Pub Date : 2025-01-01Epub Date: 2025-05-05DOI: 10.1159/000546163
Min-Hyeok Jang, Song-Young Park, Sun Dong Kim, Sang Ho Lee
Background: Peripheral artery disease (PAD) is a prevalent and debilitating condition characterized by reduced blood flow to the lower limb extremities due to arterial plaque buildup. Traditional exercise/walking therapies have been used to improve vascular function and walking performance but suffer from low adherence rates due to pain and discomfort. Heat therapy has emerged as a promising alternative, showing similar improvements in vascular and cardiovascular function, often with higher adherence rates.
Summary: This review explores various forms of heat therapy, including passive and active modalities, and their effects on patients with PAD. Heat therapies have demonstrated similar or even superior outcomes compared to traditional exercise/walking therapies, with higher adherence rates.
Key messages: Despite promising results, further research is needed to standardize heat therapy protocol and understand the underlying mechanisms. Optimizing heat therapy could offer a viable, patient-friendly alternative to improve vascular function, reduce pain, and enhance quality of life in patients with PAD.
{"title":"Heat Therapy as a Viable Treatment for Peripheral Artery Disease: A Mini Review.","authors":"Min-Hyeok Jang, Song-Young Park, Sun Dong Kim, Sang Ho Lee","doi":"10.1159/000546163","DOIUrl":"10.1159/000546163","url":null,"abstract":"<p><strong>Background: </strong>Peripheral artery disease (PAD) is a prevalent and debilitating condition characterized by reduced blood flow to the lower limb extremities due to arterial plaque buildup. Traditional exercise/walking therapies have been used to improve vascular function and walking performance but suffer from low adherence rates due to pain and discomfort. Heat therapy has emerged as a promising alternative, showing similar improvements in vascular and cardiovascular function, often with higher adherence rates.</p><p><strong>Summary: </strong>This review explores various forms of heat therapy, including passive and active modalities, and their effects on patients with PAD. Heat therapies have demonstrated similar or even superior outcomes compared to traditional exercise/walking therapies, with higher adherence rates.</p><p><strong>Key messages: </strong>Despite promising results, further research is needed to standardize heat therapy protocol and understand the underlying mechanisms. Optimizing heat therapy could offer a viable, patient-friendly alternative to improve vascular function, reduce pain, and enhance quality of life in patients with PAD.</p>","PeriodicalId":17530,"journal":{"name":"Journal of Vascular Research","volume":" ","pages":"219-231"},"PeriodicalIF":2.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-07-17DOI: 10.1159/000547281
Eun-Mi Kim, Yeon-Hee Han, Phil-Sun Oh, Wang Qi, Seok-Tae Lim, Hwan-Jeong Jeong
Introduction: Mitochondria play a pivotal role as therapeutic targets in a range of disorders, including metabolic and neurodegenerative diseases. SS31, a peptide engineered to target mitochondria, offers potent antioxidant activity, positioning it as a promising therapeutic option. Nevertheless, the hydrophilic profile of SS31 poses challenges such as reduced stability, suboptimal delivery, and poor mitochondrial localization in clinical applications. This study was designed to develop a mitochondria-targeted liposomal carrier by conjugating SS31KRKC to the liposome surface (SS31-LP) and to investigate its biological effects in vitro.
Methods: A lysine-arginine-lysine-cysteine (KRKC) linker was incorporated with SS31 to facilitate surface conjugation to liposomes via thiol-based coupling. The hydrodynamic diameter and zeta potential of the resulting formulations were quantified to determine the optimal lipid-to-peptide ratio for mitochondrial targeting. The in vitro mitochondrial localization, cytotoxicity, antioxidant potential, and anti-apoptotic efficacy of SS31-LP were evaluated in HUVECs and C2C12 cells.
Results: SS31-LP demonstrated pronounced mitochondrial localization and showed variable cellular internalization based on zeta potential. Pretreatment with SS31-LP enhanced cellular viability, mitigated oxidative damage, and reduced apoptosis in response to oxidative stress caused by H2O2 or blue LEDs.
Conclusion: Overall, SS31-LP presents a valuable therapeutic strategy for cellular protection against oxidative injury and may be an advantageous platform for targeted drug-delivery applications.
{"title":"Mitochondria-Targeted SS31-Conjugated Liposome Attenuates Oxidative Stress in Endothelial and Skeletal Muscle Cells.","authors":"Eun-Mi Kim, Yeon-Hee Han, Phil-Sun Oh, Wang Qi, Seok-Tae Lim, Hwan-Jeong Jeong","doi":"10.1159/000547281","DOIUrl":"10.1159/000547281","url":null,"abstract":"<p><strong>Introduction: </strong>Mitochondria play a pivotal role as therapeutic targets in a range of disorders, including metabolic and neurodegenerative diseases. SS31, a peptide engineered to target mitochondria, offers potent antioxidant activity, positioning it as a promising therapeutic option. Nevertheless, the hydrophilic profile of SS31 poses challenges such as reduced stability, suboptimal delivery, and poor mitochondrial localization in clinical applications. This study was designed to develop a mitochondria-targeted liposomal carrier by conjugating SS31KRKC to the liposome surface (SS31-LP) and to investigate its biological effects in vitro.</p><p><strong>Methods: </strong>A lysine-arginine-lysine-cysteine (KRKC) linker was incorporated with SS31 to facilitate surface conjugation to liposomes via thiol-based coupling. The hydrodynamic diameter and zeta potential of the resulting formulations were quantified to determine the optimal lipid-to-peptide ratio for mitochondrial targeting. The in vitro mitochondrial localization, cytotoxicity, antioxidant potential, and anti-apoptotic efficacy of SS31-LP were evaluated in HUVECs and C2C12 cells.</p><p><strong>Results: </strong>SS31-LP demonstrated pronounced mitochondrial localization and showed variable cellular internalization based on zeta potential. Pretreatment with SS31-LP enhanced cellular viability, mitigated oxidative damage, and reduced apoptosis in response to oxidative stress caused by H<sub>2</sub>O<sub>2</sub> or blue LEDs.</p><p><strong>Conclusion: </strong>Overall, SS31-LP presents a valuable therapeutic strategy for cellular protection against oxidative injury and may be an advantageous platform for targeted drug-delivery applications.</p>","PeriodicalId":17530,"journal":{"name":"Journal of Vascular Research","volume":" ","pages":"274-288"},"PeriodicalIF":2.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-07-28DOI: 10.1159/000547636
Jacob Widaeus, Ingemar Fredriksson, Sara Tehrani
Background: Microvascular dysfunction is implicated in a range of acute and chronic conditions, ranging from cardiovascular disease to sepsis, often preceding organ damage and clinical symptoms. Within conditions such as diabetes or septic shock, microvascular compromise frequently correlates with disease severity and outcomes, emphasizing the importance of timely, targeted assessment. Noninvasive bedside methods for evaluating microvascular function have rapidly evolved, driven by advances in computational power, artificial intelligence, and novel imaging hardware.
Summary: This review provides an overview of clinically feasible noninvasive techniques - including optical coherence tomography angiography, handheld videomicroscopy, laser speckle contrast imaging, reflectance spectroscopy, and related techniques. These methods allow observation under resting conditions and can be combined with functional tests such as post-occlusive reactive hyperemia, heating provocation, or iontophoresis to evaluate microvascular function.
Key messages: Collectively, these methods provide valuable insights into the structural and functional aspects of the microcirculation, but their clinical application is constrained by need for standardized protocols, validation, and evidence linking microvascular metrics to meaningful patient outcomes. Collaborations among academia, industry, and healthcare remain pivotal to transitioning these methods into regulated, accessible devices. As standardization progresses and evidence grows, this integrative approach of evaluating microvascular function may emerge as a mainstay in clinical practice and translational research.
{"title":"Noninvasive Bedside Approaches for Assessing Microvascular Dysfunction.","authors":"Jacob Widaeus, Ingemar Fredriksson, Sara Tehrani","doi":"10.1159/000547636","DOIUrl":"10.1159/000547636","url":null,"abstract":"<p><strong>Background: </strong>Microvascular dysfunction is implicated in a range of acute and chronic conditions, ranging from cardiovascular disease to sepsis, often preceding organ damage and clinical symptoms. Within conditions such as diabetes or septic shock, microvascular compromise frequently correlates with disease severity and outcomes, emphasizing the importance of timely, targeted assessment. Noninvasive bedside methods for evaluating microvascular function have rapidly evolved, driven by advances in computational power, artificial intelligence, and novel imaging hardware.</p><p><strong>Summary: </strong>This review provides an overview of clinically feasible noninvasive techniques - including optical coherence tomography angiography, handheld videomicroscopy, laser speckle contrast imaging, reflectance spectroscopy, and related techniques. These methods allow observation under resting conditions and can be combined with functional tests such as post-occlusive reactive hyperemia, heating provocation, or iontophoresis to evaluate microvascular function.</p><p><strong>Key messages: </strong>Collectively, these methods provide valuable insights into the structural and functional aspects of the microcirculation, but their clinical application is constrained by need for standardized protocols, validation, and evidence linking microvascular metrics to meaningful patient outcomes. Collaborations among academia, industry, and healthcare remain pivotal to transitioning these methods into regulated, accessible devices. As standardization progresses and evidence grows, this integrative approach of evaluating microvascular function may emerge as a mainstay in clinical practice and translational research.</p>","PeriodicalId":17530,"journal":{"name":"Journal of Vascular Research","volume":" ","pages":"233-248"},"PeriodicalIF":2.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-07-24DOI: 10.1159/000547568
Narumi Fukuzaki, Kazuki Hotta, Kota Izawa, Naoki Hitosugi, Miki Sakamoto, Rin Kataoka, Shuri Arai, Kentaro Kamiya, Atsuhiko Matsunaga
Introduction: This study aimed to evaluate the effect of cecal ligation and puncture (CLP)-induced sepsis on transcapillary PO2 gradients (ΔPO2) in contracting skeletal muscles.
Methods: Male Wistar rats (n = 16, 10 weeks old) were randomly assigned to sham or CLP groups. Seven days after surgery, microvascular (PO2mv) and interstitial (PO2is) PO2 levels in the tibialis anterior muscle were measured using the phosphorescence quenching method during the transition from rest to electrically induced muscle contractions. ΔPO2 was calculated as PO2mv minus PO2is.
Results: At rest, there were no differences in PO2mv, PO2is, and ΔPO2 between the sham and CLP groups. The PO2mv and PO2is decreased during the transition from rest to contractions in both groups. During muscle contractions, the PO2mv and ΔPO2 were significantly lower in the CLP group than in the sham group (PO2mv, 7.79 ± 5.03 vs. 4.43 ± 2.23; ΔPO2, 5.50 ± 4.46 vs. 1.82 ± 2.66 mm Hg; sham vs. CLP; p < 0.05). The ΔPO2 of the rats in the sham group remained unchanged; however, it markedly decreased during muscle contractions in the CLP group.
Conclusion: Sepsis reduced ΔPO2 in contracting skeletal muscles.
目的:本研究旨在评估盲肠结扎和穿刺(CLP)诱导脓毒症对收缩骨骼肌经毛细血管PO2梯度(ΔPO2)的影响。方法:雄性Wistar大鼠(n = 16、10周龄)随机分为假手术组和CLP组。术后7天,采用磷光猝灭法测定静息到电致肌肉收缩过渡期间胫骨前肌(TA)微血管(PO2mv)和间质(PO2is) PO2水平。ΔPO2计算为PO2mv - PO2is。结果:静息时,假手术组与CLP组PO2mv、PO2is、ΔPO2均无差异。两组PO2mv和PO2is均在静息期到宫缩期的过渡中下降。在肌肉收缩过程中,CLP组PO2mv和ΔPO2明显低于假手术组(PO2mv, 7.79±5.03 vs 4.43±2.23;ΔPO2, 5.50±4.46 vs. 1.82±2.66 mmHg;sham vs. CLP;P < 0.05)。假手术组大鼠ΔPO2不变;然而,CLP组在肌肉收缩过程中明显降低。结论:脓毒症降低了收缩骨骼肌的经毛细血管PO2梯度。
{"title":"Transcapillary PO<sub>2</sub> Gradients in Contracting Muscle of Rat Model of Sepsis.","authors":"Narumi Fukuzaki, Kazuki Hotta, Kota Izawa, Naoki Hitosugi, Miki Sakamoto, Rin Kataoka, Shuri Arai, Kentaro Kamiya, Atsuhiko Matsunaga","doi":"10.1159/000547568","DOIUrl":"10.1159/000547568","url":null,"abstract":"<p><strong>Introduction: </strong>This study aimed to evaluate the effect of cecal ligation and puncture (CLP)-induced sepsis on transcapillary PO<sub>2</sub> gradients (ΔPO<sub>2</sub>) in contracting skeletal muscles.</p><p><strong>Methods: </strong>Male Wistar rats (n = 16, 10 weeks old) were randomly assigned to sham or CLP groups. Seven days after surgery, microvascular (PO<sub>2</sub>mv) and interstitial (PO<sub>2</sub>is) PO<sub>2</sub> levels in the tibialis anterior muscle were measured using the phosphorescence quenching method during the transition from rest to electrically induced muscle contractions. ΔPO<sub>2</sub> was calculated as PO<sub>2</sub>mv minus PO<sub>2</sub>is.</p><p><strong>Results: </strong>At rest, there were no differences in PO<sub>2</sub>mv, PO<sub>2</sub>is, and ΔPO<sub>2</sub> between the sham and CLP groups. The PO<sub>2</sub>mv and PO<sub>2</sub>is decreased during the transition from rest to contractions in both groups. During muscle contractions, the PO<sub>2</sub>mv and ΔPO<sub>2</sub> were significantly lower in the CLP group than in the sham group (PO<sub>2</sub>mv, 7.79 ± 5.03 vs. 4.43 ± 2.23; ΔPO<sub>2</sub>, 5.50 ± 4.46 vs. 1.82 ± 2.66 mm Hg; sham vs. CLP; p < 0.05). The ΔPO<sub>2</sub> of the rats in the sham group remained unchanged; however, it markedly decreased during muscle contractions in the CLP group.</p><p><strong>Conclusion: </strong>Sepsis reduced ΔPO<sub>2</sub> in contracting skeletal muscles.</p>","PeriodicalId":17530,"journal":{"name":"Journal of Vascular Research","volume":" ","pages":"266-273"},"PeriodicalIF":2.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144707942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-02-05DOI: 10.1159/000543768
Amanda Balboa Ramilo, Nikiforos Chandrinos, Elefantia Tsichlia, Josefin Jönsson, Kevin Mani, Anders Wanhainen, Dick Wågsäter
Introduction: Abdominal aortic aneurysm (AAA) development is inversely associated with diabetes mellitus. Targeting glucose metabolism seems to be a beneficial strategy for preventing AAA growth. Several metabolism-related factors are associated with AAA development. This study aimed to analyse the expression of the so far unstudied proteins irisin, follistatin, activin A, and ghrelin (ligand and receptor) in human and murine aneurysmal tissue, to assess the involvement of these pathways in AAA.
Methods: Gene and protein expression was evaluated in aneurysmal and control tissue samples, by qPCR and immunohistochemistry. Vascular smooth muscle cells (VSMCs) were studied in vitro for expression. Circulating levels of the proteins of interest in human plasma samples were evaluated by ELISA.
Results: In human aneurysmal tissue, the proteins of interest were predominantly expressed by VSMCs in neovessels. Expression by human VSMCs was confirmed in vitro. In human plasma, the concentration of irisin was higher in AAA (+/- diabetes) compared to controls. Patients with AAA and type 2 diabetes treated with metformin had lower levels of follistatin and ghrelin.
Conclusion: This study demonstrates irisin, follistatin, and ghrelin as interesting proteins to be studied in the context of the observed negative association between AAA development and type 2 diabetes.
{"title":"Evaluation of Metabolism-Associated Proteins in Abdominal Aortic Aneurysm.","authors":"Amanda Balboa Ramilo, Nikiforos Chandrinos, Elefantia Tsichlia, Josefin Jönsson, Kevin Mani, Anders Wanhainen, Dick Wågsäter","doi":"10.1159/000543768","DOIUrl":"10.1159/000543768","url":null,"abstract":"<p><strong>Introduction: </strong>Abdominal aortic aneurysm (AAA) development is inversely associated with diabetes mellitus. Targeting glucose metabolism seems to be a beneficial strategy for preventing AAA growth. Several metabolism-related factors are associated with AAA development. This study aimed to analyse the expression of the so far unstudied proteins irisin, follistatin, activin A, and ghrelin (ligand and receptor) in human and murine aneurysmal tissue, to assess the involvement of these pathways in AAA.</p><p><strong>Methods: </strong>Gene and protein expression was evaluated in aneurysmal and control tissue samples, by qPCR and immunohistochemistry. Vascular smooth muscle cells (VSMCs) were studied in vitro for expression. Circulating levels of the proteins of interest in human plasma samples were evaluated by ELISA.</p><p><strong>Results: </strong>In human aneurysmal tissue, the proteins of interest were predominantly expressed by VSMCs in neovessels. Expression by human VSMCs was confirmed in vitro. In human plasma, the concentration of irisin was higher in AAA (+/- diabetes) compared to controls. Patients with AAA and type 2 diabetes treated with metformin had lower levels of follistatin and ghrelin.</p><p><strong>Conclusion: </strong>This study demonstrates irisin, follistatin, and ghrelin as interesting proteins to be studied in the context of the observed negative association between AAA development and type 2 diabetes.</p>","PeriodicalId":17530,"journal":{"name":"Journal of Vascular Research","volume":" ","pages":"145-156"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12136604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-08-26DOI: 10.1159/000548035
Shaoyi Peng, Hailong Li, Kaiyuan Li
Introduction: Heart failure (HF) and renal failure (RF) frequently coexist as cardiorenal syndrome, but their underlying causal mechanisms remain poorly defined.
Methods: This study applied Mendelian randomization (MR) using genome-wide association study (GWAS) datasets to investigate the causal effect of HF on RF. The inverse variance weighted method assessed causality, and summary-data-based MR (SMR) was used to identify therapeutic targets. Additional analyses included 211 gut microbiota traits and 1,400 serum metabolites. Validation was performed using the MIMIC-IV database. Transcriptomic data were analyzed to identify differentially expressed genes (DEGs) and key transcription factors (TFs).
Results: This study found that HF significantly increases the risk of RF (OR = 1.54, 95% CI: 1.07-2.23, p = 0.020). SMR analysis identified SURF1 and MAP3K11 as potential therapeutic targets for HF and RF. One gut microbiota genus and one serum metabolite showed causal associations with both diseases. MIMIC-IV data supported the HF-RF association (OR = 2.94, 95% CI: 2.81-3.07, p < 0.001). A total of 11 overlapping DEGs were enriched in the MAPK cascade, with RELA identified as a key TF.
Conclusion: This study provides genetic and molecular evidence supporting a causal role of HF in RF, highlighting microbial, metabolic, and immune mechanisms as potential therapeutic targets.
.
背景:心衰(HF)和肾功能衰竭(RF)经常作为心肾综合征共存,但其潜在的因果机制尚未明确。方法:本研究采用孟德尔随机化(MR)方法,使用全基因组关联研究(GWAS)数据集来研究HF对RF的因果关系。反方差加权(IVW)方法评估因果关系,基于汇总数据的MR (SMR)用于确定治疗靶点。额外的分析包括211个肠道微生物群特征和1400个血清代谢物。使用MIMIC-IV数据库进行验证。分析转录组学数据以鉴定差异表达基因(DEGs)和关键转录因子。结果:本研究发现HF显著增加RF的风险(OR = 1.54, 95% CI: 1.07-2.23, P = 0.020)。SMR分析发现SURF1和MAP3K11是HF和RF的潜在治疗靶点。一种肠道菌群属和一种血清代谢物显示出与两种疾病的因果关系。MIMIC-IV数据支持HF-RF相关性(OR = 2.94, 95% CI: 2.81-3.07, P < 0.001)。在MAPK级联中富集了11个重叠的deg,其中RELA被确定为关键转录因子。结论:本研究提供了遗传和分子证据,支持HF在RF中的因果作用,强调微生物、代谢和免疫机制是潜在的治疗靶点。
{"title":"Exploring Potential Causality and Molecular Mechanisms between Heart Failure and Renal Failure: Insights from Mendelian Randomization Studies, the MIMIC-IV Database and the Gene Expression Omnibus Database.","authors":"Shaoyi Peng, Hailong Li, Kaiyuan Li","doi":"10.1159/000548035","DOIUrl":"10.1159/000548035","url":null,"abstract":"<p><p><p>Introduction: Heart failure (HF) and renal failure (RF) frequently coexist as cardiorenal syndrome, but their underlying causal mechanisms remain poorly defined.</p><p><strong>Methods: </strong>This study applied Mendelian randomization (MR) using genome-wide association study (GWAS) datasets to investigate the causal effect of HF on RF. The inverse variance weighted method assessed causality, and summary-data-based MR (SMR) was used to identify therapeutic targets. Additional analyses included 211 gut microbiota traits and 1,400 serum metabolites. Validation was performed using the MIMIC-IV database. Transcriptomic data were analyzed to identify differentially expressed genes (DEGs) and key transcription factors (TFs).</p><p><strong>Results: </strong>This study found that HF significantly increases the risk of RF (OR = 1.54, 95% CI: 1.07-2.23, p = 0.020). SMR analysis identified SURF1 and MAP3K11 as potential therapeutic targets for HF and RF. One gut microbiota genus and one serum metabolite showed causal associations with both diseases. MIMIC-IV data supported the HF-RF association (OR = 2.94, 95% CI: 2.81-3.07, p < 0.001). A total of 11 overlapping DEGs were enriched in the MAPK cascade, with RELA identified as a key TF.</p><p><strong>Conclusion: </strong>This study provides genetic and molecular evidence supporting a causal role of HF in RF, highlighting microbial, metabolic, and immune mechanisms as potential therapeutic targets. </p>.</p>","PeriodicalId":17530,"journal":{"name":"Journal of Vascular Research","volume":" ","pages":"330-350"},"PeriodicalIF":2.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12503801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-01-17DOI: 10.1159/000542481
Anna Cantalupo, Keiichi Asano, Sergey Dikalov, Dylan Gordon, Francesco Ramirez
Introduction: The pathogenic role of nitric oxide (NO) signaling during development of thoracic aortic aneurysm (TAA) in Marfan syndrome (MFS) is currently unclear. We characterized vasomotor function and its relationship to the activity of the NO-generating enzymes in mice with early onset progressively severe MFS.
Methods: Wire myography, immunoblotting, measurements of aortic NO, and superoxide levels were used to compare vasomotor function, contractile protein levels, and the activity of endothelial and inducible NO synthase (eNOS and iNOS, respectively) in ascending thoracic aortas of Fbn1mgR/mgR mice relative to wild-type littermates.
Results: Isometric force measurements of aortic rings from 16-day-old male Fbn1mgR/mgR mice revealed a significant reduction in acetylcholine-induced relaxation and increased phenylephrine (PE)-promoted contractility, associated with abnormally low eNOSSer1177 phosphorylation, decreased NO production, and augmented superoxide levels. Greater aortic contractility was associated with α1-adrenoceptor upregulation and normal levels of contractile proteins. While iNOS inhibition had no effect on vasomotor functions, mutant aortic rings preincubated with a nonspecific NOS inhibitor yielded a greater PE response, implying a significant contribution of endothelial dysfunction to aortic hypercontractility.
Conclusion: Impaired eNOS signaling disrupts aortic cholinergic relaxation and adrenergic contraction in MFS mice with dissecting TAA.
Introduction: The pathogenic role of nitric oxide (NO) signaling during development of thoracic aortic aneurysm (TAA) in Marfan syndrome (MFS) is currently unclear. We characterized vasomotor function and its relationship to the activity of the NO-generating enzymes in mice with early onset progressively severe MFS.
Methods: Wire myography, immunoblotting, measurements of aortic NO, and superoxide levels were used to compare vasomotor function, contractile protein levels, and the activity of endothelial and inducible NO synthase (eNOS and iNOS, respectively) in ascending thoracic aortas of Fbn1mgR/mgR mice relative to wild-type littermates.
Results: Isometric force measurements of aortic rings from 16-day-old male Fbn1mgR/mgR mice revealed a significant reduction in acetylcholine-induced relaxation and increased phenylephrine (PE)-promoted contractility, associated with abnormally low eNOSSer1177 phosphorylation, decreased NO production, and augmented superoxide levels. Greater aortic contractility was associated with α1-adrenoceptor upregulation and normal levels of contractile proteins. While iNOS inhibition had no effect on vasomotor functions, mutant aortic rings preincubated with a nonspecific NOS inhibitor yielded a greater PE response, implying a significant contribution of endothelial dysfunction to aortic hypercontractil
{"title":"Fibrillin-1 Deficiency Perturbs Aortic Cholinergic Relaxation and Adrenergic Contraction in a Mouse Model of Early Onset Progressively Severe Marfan Syndrome.","authors":"Anna Cantalupo, Keiichi Asano, Sergey Dikalov, Dylan Gordon, Francesco Ramirez","doi":"10.1159/000542481","DOIUrl":"10.1159/000542481","url":null,"abstract":"<p><strong>Introduction: </strong>The pathogenic role of nitric oxide (NO) signaling during development of thoracic aortic aneurysm (TAA) in Marfan syndrome (MFS) is currently unclear. We characterized vasomotor function and its relationship to the activity of the NO-generating enzymes in mice with early onset progressively severe MFS.</p><p><strong>Methods: </strong>Wire myography, immunoblotting, measurements of aortic NO, and superoxide levels were used to compare vasomotor function, contractile protein levels, and the activity of endothelial and inducible NO synthase (eNOS and iNOS, respectively) in ascending thoracic aortas of Fbn1mgR/mgR mice relative to wild-type littermates.</p><p><strong>Results: </strong>Isometric force measurements of aortic rings from 16-day-old male Fbn1mgR/mgR mice revealed a significant reduction in acetylcholine-induced relaxation and increased phenylephrine (PE)-promoted contractility, associated with abnormally low eNOSSer1177 phosphorylation, decreased NO production, and augmented superoxide levels. Greater aortic contractility was associated with α1-adrenoceptor upregulation and normal levels of contractile proteins. While iNOS inhibition had no effect on vasomotor functions, mutant aortic rings preincubated with a nonspecific NOS inhibitor yielded a greater PE response, implying a significant contribution of endothelial dysfunction to aortic hypercontractility.</p><p><strong>Conclusion: </strong>Impaired eNOS signaling disrupts aortic cholinergic relaxation and adrenergic contraction in MFS mice with dissecting TAA.</p><p><strong>Introduction: </strong>The pathogenic role of nitric oxide (NO) signaling during development of thoracic aortic aneurysm (TAA) in Marfan syndrome (MFS) is currently unclear. We characterized vasomotor function and its relationship to the activity of the NO-generating enzymes in mice with early onset progressively severe MFS.</p><p><strong>Methods: </strong>Wire myography, immunoblotting, measurements of aortic NO, and superoxide levels were used to compare vasomotor function, contractile protein levels, and the activity of endothelial and inducible NO synthase (eNOS and iNOS, respectively) in ascending thoracic aortas of Fbn1mgR/mgR mice relative to wild-type littermates.</p><p><strong>Results: </strong>Isometric force measurements of aortic rings from 16-day-old male Fbn1mgR/mgR mice revealed a significant reduction in acetylcholine-induced relaxation and increased phenylephrine (PE)-promoted contractility, associated with abnormally low eNOSSer1177 phosphorylation, decreased NO production, and augmented superoxide levels. Greater aortic contractility was associated with α1-adrenoceptor upregulation and normal levels of contractile proteins. While iNOS inhibition had no effect on vasomotor functions, mutant aortic rings preincubated with a nonspecific NOS inhibitor yielded a greater PE response, implying a significant contribution of endothelial dysfunction to aortic hypercontractil","PeriodicalId":17530,"journal":{"name":"Journal of Vascular Research","volume":" ","pages":"96-108"},"PeriodicalIF":2.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-02-05DOI: 10.1159/000544029
Priyanka Böttger, Tilo Grosser, Waltraut Ibe, Jean-Paul Boissel, Stephan Lindemann, Karl Werdan, HansJörg Schwertz, Harald Darius, Michael Buerke
Introduction: Vascular smooth muscle cell (SMC) proliferation and vascular homeostasis are thought to be regulated by nitric oxide and prostaglandins. The loss of these endogenous mediators seems to play an important role for the development of restenosis following balloon angioplasty.
Methods: We examined the effect of exogenous linsidomine, a nitric oxide (NO) releasing compound, in a model of balloon injury iliac arteries of rabbits. On the cellular levels, NO can exert effects like cell survival, growth, and proliferation inhibition, has effects on transcription and proteasome effects and mitochondria-related effects in SMCs. SMC proliferation was quantified as a change of intima-media ratio. Linsidomine injection or its vehicle was performed with an infusion-balloon catheter directly into the dilated vessel wall.
Results: Balloon angioplasty resulted in a significant increase of intima-media ratio during the first 3 weeks. Linsidomine treatment decreased the intima-media ratio significantly compared to vehicle treated animals 3 weeks after balloon angioplasty (0.65 ± 0.05 vs 1.2 ± 0.2 intima-media ratio, p < 0.05). However, control vessels had an intima-media ratio of 0.15 ± 0.02. This effect was similar to NOS-2 transfected vessels following angioplasty. Immunohistochemical analysis demonstrated the expression of the proliferating cellular nuclear antigen in dilated vessel of vehicle treated animals, which was reduced in linsidomine-treated rabbits. In in vitro experiments, linsidomine inhibited significantly and dose-dependently rabbit SMC proliferation measured by BrdU incorporation. Further linsidomine increased rate of apoptotic SMCs, however, this effect was p53 independent.
Conclusion: Simultaneous angioplasty of the rabbit iliac artery and direct injection of linsidomine into the vessel wall seem to be an effective strategy to reduce neointima formation. Similar, local application of liposome encapsulation of human nitric oxide synthase-2 transfection resulted in potent inhibition of intima proliferation and SMC proliferation due to local restoration NO within the injured vasculature.
血管平滑肌细胞增殖和血管稳态被认为是由一氧化氮和前列腺素调节的。我们研究了外源性一氧化氮释放化合物林多明对兔髂动脉球囊损伤模型的影响。在细胞水平上,NO具有抑制细胞存活、生长和增殖等作用。平滑肌细胞(SMC)增殖以内膜-介质比变化为指标。林多明注射剂或其载体通过球囊导管直接输注血管壁。球囊血管成形术使内膜-中膜比在三周内显著增加。林多明治疗显著降低内膜-中膜比(0.65±0.05 vs 1,2±0.2,p
{"title":"Single Intraluminal Delivery of a Nitric Oxide-Donor Results in Inhibition of Intimal Thickening in the Rabbit Femoral Artery.","authors":"Priyanka Böttger, Tilo Grosser, Waltraut Ibe, Jean-Paul Boissel, Stephan Lindemann, Karl Werdan, HansJörg Schwertz, Harald Darius, Michael Buerke","doi":"10.1159/000544029","DOIUrl":"10.1159/000544029","url":null,"abstract":"<p><strong>Introduction: </strong>Vascular smooth muscle cell (SMC) proliferation and vascular homeostasis are thought to be regulated by nitric oxide and prostaglandins. The loss of these endogenous mediators seems to play an important role for the development of restenosis following balloon angioplasty.</p><p><strong>Methods: </strong>We examined the effect of exogenous linsidomine, a nitric oxide (NO) releasing compound, in a model of balloon injury iliac arteries of rabbits. On the cellular levels, NO can exert effects like cell survival, growth, and proliferation inhibition, has effects on transcription and proteasome effects and mitochondria-related effects in SMCs. SMC proliferation was quantified as a change of intima-media ratio. Linsidomine injection or its vehicle was performed with an infusion-balloon catheter directly into the dilated vessel wall.</p><p><strong>Results: </strong>Balloon angioplasty resulted in a significant increase of intima-media ratio during the first 3 weeks. Linsidomine treatment decreased the intima-media ratio significantly compared to vehicle treated animals 3 weeks after balloon angioplasty (0.65 ± 0.05 vs 1.2 ± 0.2 intima-media ratio, p < 0.05). However, control vessels had an intima-media ratio of 0.15 ± 0.02. This effect was similar to NOS-2 transfected vessels following angioplasty. Immunohistochemical analysis demonstrated the expression of the proliferating cellular nuclear antigen in dilated vessel of vehicle treated animals, which was reduced in linsidomine-treated rabbits. In in vitro experiments, linsidomine inhibited significantly and dose-dependently rabbit SMC proliferation measured by BrdU incorporation. Further linsidomine increased rate of apoptotic SMCs, however, this effect was p53 independent.</p><p><strong>Conclusion: </strong>Simultaneous angioplasty of the rabbit iliac artery and direct injection of linsidomine into the vessel wall seem to be an effective strategy to reduce neointima formation. Similar, local application of liposome encapsulation of human nitric oxide synthase-2 transfection resulted in potent inhibition of intima proliferation and SMC proliferation due to local restoration NO within the injured vasculature.</p>","PeriodicalId":17530,"journal":{"name":"Journal of Vascular Research","volume":" ","pages":"193-203"},"PeriodicalIF":2.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-02-13DOI: 10.1159/000543322
Felipe T de Freitas Barão, Gina C Rocha Silvestre, Alexandre Queiroz Silva, Erasmo Simão da Silva
Introduction: Aortic aneurysm (AA) carries significant clinical implications due to its prevalence and potential complications. However, its etiopathogenesis remains poorly understood. The association between smoking and AA development has been consistently confirmed. Although AA was initially attributed to atherosclerosis, a negative association between diabetes (a major risk factor for atherosclerosis) and vascular aneurysmal disease has been observed. Investigating the biomechanical and histological properties of the aortic wall may shed light on the etiopathogenesis of aneurysms.
Methods: This study involved 75 Wistar rats, divided into four groups: control (CG), smoker (SG), diabetic (DG), and diabetic plus smoker (DSG). Rats in the SG and DSG groups were exposed to cigarette smoke for 30 min daily, 5 days a week. Diabetes was induced by intravenous injection of streptozotocin. After 16 weeks, the animals were sacrificed to collect the thoracic aorta. Destructive uniaxial tensile tests were performed to obtain the following biomechanical failure properties: force, tension, stress, strain, and strain energy. Histological analysis of these fragments consisted of the percentage evaluation of collagen and elastic fibers and verification of the magnitude of the inflammatory process in the arterial wall. Metalloproteinase-9 activity in the aortic specimens was quantified through zymography.
Results: Valid biomechanical tests of 36 specimens were analyzed, with 8 belonging to CG, 9 to DG, 11 to SG, and 8 to DSG. Biomechanical analysis of the fragments revealed that the maximum force and stress until rupture were lower in the DSG than in the SG with statistical significance. Evaluations of the percentage of collagen and elastic fibers as well as the inflammatory process showed no statistically significant difference among the groups studied. MMP-9 activity did not present a statistically significant difference among the different groups.
Conclusions: The biomechanical properties related to resistance are lower in DSG than in SG while elasticity, histological changes related to collagen fiber, elastic fiber, and inflammatory process, and MMP-9 activity of the aortic wall of rats do not show differences between CG and DG, SG, and DSG. Based on the methodology employed in this study, it appears that the thoracic aorta is resilient against aneurysm development.
{"title":"Study of the Biomechanical and Histological Properties of the Thoracic Aorta of Diabetic Rats and Exposed to Cigarette Smoke.","authors":"Felipe T de Freitas Barão, Gina C Rocha Silvestre, Alexandre Queiroz Silva, Erasmo Simão da Silva","doi":"10.1159/000543322","DOIUrl":"10.1159/000543322","url":null,"abstract":"<p><strong>Introduction: </strong>Aortic aneurysm (AA) carries significant clinical implications due to its prevalence and potential complications. However, its etiopathogenesis remains poorly understood. The association between smoking and AA development has been consistently confirmed. Although AA was initially attributed to atherosclerosis, a negative association between diabetes (a major risk factor for atherosclerosis) and vascular aneurysmal disease has been observed. Investigating the biomechanical and histological properties of the aortic wall may shed light on the etiopathogenesis of aneurysms.</p><p><strong>Methods: </strong>This study involved 75 Wistar rats, divided into four groups: control (CG), smoker (SG), diabetic (DG), and diabetic plus smoker (DSG). Rats in the SG and DSG groups were exposed to cigarette smoke for 30 min daily, 5 days a week. Diabetes was induced by intravenous injection of streptozotocin. After 16 weeks, the animals were sacrificed to collect the thoracic aorta. Destructive uniaxial tensile tests were performed to obtain the following biomechanical failure properties: force, tension, stress, strain, and strain energy. Histological analysis of these fragments consisted of the percentage evaluation of collagen and elastic fibers and verification of the magnitude of the inflammatory process in the arterial wall. Metalloproteinase-9 activity in the aortic specimens was quantified through zymography.</p><p><strong>Results: </strong>Valid biomechanical tests of 36 specimens were analyzed, with 8 belonging to CG, 9 to DG, 11 to SG, and 8 to DSG. Biomechanical analysis of the fragments revealed that the maximum force and stress until rupture were lower in the DSG than in the SG with statistical significance. Evaluations of the percentage of collagen and elastic fibers as well as the inflammatory process showed no statistically significant difference among the groups studied. MMP-9 activity did not present a statistically significant difference among the different groups.</p><p><strong>Conclusions: </strong>The biomechanical properties related to resistance are lower in DSG than in SG while elasticity, histological changes related to collagen fiber, elastic fiber, and inflammatory process, and MMP-9 activity of the aortic wall of rats do not show differences between CG and DG, SG, and DSG. Based on the methodology employed in this study, it appears that the thoracic aorta is resilient against aneurysm development.</p>","PeriodicalId":17530,"journal":{"name":"Journal of Vascular Research","volume":" ","pages":"170-182"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-11-21DOI: 10.1159/000542571
Baiyu Li, Zexia Ling, Yanyan Wang, Yinhua Xing
Introduction: Neutrophil infiltration is responsible for the neuroinflammation during an ischemic stroke. Here, we explored the role of receptor-interacting protein kinase 3 (RIP3) in neutrophil infiltration during an ischemic stroke.
Methods: The rat middle cerebral artery occlusion (MCAO) model was utilized to identify pivotal proteins involved in neutrophil infiltration during an ischemic stroke. Neutrophils were isolated from the peripheral blood of mice, and a co-immunoprecipitation (co-IP) assay was performed to identify the proteins that interact with RIP3.
Results: The rat MCAO model was successfully established. Myeloperoxidase (MPO) was significantly upregulated in the MCAO group, indicating the presence of neutrophil infiltration. RIP3 protein level exhibited a similar trend to MPO protein level, suggesting that neuroinflammation might be partly activated by RIP3 through the promotion of neutrophil infiltration. Co-IP and mass spectrometry analyses suggested that RIP3 facilitated neutrophil infiltration partly by affecting protein kinases (Rock1 and Prkaca) downstream of RIP3, and the interaction between RIP3 and Rock1 or Prkaca was validated by IF and co-IP assays.
Conclusion: In this study, it was observed that RIP3 affects neutrophil infiltration, a critical phenomenon associated with neuronal injury during ischemic stroke, partly by the modulation of downstream proteins such as Rock1 and Prkaca.
{"title":"Receptor-Interacting Protein Kinase 3 Augments Neuroinflammation by Facilitating Neutrophil Infiltration during an Ischemic Stroke.","authors":"Baiyu Li, Zexia Ling, Yanyan Wang, Yinhua Xing","doi":"10.1159/000542571","DOIUrl":"10.1159/000542571","url":null,"abstract":"<p><strong>Introduction: </strong>Neutrophil infiltration is responsible for the neuroinflammation during an ischemic stroke. Here, we explored the role of receptor-interacting protein kinase 3 (RIP3) in neutrophil infiltration during an ischemic stroke.</p><p><strong>Methods: </strong>The rat middle cerebral artery occlusion (MCAO) model was utilized to identify pivotal proteins involved in neutrophil infiltration during an ischemic stroke. Neutrophils were isolated from the peripheral blood of mice, and a co-immunoprecipitation (co-IP) assay was performed to identify the proteins that interact with RIP3.</p><p><strong>Results: </strong>The rat MCAO model was successfully established. Myeloperoxidase (MPO) was significantly upregulated in the MCAO group, indicating the presence of neutrophil infiltration. RIP3 protein level exhibited a similar trend to MPO protein level, suggesting that neuroinflammation might be partly activated by RIP3 through the promotion of neutrophil infiltration. Co-IP and mass spectrometry analyses suggested that RIP3 facilitated neutrophil infiltration partly by affecting protein kinases (Rock1 and Prkaca) downstream of RIP3, and the interaction between RIP3 and Rock1 or Prkaca was validated by IF and co-IP assays.</p><p><strong>Conclusion: </strong>In this study, it was observed that RIP3 affects neutrophil infiltration, a critical phenomenon associated with neuronal injury during ischemic stroke, partly by the modulation of downstream proteins such as Rock1 and Prkaca.</p>","PeriodicalId":17530,"journal":{"name":"Journal of Vascular Research","volume":" ","pages":"51-62"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}