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Reply to “Embracing imatinib: a novel approach to safeguarding the endothelial barrier in patients with COVID-19” 回复“拥抱伊马替尼:保护新冠肺炎患者内皮屏障的新方法”。
IF 9.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-02 DOI: 10.1007/s10456-023-09894-5
Xiaoming Wu, Jialan Shi
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引用次数: 0
The modes of angiogenesis: an updated perspective 血管生成的模式:一个更新的视角。
IF 9.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-28 DOI: 10.1007/s10456-023-09895-4
Andrew C. Dudley, Arjan W. Griffioen

Following the process of vasculogenesis during development, angiogenesis generates new vascular structures through a variety of different mechanisms or modes. These different modes of angiogenesis involve, for example, increasing microvasculature density by sprouting of endothelial cells, splitting of vessels to increase vascular surface area by intussusceptive angiogenesis, fusion of capillaries to increase blood flow by coalescent angiogenesis, and the recruitment of non-endothelial cells by vasculogenic mimicry. The recent reporting on coalescent angiogenesis as a new mode of vessel formation warrants a brief overview of angiogenesis mechanisms to provide a more complete picture. The journal Angiogenesis is devoted to the delineation of the different modes and mechanisms that collectively dictate blood vessel formation, inhibition, and function in health and disease.

在发育过程中,血管生成通过各种不同的机制或模式产生新的血管结构。这些不同的血管生成模式包括,例如,通过内皮细胞的发芽来增加微血管密度,通过套叠血管生成来分裂血管以增加血管表面积,通过聚结血管生成来融合毛细血管以增加血流量,以及通过血管生成拟态来募集非内皮细胞。最近关于聚结血管生成作为一种新的血管形成模式的报道保证了对血管生成机制的简要概述,以提供更完整的图像。《血管生成》杂志致力于描述不同的模式和机制,这些模式和机制共同决定了血管的形成、抑制以及在健康和疾病中的功能。
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引用次数: 2
Correction: Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation 更正:COVID-19后综合征的持续性内皮功能障碍及其与症状严重程度和慢性炎症的关系
IF 9.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-23 DOI: 10.1007/s10456-023-09892-7
Timon Kuchler, Roman Günthner, Andrea Ribeiro, Renate Hausinger, Lukas Streese, Anna Wöhnl, Veronika Kesseler, Johanna Negele, Tarek Assali, Javier Carbajo-Lozoya, Maciej Lech, Heike Schneider, Kristina Adorjan, Hans Christian Stubbe, Henner Hanssen, Konstantin Kotilar, Bernhard Haller, Uwe Heemann, Christoph Schmaderer
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引用次数: 0
Aging impairs the ability of vascular endothelial stem cells to generate endothelial cells in mice 衰老损害了小鼠血管内皮干细胞产生内皮细胞的能力。
IF 9.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-10 DOI: 10.1007/s10456-023-09891-8
Shota Shimizu, Tomohiro Iba, Hisamichi Naito, Fitriana Nur Rahmawati, Hirotaka Konishi, Weizhen Jia, Fumitaka Muramatsu, Nobuyuki Takakura

Tissue-resident vascular endothelial stem cells (VESCs), marked by expression of CD157, possess long-term repopulating potential and contribute to vascular regeneration and homeostasis in mice. Stem cell exhaustion is regarded as one of the hallmarks of aging and is being extensively studied in several types of tissue-resident stem cells; however, how aging affects VESCs has not been clarified yet. In the present study, we isolated VESCs from young and aged mice to compare their potential to differentiate into endothelial cells in vitro and in vivo. Here, we report that the number of liver endothelial cells (ECs) including VESCs was lower in aged (27–28 month-old) than young (2–3 month-old) mice. In vitro culture of primary VESCs revealed that the potential to generate ECs is impaired in aged VESCs isolated from liver and lung relative to young VESCs. Orthotopic transplantation of VESCs showed that aged VESCs and their progeny expand less efficiently than their young counterparts when transplanted into aged mice, but they are equally functional in young recipients. Gene expression analysis indicated that inflammatory signaling was more activated in aged ECs including VESCs. Using single-cell RNA sequencing data from the Tabula Muris Consortium, we show that T cells and monocyte/macrophage lineage cells including Kupffer cells are enriched in the aged liver. These immune cells produce IL-1β and several chemokines, suggesting the possible involvement of age-associated inflammation in the functional decline of VESCs with age.

以CD157表达为标志的组织驻留血管内皮干细胞(VESCs)具有长期的再增殖潜力,有助于小鼠的血管再生和稳态。干细胞耗竭被认为是衰老的标志之一,并且正在几种类型的组织固有干细胞中进行广泛研究;然而,衰老对VESC的影响还没有明确。在本研究中,我们从年轻和老年小鼠中分离出VESCs,以比较它们在体外和体内分化为内皮细胞的潜力。在这里,我们报道了老年(27-28个月大)小鼠的肝内皮细胞(EC)(包括VESCs)的数量低于年轻(2-3个月大的)小鼠。原代VESCs的体外培养显示,与年轻的VESCs相比,从肝脏和肺部分离的老年VESCs产生EC的潜力受损。VESCs的原位移植表明,当移植到老年小鼠中时,老年VESCs及其后代的扩增效率不如年轻的VESCs,但它们在年轻受体中的功能相同。基因表达分析表明,包括VESCs在内的老年内皮细胞中炎症信号传导更为活跃。使用Tabula Muris Consortium的单细胞RNA测序数据,我们发现T细胞和单核细胞/巨噬细胞谱系细胞(包括库普弗细胞)在衰老的肝脏中富集。这些免疫细胞产生IL-1β和几种趋化因子,表明年龄相关炎症可能参与了VESCs随年龄的功能下降。
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引用次数: 0
Embracing Imatinib: a novel approach to safeguarding the endothelial barrier in patients with COVID-19 拥抱伊马替尼:一种保护新冠肺炎患者内皮屏障的新方法。
IF 9.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-02 DOI: 10.1007/s10456-023-09889-2
Chia Siang Kow, Dinesh Sangarran Ramachandram, Syed Shahzad Hasan

Imatinib, an ABL tyrosine-kinase inhibitor, shows promise in restoring endothelial barrier function in patients with COVID-19, thus, preventing cytokine leakage from the alveolar compartment to the systemic compartment. COVID-19 is characterized by an alveolar cytokine storm, and imatinib has been shown to strengthen the endothelial barrier and mitigate alveolar inflammatory responses by modulating NF-κB signaling. Incorporating imatinib into COVID-19 treatment strategies offers a novel approach to safeguard the endothelial barrier and address the complex pathophysiology of the disease, including its potential implications in long COVID. Given that endothelial dysfunction plays a central role in COVID-19 progression and long COVID development, protecting the endothelial barrier during acute infection is crucial in preventing the persistent endothelial dysfunction associated with long COVID.

伊马替尼是一种ABL酪氨酸激酶抑制剂,有望恢复新冠肺炎患者的内皮屏障功能,从而防止细胞因子从肺泡室泄漏到全身室。新冠肺炎的特征是肺泡细胞因子风暴,伊马替尼已被证明通过调节NF-κB信号增强内皮屏障并减轻肺泡炎症反应。将伊马替尼纳入新冠肺炎治疗策略提供了一种新的方法来保护内皮屏障并解决该疾病的复杂病理生理学,包括其对长期COVID的潜在影响。鉴于内皮功能障碍在新冠肺炎进展和长期新冠肺炎发展中起着核心作用,在急性感染期间保护内皮屏障对于预防与长期新冠病毒相关的持续内皮功能障碍至关重要。
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引用次数: 0
VEGF-A plasma levels are associated with impaired DLCO and radiological sequelae in long COVID patients VEGF-A血浆水平与长COVID患者的DLCO受损和放射学后遗症有关。
IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE Pub Date : 2023-08-01 DOI: 10.1007/s10456-023-09890-9
Aurélien Philippe, Sven Günther, Jeanne Rancic, Pauline Cavagna, Bertrand Renaud, Nicolas Gendron, Elie Mousseaux, Thông Hua-Huy, Guillaume Reverdito, Benjamin Planquette, Olivier Sanchez, Pascale Gaussem, Dominique Salmon, Jean-Luc Diehl, David M. Smadja

Background

Long COVID, also known as post-acute sequelae of COVID-19 (PASC), is characterized by persistent clinical symptoms following COVID-19.

Objective

To correlate biomarkers of endothelial dysfunction with persistent clinical symptoms and pulmonary function defects at distance from COVID-19.

Methods

Consecutive patients with long COVID-19 suspicion were enrolled. A panel of endothelial biomarkers was measured in each patient during clinical evaluation and pulmonary function test (PFT).

Results

The study included 137 PASC patients, mostly male (68%), with a median age of 55 years. A total of 194 PFTs were performed between months 3 and 24 after an episode of SARS-CoV-2 infection. We compared biomarkers evaluated in PASC patients with 20 healthy volunteers (HVs) and acute hospitalized COVID-19 patients (n = 88). The study found that angiogenesis-related biomarkers and von Willebrand factor (VWF) levels were increased in PASC patients compared to HVs without increased inflammatory or platelet activation markers. Moreover, VEGF-A and VWF were associated with persistent lung CT scan lesions and impaired diffusing capacity of the lungs for carbon monoxide (DLCO) measurement. By employing a Cox proportional hazards model adjusted for age, sex, and body mass index, we further confirmed the accuracy of VEGF-A and VWF. Following adjustment, VEGF-A emerged as the most significant predictive factor associated with persistent lung CT scan lesions and impaired DLCO measurement.

Conclusion

VEGF-A is a relevant predictive factor for DLCO impairment and radiological sequelae in PASC. Beyond being a biomarker, we hypothesize that the persistence of angiogenic disorders may contribute to long COVID symptoms.

背景:长COVID又称COVID-19急性后遗症(PASC),其特征是COVID-19后出现持续性临床症状:目的:将内皮功能障碍的生物标志物与COVID-19后的持续临床症状和肺功能缺陷相关联:方法:连续招募长期怀疑 COVID-19 的患者。在临床评估和肺功能测试(PFT)期间,对每位患者的一系列内皮生物标志物进行了测量:研究共纳入 137 名 PASC 患者,大部分为男性(68%),中位年龄为 55 岁。在感染 SARS-CoV-2 后的第 3 个月至第 24 个月期间,共进行了 194 次肺功能测试。我们将 PASC 患者与 20 名健康志愿者(HVs)和 COVID-19 急性住院患者(n = 88)的生物标志物进行了比较。研究发现,与健康志愿者相比,PASC 患者的血管生成相关生物标志物和冯-威廉因子(VWF)水平升高,但炎症或血小板活化标志物并未升高。此外,VEGF-A 和 VWF 与肺部 CT 扫描病灶持续存在和一氧化碳肺弥散能力(DLCO)测量受损有关。通过采用调整年龄、性别和体重指数的 Cox 比例危险模型,我们进一步证实了 VEGF-A 和 VWF 的准确性。经过调整,VEGF-A 成为与肺部 CT 扫描病灶持续存在和 DLCO 测量受损相关的最重要预测因素:结论:VEGF-A 是 PASC 中 DLCO 受损和放射学后遗症的相关预测因素。结论:VEGF-A 是 PASC 患者 DLCO 损伤和放射学后遗症的相关预测因素。除了作为生物标志物外,我们还假设血管生成障碍的持续存在可能会导致 COVID 症状的长期存在。
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引用次数: 0
Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation COVID-19后综合征的持续性内皮功能障碍及其与症状严重程度和慢性炎症的关系。
IF 9.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-07-28 DOI: 10.1007/s10456-023-09885-6
Timon Kuchler, Roman Günthner, Andrea Ribeiro, Renate Hausinger, Lukas Streese, Anna Wöhnl, Veronika Kesseler, Johanna Negele, Tarek Assali, Javier Carbajo-Lozoya, Maciej Lech, Heike Schneider, Kristina Adorjan, Hans Christian Stubbe, Henner Hanssen, Konstantin Kotilar, Bernhard Haller, Uwe Heemann, Christoph Schmaderer

Background

Post-COVID-19 syndrome (PCS) is a lingering disease with ongoing symptoms such as fatigue and cognitive impairment resulting in a high impact on the daily life of patients. Understanding the pathophysiology of PCS is a public health priority, as it still poses a diagnostic and treatment challenge for physicians.

Methods

In this prospective observational cohort study, we analyzed the retinal microcirculation using Retinal Vessel Analysis (RVA) in a cohort of patients with PCS and compared it to an age- and gender-matched healthy cohort (n = 41, matched out of n = 204).

Measurements and main results

PCS patients exhibit persistent endothelial dysfunction (ED), as indicated by significantly lower venular flicker-induced dilation (vFID; 3.42% ± 1.77% vs. 4.64% ± 2.59%; p = 0.02), narrower central retinal artery equivalent (CRAE; 178.1 [167.5–190.2] vs. 189.1 [179.4–197.2], p = 0.01) and lower arteriolar-venular ratio (AVR; (0.84 [0.8–0.9] vs. 0.88 [0.8–0.9], p = 0.007). When combining AVR and vFID, predicted scores reached good ability to discriminate groups (area under the curve: 0.75). Higher PCS severity scores correlated with lower AVR (R = − 0.37 p = 0.017). The association of microvascular changes with PCS severity were amplified in PCS patients exhibiting higher levels of inflammatory parameters.

Conclusion

Our results demonstrate that prolonged endothelial dysfunction is a hallmark of PCS, and impairments of the microcirculation seem to explain ongoing symptoms in patients. As potential therapies for PCS emerge, RVA parameters may become relevant as clinical biomarkers for diagnosis and therapy management.

Trial registration

This study was previously registered at ClinicalTrials (“All Eyes on PCS—Analysis of the Retinal Microvasculature in Patients with Post-COVID-19 Syndrome”. NCT05635552. https://clinicaltrials.gov/ct2/show/NCT05635552).

Graphical abstract

Persistent endothelial dysfunction in post-COVID-19 syndrome. Acute SARS-CoV-2 infection indirectly or directly causes endotheliitis in patients. N = 41 PCS patients were recruited and retinal vessel analysis was performed to assess microvascular endothelial function. Images of SVA and DVA are illustrative for RVA data analysis. For each PCS patient and healthy cohort, venular vessel diameter of the three measurement cycles was calculated and plotted on a diameter-time curve. Patients exhibited reduced flicker-induced dilation in veins (vFID) measured by dynamic vessel analysis (DVA) and lower central retinal arteriolar equivalent (CRAE) and arteriolar-venular ratio (AVR) and a tendency towards higher central retinal venular equivalent (CRVE) when compared to SARS-CoV-2 infection naïve participants. Created with BioRender.com

背景:COVID-19后综合征(PCS)是一种持续存在的疾病,其症状包括疲劳和认知障碍,对患者的日常生活产生很大影响。了解PCS的病理生理学是公共卫生的优先事项,因为它仍然对医生的诊断和治疗构成挑战。方法:在这项前瞻性观察性队列研究中,我们使用视网膜血管分析(RVA)分析了一组PCS患者的视网膜微循环,并将其与年龄和性别匹配的健康队列(n = 41,匹配n个 = 204)。测量和主要结果:PCS患者表现出持续的内皮功能障碍(ED),表现为小静脉闪烁诱导的扩张显著降低(vFID;3.42% ± 1.77%对4.64% ± 2.59%;p = 0.02),较窄的视网膜中央动脉当量(CRAE;178.1[167.5-190.2]对189.1[179.4-197.2],p = 0.01)和较低的小动脉-小静脉比率(AVR;(0.84[0.8-0.9]对0.88[0.8-09],p = 0.007)。当结合AVR和vFID时,预测得分达到了良好的区分群体的能力(曲线下面积:0.75)。PCS严重程度得分越高,AVR越低(R = -0.37便士 = 0.017)。在表现出较高炎症参数水平的PCS患者中,微血管变化与PCS严重程度的相关性被放大。结论:我们的研究结果表明,内皮功能障碍延长是PCS的标志,微循环障碍似乎可以解释患者持续的症状。随着PCS潜在疗法的出现,RVA参数可能成为诊断和治疗管理的临床生物标志物。试验注册:本研究之前已在临床试验中注册(“所有人的眼睛都在PCS-AnalysisofRetinal Microvasculation in Patients with Post-COVID-19 Syndrome”,NCT05635552)。https://clinicaltrials.gov/ct2/show/NCT05635552)。COVID-19后综合征的持续性内皮功能障碍。急性严重急性呼吸系统综合征冠状病毒2型感染间接或直接导致患者内皮炎。N = 招募了41名PCS患者,并进行视网膜血管分析以评估微血管内皮功能。SVA和DVA的图像用于RVA数据分析。对于每个PCS患者和健康队列,计算三个测量周期的小静脉血管直径,并绘制在直径-时间曲线上。通过动态血管分析(DVA)测量,患者表现出闪烁诱导的静脉扩张(vFID)减少,视网膜中央小动脉当量(CRAE)和小动脉-小静脉比率(AVR)降低,与严重急性呼吸系统综合征冠状病毒2型感染的幼稚参与者相比,患者有更高的视网膜中央小静脉当量(CRVE)的趋势。使用BioRender.com创建。
{"title":"Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation","authors":"Timon Kuchler,&nbsp;Roman Günthner,&nbsp;Andrea Ribeiro,&nbsp;Renate Hausinger,&nbsp;Lukas Streese,&nbsp;Anna Wöhnl,&nbsp;Veronika Kesseler,&nbsp;Johanna Negele,&nbsp;Tarek Assali,&nbsp;Javier Carbajo-Lozoya,&nbsp;Maciej Lech,&nbsp;Heike Schneider,&nbsp;Kristina Adorjan,&nbsp;Hans Christian Stubbe,&nbsp;Henner Hanssen,&nbsp;Konstantin Kotilar,&nbsp;Bernhard Haller,&nbsp;Uwe Heemann,&nbsp;Christoph Schmaderer","doi":"10.1007/s10456-023-09885-6","DOIUrl":"10.1007/s10456-023-09885-6","url":null,"abstract":"<div><h3>Background</h3><p>Post-COVID-19 syndrome (PCS) is a lingering disease with ongoing symptoms such as fatigue and cognitive impairment resulting in a high impact on the daily life of patients. Understanding the pathophysiology of PCS is a public health priority, as it still poses a diagnostic and treatment challenge for physicians.</p><h3>Methods</h3><p>In this prospective observational cohort study, we analyzed the retinal microcirculation using Retinal Vessel Analysis (RVA) in a cohort of patients with PCS and compared it to an age- and gender-matched healthy cohort (<i>n</i> = 41, matched out of <i>n</i> = 204).</p><h3>Measurements and main results</h3><p>PCS patients exhibit persistent endothelial dysfunction (ED), as indicated by significantly lower venular flicker-induced dilation (vFID; 3.42% ± 1.77% vs. 4.64% ± 2.59%; <i>p</i> = 0.02), narrower central retinal artery equivalent (CRAE; 178.1 [167.5–190.2] vs. 189.1 [179.4–197.2], <i>p</i> = 0.01) and lower arteriolar-venular ratio (AVR; (0.84 [0.8–0.9] vs. 0.88 [0.8–0.9], <i>p</i> = 0.007). When combining AVR and vFID, predicted scores reached good ability to discriminate groups (area under the curve: 0.75). Higher PCS severity scores correlated with lower AVR (<i>R</i> = − 0.37 <i>p</i> = 0.017). The association of microvascular changes with PCS severity were amplified in PCS patients exhibiting higher levels of inflammatory parameters.</p><h3>Conclusion</h3><p>Our results demonstrate that prolonged endothelial dysfunction is a hallmark of PCS, and impairments of the microcirculation seem to explain ongoing symptoms in patients. As potential therapies for PCS emerge, RVA parameters may become relevant as clinical biomarkers for diagnosis and therapy management.</p><h3>Trial registration</h3><p>This study was previously registered at ClinicalTrials (“All Eyes on PCS—Analysis of the Retinal Microvasculature in Patients with Post-COVID-19 Syndrome”. NCT05635552. https://clinicaltrials.gov/ct2/show/NCT05635552).</p><h3>Graphical abstract</h3><p>Persistent endothelial dysfunction in post-COVID-19 syndrome. Acute SARS-CoV-2 infection indirectly or directly causes endotheliitis in patients. <i>N</i> = 41 PCS patients were recruited and retinal vessel analysis was performed to assess microvascular endothelial function. Images of SVA and DVA are illustrative for RVA data analysis. For each PCS patient and healthy cohort, venular vessel diameter of the three measurement cycles was calculated and plotted on a diameter-time curve. Patients exhibited reduced flicker-induced dilation in veins (vFID) measured by dynamic vessel analysis (DVA) and lower central retinal arteriolar equivalent (CRAE) and arteriolar-venular ratio (AVR) and a tendency towards higher central retinal venular equivalent (CRVE) when compared to SARS-CoV-2 infection naïve participants. Created with BioRender.com</p>\u0000 <div><figure><div><div><picture><source><img></source></picture></div></div></figure></div>\u0000","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2023-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-023-09885-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41188890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Phenotypic screening in Organ-on-a-Chip systems: a 1537 kinase inhibitor library screen on a 3D angiogenesis assay 芯片上器官系统的表型筛选:在三维血管生成试验中筛选 1537 种激酶抑制剂库。
IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE Pub Date : 2023-07-26 DOI: 10.1007/s10456-023-09888-3
Camilla Soragni, Karla Queiroz, Chee Ping Ng, Arthur Stok, Thomas Olivier, Dora Tzagkaraki, Jeroen Heijmans, Johnny Suijker, Sander P. M. de Ruiter, Aleksandra Olczyk, Marleen Bokkers, Frederik Schavemaker, Sebastian J. Trietsch, Henriëtte L. Lanz, Paul Vulto, Jos Joore

Modern drug development increasingly requires comprehensive models that can be utilized in the earliest stages of compound and target discovery. Here we report a phenotypic screening exercise in a high-throughput Organ-on-a-Chip setup. We assessed the inhibitory effect of 1537 protein kinase inhibitors in an angiogenesis assay. Over 4000 micro-vessels were grown under perfusion flow in microfluidic chips, exposed to a cocktail of pro-angiogenic factors and subsequently exposed to the respective kinase inhibitors. Efficacy of compounds was evaluated by reduced angiogenic sprouting, whereas reduced integrity of the main micro-vessel was taken as a measure for toxicity. The screen yielded 53 hits with high anti-angiogenicity and low toxicity, of which 44 were previously unassociated with angiogenic pathways. This study demonstrates that Organ-on-a-Chip models can be screened in high numbers to identify novel compounds and targets. This will ultimately reduce bias in early-stage drug development and increases probability to identify first in class compounds and targets for today’s intractable diseases.

现代药物开发越来越需要在化合物和靶点发现的最初阶段就能利用的综合模型。在这里,我们报告了在高通量器官芯片装置中进行的表型筛选工作。我们在血管生成试验中评估了 1537 种蛋白激酶抑制剂的抑制作用。在微流控芯片中,4000 多个微血管在灌注流下生长,暴露于鸡尾酒促血管生成因子,随后暴露于相应的激酶抑制剂。化合物的疗效通过血管生成萌芽的减少来评估,而主要微血管完整性的降低则作为毒性的衡量标准。筛选结果显示,53 种化合物具有高抗血管生成性和低毒性,其中 44 种以前与血管生成途径无关。这项研究表明,芯片上器官模型可以通过大量筛选来确定新型化合物和靶点。这将最终减少早期药物开发中的偏差,并增加为当今棘手疾病找到一流化合物和靶点的可能性。
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引用次数: 0
FOXO1 promotes endothelial cell elongation and angiogenesis by up-regulating the phosphorylation of myosin light chain 2 FOXO1通过上调肌球蛋白轻链2的磷酸化来促进内皮细胞的延伸和血管生成。
IF 9.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-07-24 DOI: 10.1007/s10456-023-09884-7
Kiyomi Tsuji-Tamura, Minetaro Ogawa

The forkhead box O1 (FOXO1) is an important transcription factor related to proliferation, metabolism, and homeostasis, while the major phenotype of FOXO1-null mice is abnormal vascular morphology, such as vessel enlargement and dilation. In in vitro mouse embryonic stem cell (ESC)-differentiation system, Foxo1−/− vascular endothelial cells (ECs) fail to elongate, and mimic the abnormalities of FOXO1-deficiency in vivo. Here, we identified the PPP1R14C gene as the FOXO1 target genes responsible for elongating using transcriptome analyses in ESC-derived ECs (ESC-ECs), and found that the FOXO1-PPP1R14C-myosin light chain 2 (MLC2) axis is required for EC elongation during angiogenesis. MLC2 is phosphorylated by MLC kinase (MLCK) and dephosphorylated by MLC phosphatase (MLCP). PPP1R14C is an inhibitor of PP1, the catalytic subunit of MLCP. The abnormal morphology of Foxo1−/− ESC-ECs was associated with low level of PPP1R14C and loss of MLC2 phosphorylation, which were reversed by PPP1R14C-introduction. Knockdown of either FOXO1 or PPP1R14C suppressed vascular cord formation and reduced MLC2 phosphorylation in human ECs (HUVECs). The mouse and human PPP1R14C locus possesses an enhancer element containing conserved FOXO1-binding motifs. In vivo chemical inhibition of MLC2 phosphorylation caused dilated vascular structures in mouse embryos. Furthermore, foxo1 or ppp1r14c-knockdown zebrafish exhibited vascular malformations, which were also restored by PPP1R14C-introduction. Mechanistically, FOXO1 suppressed MLCP activity by up-regulating PPP1R14C expression, thereby promoting MLC2 phosphorylation and EC elongation, which are necessary for vascular development. Given the importance of MLC2 phosphorylation in cell morphogenesis, this study may provide novel insights into the role of FOXO1 in control of angiogenesis.

叉头盒O1(FOXO1)是一种与增殖、代谢和稳态相关的重要转录因子,而FOXO1缺失小鼠的主要表型是异常的血管形态,如血管增大和扩张。在体外小鼠胚胎干细胞(ESC)分化系统中,Foxo1-/-血管内皮细胞(EC)不能伸长,并在体内模拟Foxo1缺乏的异常。在这里,我们使用ESC衍生的EC(ESC-ECs)中的转录组分析将PPP1R14C基因鉴定为负责伸长的FOXO1靶基因,并发现FOXO1-PPP1R14C-肌球蛋白轻链2(MLC2)轴是血管生成过程中EC伸长所必需的。MLC2被MLC激酶(MLCK)磷酸化,并被MLC磷酸酶(MLCP)去磷酸化。PPP1R14C是MLCP催化亚基PP1的抑制剂。Foxo1-/-ESC EC的异常形态与低水平的PPP1R14C和MLC2磷酸化的丧失有关,PPP1R14C的引入逆转了这一点。敲除FOXO1或PPP1R14C抑制人内皮细胞(HUVECs)中的血管索形成并降低MLC2磷酸化。小鼠和人PPP1R14C基因座具有包含保守的FOXO1结合基序的增强子元件。MLC2磷酸化的体内化学抑制导致小鼠胚胎中血管结构扩张。此外,敲除foxo1或ppp1r14c的斑马鱼表现出血管畸形,ppp1r14c的引入也使其恢复。从机制上讲,FOXO1通过上调PPP1R14C的表达来抑制MLCP活性,从而促进MLC2磷酸化和EC延伸,这是血管发育所必需的。鉴于MLC2磷酸化在细胞形态发生中的重要性,本研究可能为FOXO1在控制血管生成中的作用提供新的见解。
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引用次数: 0
Correction to: BI1 is associated with microvascular protection in cardiac ischemia reperfusion injury via repressing Syk-Nox2-Drp1-mitochondrial fission pathways 更正:BI1通过抑制Syk-Nox2-Drp1-线粒体分裂途径与心脏缺血再灌注损伤中的微血管保护有关
IF 9.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-06-30 DOI: 10.1007/s10456-023-09882-9
Hao Zhou, Chen Shi, Shunying Hu, Hong Zhu, Jun Ren, Yundai Chen
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引用次数: 6
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Angiogenesis
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