modifiability of this process by exercise; impose peripheral arterial disease (PAD) hemodynamics on murine femoral arteries and to deliver focal atherosclerotic plaque to femoral arteries; and test piezo-type mechanosensitive ion channel component 1 (PIEZO1) expression in human and murine femoral arteries of PAD.
Methods
We used a running wheel to exercise young and old S129 mice and biomechanical testing to quantify changes in arterial stiffness. We created a novel partial femoral artery ligation (PFL) model to impose PAD hemodynamics via low wall shear stress (WSS) to create a flow-mediated model of arterial aging in femoral arteries. In vivo mechanics were defined with ultrasound. Ex vivo arteries underwent biaxial tests. Atherogenic conditions were induced using PCSK9 infection and a high-fat diet. Arterial remodeling and PIEZO1 expression were quantified by histology.
Results
Femoral arteries are naturally stiffer than carotid arteries; both stiffen further with aging, but exercise improved compliance in old femoral arteries. PFL imposed low WSS and stiffening, similar to that seen in aging. Under atherogenic conditions, PFL delivered focal atherosclerotic plaques in femoral arteries. Low WSS increased PIEZO1 expression in femoral arteries (∼1.8× in endothelial cells, ∼2.4× in smooth muscle cells, and ∼2.8× in macrophages). Human PAD arteries with high-grade stenosis validated increased PIEZO1 mRNA (∼1.83×).
Conclusions
Femoral artery mechanics differ significantly from the carotid artery but can be modified by exercise. This PFL model confers arterial stiffness, and under atherogenic conditions, delivers focal femoral atherosclerotic plaque. PIEZO1 expression increases in both PFL-treated mouse femoral arteries and human PAD arteries with severe stenosis, supporting this as a translational target for PAD.
Clinical Relevance
Peripheral artery disease (PAD) is the third most common atherosclerotic bed. PAD is associated with increased risk of limb loss and death, but the mechanisms driving site-specific arterial remodeling in PAD remain unclear. This work uniquely creates a model of PAD that incorporates arterial stiffening via aging and flow disturbances and inducing atherosclerotic plaque into the murine femoral artery. By comparing murine femoral arteries with PAD arteries, piezo-type mechanosensitive ion channel component 1 (PIEZO1) was discovered as key mediator linking PAD blood flow and stiffening to untoward changes in endothelial cells, smooth muscle cells, and macrophages within femoral arteries. Targeted modulation of PIEZO1 activity provide PAD-centric therapeutic strategies and help promote the vascular health, life, and limb outcomes in patients with PAD.
{"title":"Piezo-type mechanosensitive ion channel component 1 (PIEZO1) is upregulated in peripheral arterial disease (PAD) and a novel murine PAD model","authors":"Fujie Zhao MD, PhD , Feifei Li MD, PhD , Farbod Sedaghati PhD , Hai Dong PhD , Sandeep Kumar PhD , Dennis Gene Foster MD , Jim Otto PhD , Dana Giangiacomo BS , Lucas H. Timmins PhD , Maiko Sasaki MS, MPH , Gloriani Sanchez Marrero BS , Kyung In Baek PhD , Michael Tu BS , Sandra Peprah MD , Xiangqin Cui PhD , Jeffrey H. Lawson MD, PhD , Rudolph L. Gleason PhD , Hanjoong Jo PhD , Luke Brewster MD, PhD","doi":"10.1016/j.jvssci.2025.100394","DOIUrl":"10.1016/j.jvssci.2025.100394","url":null,"abstract":"<div><h3>Objective</h3><div>The objectives of this work are to: define murine femoral artery stiffening with age and the modifiability of this process by exercise; impose peripheral arterial disease (PAD) hemodynamics on murine femoral arteries and to deliver focal atherosclerotic plaque to femoral arteries; and test piezo-type mechanosensitive ion channel component 1 (PIEZO1) expression in human and murine femoral arteries of PAD.</div></div><div><h3>Methods</h3><div>We used a running wheel to exercise young and old S129 mice and biomechanical testing to quantify changes in arterial stiffness. We created a novel partial femoral artery ligation (PFL) model to impose PAD hemodynamics via low wall shear stress (WSS) to create a flow-mediated model of arterial aging in femoral arteries. In vivo mechanics were defined with ultrasound. Ex vivo arteries underwent biaxial tests. Atherogenic conditions were induced using PCSK9 infection and a high-fat diet. Arterial remodeling and PIEZO1 expression were quantified by histology.</div></div><div><h3>Results</h3><div>Femoral arteries are naturally stiffer than carotid arteries; both stiffen further with aging, but exercise improved compliance in old femoral arteries. PFL imposed low WSS and stiffening, similar to that seen in aging. Under atherogenic conditions, PFL delivered focal atherosclerotic plaques in femoral arteries. Low WSS increased PIEZO1 expression in femoral arteries (∼1.8× in endothelial cells, ∼2.4× in smooth muscle cells, and ∼2.8× in macrophages). Human PAD arteries with high-grade stenosis validated increased PIEZO1 mRNA (∼1.83×).</div></div><div><h3>Conclusions</h3><div>Femoral artery mechanics differ significantly from the carotid artery but can be modified by exercise. This PFL model confers arterial stiffness, and under atherogenic conditions, delivers focal femoral atherosclerotic plaque. PIEZO1 expression increases in both PFL-treated mouse femoral arteries and human PAD arteries with severe stenosis, supporting this as a translational target for PAD.</div></div><div><h3>Clinical Relevance</h3><div>Peripheral artery disease (PAD) is the third most common atherosclerotic bed. PAD is associated with increased risk of limb loss and death, but the mechanisms driving site-specific arterial remodeling in PAD remain unclear. This work uniquely creates a model of PAD that incorporates arterial stiffening via aging and flow disturbances and inducing atherosclerotic plaque into the murine femoral artery. By comparing murine femoral arteries with PAD arteries, piezo-type mechanosensitive ion channel component 1 (PIEZO1) was discovered as key mediator linking PAD blood flow and stiffening to untoward changes in endothelial cells, smooth muscle cells, and macrophages within femoral arteries. Targeted modulation of PIEZO1 activity provide PAD-centric therapeutic strategies and help promote the vascular health, life, and limb outcomes in patients with PAD.</div></div>","PeriodicalId":74035,"journal":{"name":"JVS-vascular science","volume":"6 ","pages":"Article 100394"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145527958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-12-18DOI: 10.1016/j.jvssci.2024.100277
Blair E. Warren MD, MSCS , Kong-Teng Tan MD , Dheeraj K. Rajan MD , Miranda Witheford MD, PhD , Sean Crawford MD, MSc , Arash Jaberi MD, MEd , Sebastian Mafeld MBBS
Background
Peripheral arterial disease (PAD) is a common source of morbidity and mortality globally and is expected to raise increase in prevalence. Many endovascular techniques exist to manage PAD; however, there remains room for improvement, especially as it relates to below-the-knee vessels. Recent evidence and devices are leading to a resurgence of interest in bioresorbable vascular scaffolds and the -limus family of antiproliferative drugs in the PAD treatment space.
Methods
This nonsystematic review examines emerging technology for treatment of PAD with a specific focus on below-the-knee vessels and bioresorbable vascular scaffolds. Additional emerging and early technology such as novel delivery platforms are also briefly discussed with directions of future research highlighted.
Results
Bioresorbable vascular scaffold biomechanics and history are highlighted. Foundational knowledge of antiproliferative agents and evolving agents in peripheral vascular disease are also described.
Conclusions
Bioresorbable vascular scaffolds are an additional endovascular tool for the treatment of peripheral vascular disease. The integration with an antiproliferative agent may result in improved patency and performance; however, there is a paucity of data in the literature at present.
{"title":"Moving away from metal: Step toward the future with bioresorbable vascular scaffolds and novel antiproliferative agents","authors":"Blair E. Warren MD, MSCS , Kong-Teng Tan MD , Dheeraj K. Rajan MD , Miranda Witheford MD, PhD , Sean Crawford MD, MSc , Arash Jaberi MD, MEd , Sebastian Mafeld MBBS","doi":"10.1016/j.jvssci.2024.100277","DOIUrl":"10.1016/j.jvssci.2024.100277","url":null,"abstract":"<div><h3>Background</h3><div>Peripheral arterial disease (PAD) is a common source of morbidity and mortality globally and is expected to raise increase in prevalence. Many endovascular techniques exist to manage PAD; however, there remains room for improvement, especially as it relates to below-the-knee vessels. Recent evidence and devices are leading to a resurgence of interest in bioresorbable vascular scaffolds and the -limus family of antiproliferative drugs in the PAD treatment space.</div></div><div><h3>Methods</h3><div>This nonsystematic review examines emerging technology for treatment of PAD with a specific focus on below-the-knee vessels and bioresorbable vascular scaffolds. Additional emerging and early technology such as novel delivery platforms are also briefly discussed with directions of future research highlighted.</div></div><div><h3>Results</h3><div>Bioresorbable vascular scaffold biomechanics and history are highlighted. Foundational knowledge of antiproliferative agents and evolving agents in peripheral vascular disease are also described.</div></div><div><h3>Conclusions</h3><div>Bioresorbable vascular scaffolds are an additional endovascular tool for the treatment of peripheral vascular disease. The integration with an antiproliferative agent may result in improved patency and performance; however, there is a paucity of data in the literature at present.</div></div>","PeriodicalId":74035,"journal":{"name":"JVS-vascular science","volume":"6 ","pages":"Article 100277"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143139171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01DOI: 10.1016/j.jvssci.2024.100195
Ali H. Hakim, Ulf Hedin
{"title":"Toll-Like Receptor 4, a potential therapeutic target of lower limb ischemic myopathy that raises further questions","authors":"Ali H. Hakim, Ulf Hedin","doi":"10.1016/j.jvssci.2024.100195","DOIUrl":"https://doi.org/10.1016/j.jvssci.2024.100195","url":null,"abstract":"","PeriodicalId":74035,"journal":{"name":"JVS-vascular science","volume":"60 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139824700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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