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Notch1 and Notch4 core binding domain peptibodies exhibit distinct ligand-binding and anti-angiogenic properties Notch1和Notch4核心结合结构域蛋白抗体表现出不同的配体结合和抗血管生成特性。
IF 9.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-11-15 DOI: 10.1007/s10456-022-09861-6
Timothy Sargis, Seock-Won Youn, Krishna Thakkar, L. A. Naiche, Na Yoon Paik, Kostandin V. Pajcini, Jan K. Kitajewski

The Notch signaling pathway is an important therapeutic target for the treatment of inflammatory diseases and cancer. We previously created ligand-specific inhibitors of Notch signaling comprised of Fc fusions to specific EGF-like repeats of the Notch1 extracellular domain, called Notch decoys, which bound ligands, blocked Notch signaling, and showed anti-tumor activity with low toxicity. However, the study of their function depended on virally mediated expression, which precluded dosage control and limited clinical applicability. We have refined the decoy design to create peptibody-based Notch inhibitors comprising the core binding domains, EGF-like repeats 10–14, of either Notch1 or Notch4. These Notch peptibodies showed high secretion properties and production yields that were improved by nearly 100-fold compared to previous Notch decoys. Using surface plasmon resonance spectroscopy coupled with co-immunoprecipitation assays, we observed that Notch1 and Notch4 peptibodies demonstrate strong but distinct binding properties to Notch ligands DLL4 and JAG1. Both Notch1 and Notch4 peptibodies interfere with Notch signaling in endothelial cells and reduce expression of canonical Notch targets after treatment. While prior DLL4 inhibitors cause hyper-sprouting, the Notch1 peptibody reduced angiogenesis in a 3-dimensional in vitro sprouting assay. Administration of Notch1 peptibodies to neonate mice resulted in reduced radial outgrowth of retinal vasculature, confirming anti-angiogenic properties. We conclude that purified Notch peptibodies comprising EGF-like repeats 10–14 bind to both DLL4 and JAG1 ligands and exhibit anti-angiogenic properties. Based on their secretion profile, unique Notch inhibitory activities, and anti-angiogenic properties, Notch peptibodies present new opportunities for therapeutic Notch inhibition.

Notch信号通路是治疗炎症性疾病和癌症的重要治疗靶点。我们之前创建了Notch信号传导的配体特异性抑制剂,由Fc融合到Notch1细胞外结构域的特定EGF样重复序列组成,称为Notch诱饵,它结合配体,阻断Notch信号,并显示出低毒的抗肿瘤活性。然而,对其功能的研究依赖于病毒介导的表达,这阻碍了剂量控制,限制了临床应用。我们已经改进了诱饵设计,以产生基于肽体的Notch抑制剂,其包括Notch1或Notch4的核心结合结构域,EGF样重复10-14。这些Notch蛋白抗体显示出高分泌特性和生产产量,与以前的Notch诱饵相比提高了近100倍。使用表面等离子体共振光谱与共免疫沉淀分析相结合,我们观察到Notch1和Notch4蛋白抗体与Notch配体DLL4和JAG1表现出强烈但不同的结合特性。Notch1和Notch4蛋白抗体均干扰内皮细胞中的Notch信号传导,并在治疗后降低典型Notch靶标的表达。虽然先前的DLL4抑制剂导致超发芽,但在三维体外发芽测定中,Notch1蛋白体减少了血管生成。对新生小鼠施用Notch1蛋白抗体导致视网膜血管系统的径向生长减少,证实了抗血管生成特性。我们得出的结论是,包含EGF样重复10-14的纯化的Notch蛋白抗体与DLL4和JAG1配体结合,并表现出抗血管生成特性。基于其分泌特征、独特的Notch抑制活性和抗血管生成特性,Notch蛋白抗体为治疗性Notch抑制提供了新的机会。
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引用次数: 0
Inflammation and vascular remodeling in COVID-19 hearts 新冠肺炎心脏的炎症和血管重塑。
IF 9.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-11-12 DOI: 10.1007/s10456-022-09860-7
Christopher Werlein, Maximilian Ackermann, Helge Stark, Harshit R. Shah, Alexandar Tzankov, Jasmin Dinonne Haslbauer, Saskia von Stillfried, Roman David Bülow, Ali El-Armouche, Stephan Kuenzel, Jan Lukas Robertus, Marius Reichardt, Axel Haverich, Anne Höfer, Lavinia Neubert, Edith Plucinski, Peter Braubach, Stijn Verleden, Tim Salditt, Nikolaus Marx, Tobias Welte, Johann Bauersachs, Hans-Heinrich Kreipe, Steven J. Mentzer, Peter Boor, Stephen M. Black, Florian Länger, Mark Kuehnel, Danny Jonigk

A wide range of cardiac symptoms have been observed in COVID-19 patients, often significantly influencing the clinical outcome. While the pathophysiology of pulmonary COVID-19 manifestation has been substantially unraveled, the underlying pathomechanisms of cardiac involvement in COVID-19 are largely unknown. In this multicentre study, we performed a comprehensive analysis of heart samples from 24 autopsies with confirmed SARS-CoV-2 infection and compared them to samples of age-matched Influenza H1N1 A (n = 16), lymphocytic non-influenza myocarditis cases (n = 8), and non-inflamed heart tissue (n = 9). We employed conventional histopathology, multiplexed immunohistochemistry (MPX), microvascular corrosion casting, scanning electron microscopy, X-ray phase-contrast tomography using synchrotron radiation, and direct multiplexed measurements of gene expression, to assess morphological and molecular changes holistically. Based on histopathology, none of the COVID-19 samples fulfilled the established diagnostic criteria of viral myocarditis. However, quantification via MPX showed a significant increase in perivascular CD11b/TIE2 + —macrophages in COVID-19 over time, which was not observed in influenza or non-SARS-CoV-2 viral myocarditis patients. Ultrastructurally, a significant increase in intussusceptive angiogenesis as well as multifocal thrombi, inapparent in conventional morphological analysis, could be demonstrated. In line with this, on a molecular level, COVID-19 hearts displayed a distinct expression pattern of genes primarily coding for factors involved in angiogenesis and epithelial-mesenchymal transition (EMT), changes not seen in any of the other patient groups. We conclude that cardiac involvement in COVID-19 is an angiocentric macrophage-driven inflammatory process, distinct from classical anti-viral inflammatory responses, and substantially underappreciated by conventional histopathologic analysis. For the first time, we have observed intussusceptive angiogenesis in cardiac tissue, which we previously identified as the linchpin of vascular remodeling in COVID-19 pneumonia, as a pathognomic sign in affected hearts. Moreover, we identified CD11b + /TIE2 + macrophages as the drivers of intussusceptive angiogenesis and set forward a putative model for the molecular regulation of vascular alterations.

在新冠肺炎患者中观察到广泛的心脏症状,通常会显著影响临床结果。虽然肺新冠肺炎表现的病理生理学已基本阐明,但新冠肺炎心脏受累的潜在病理机制在很大程度上尚不清楚。在这项多中心研究中,我们对24例确诊感染严重急性呼吸系统综合征冠状病毒2型的尸检心脏样本进行了全面分析,并将其与年龄匹配的甲型H1N1流感(n = 16) ,淋巴细胞性非流感性心肌炎病例(n = 8) 和未发炎的心脏组织(n = 9) 。我们采用了传统的组织病理学、多重免疫组织化学(MPX)、微血管腐蚀铸造、扫描电子显微镜、使用同步辐射的X射线相位对比断层扫描和基因表达的直接多重测量,来全面评估形态学和分子变化。根据组织病理学,新冠肺炎样本均未达到病毒性心肌炎的既定诊断标准。然而,通过MPX的定量显示血管周CD11b/TIE2显著增加 + -新冠肺炎随时间变化的巨噬细胞,这在流感或非SARS-CoV-2病毒性心肌炎患者中未观察到。在超微结构上,可以证明肠套叠感受性血管生成和多灶性血栓的显著增加,这在传统的形态学分析中是不明显的。与此相一致,在分子水平上,新冠肺炎心脏显示出主要编码参与血管生成和上皮-间质转化(EMT)的因子的基因的独特表达模式,这些变化在任何其他患者组中都没有看到。我们得出的结论是,新冠肺炎的心脏受累是一种血管中心巨噬细胞驱动的炎症过程,不同于经典的抗病毒炎症反应,传统的组织病理学分析基本上未得到重视。我们首次在心脏组织中观察到套叠血管生成,我们之前将其确定为新冠肺炎肺炎血管重塑的关键,并将其作为受影响心脏的病理标志。此外,我们鉴定了CD11b + /TIE2 + 巨噬细胞是肠套叠血管生成的驱动因素,并为血管改变的分子调控建立了一个假定的模型。
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引用次数: 10
BMP10 functions independently from BMP9 for the development of a proper arteriovenous network BMP10的功能独立于BMP9,用于开发合适的动静脉网络
IF 9.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-11-08 DOI: 10.1007/s10456-022-09859-0
Hyunwoo Choi, Bo-Gyeong Kim, Yong Hwan Kim, Se-Jin Lee, Young Jae Lee, S. Paul Oh

Hereditary hemorrhagic telangiectasia (HHT) is a genetic vascular disorder characterized by the presence of arteriovenous malformation (AVM) in multiple organs. HHT is caused by mutations in genes encoding major constituents for transforming growth factor-β (TGF-β) family signaling: endoglin (ENG), activin receptor-like kinase 1 (ALK1), and SMAD4. The identity of physiological ligands for this ENG-ALK1 signaling pertinent to AVM formation has yet to be clearly determined. To investigate whether bone morphogenetic protein 9 (BMP9), BMP10, or both are physiological ligands of ENG-ALK1 signaling involved in arteriovenous network formation, we generated a novel Bmp10 conditional knockout mouse strain. We examined whether global Bmp10-inducible knockout (iKO) mice develop AVMs at neonatal and adult stages in comparison with control, Bmp9-KO, and Bmp9/10-double KO (dKO) mice. Bmp10-iKO and Bmp9/10-dKO mice showed AVMs in developing retina, postnatal brain, and adult wounded skin, while Bmp9-KO did not display any noticeable vascular defects. Bmp10 deficiency resulted in increased proliferation and size of endothelial cells in AVM vessels. The impaired neurovascular integrity in the brain and retina of Bmp10-iKO and Bmp9/10-dKO mice was detected. Bmp9/10-dKO mice exhibited the lethality and vascular malformation similar to Bmp10-iKO mice, but their phenotypes were more pronounced. Administration of BMP10 protein, but not BMP9 protein, prevented retinal AVM in Bmp9/10-dKO and endothelial-specific Eng-iKO mice. These data indicate that BMP10 is indispensable for the development of a proper arteriovenous network, whereas BMP9 has limited compensatory functions for the loss of BMP10. We suggest that BMP10 is the most relevant physiological ligand of the ENG-ALK1 signaling pathway pertinent to HHT pathogenesis.

遗传性出血性毛细血管扩张症(HHT)是一种以多器官动静脉畸形(AVM)为特征的遗传性血管疾病。HHT是由编码转化生长因子-β(TGF-β)家族信号传导主要成分的基因突变引起的:endoglin(ENG)、激活素受体样激酶1(ALK1)和SMAD4。与AVM形成相关的这种ENG-ALK1信号传导的生理配体的身份尚未明确确定。为了研究骨形态发生蛋白9(BMP9)、BMP10或两者是否是参与动静脉网络形成的ENG-ALK1信号的生理配体,我们产生了一种新的BMP10条件敲除小鼠株。我们检测了与对照、Bmp9-KO和Bmp9/10双KO(dKO)小鼠相比,全局Bmp10诱导型敲除(iKO)鼠是否在新生儿和成年阶段发展为AVMs。Bmp10 iKO和Bmp9/10 dKO小鼠在发育中的视网膜、出生后的大脑和成人受伤的皮肤中显示出AVM,而Bmp9 KO没有显示出任何明显的血管缺陷。Bmp10缺乏导致AVM血管中内皮细胞的增殖和大小增加。在Bmp10 iKO和Bmp9/10 dKO小鼠的大脑和视网膜中检测到受损的神经血管完整性。Bmp9/10-dKO小鼠表现出与Bmp10-iKO小鼠相似的致死性和血管畸形,但它们的表型更明显。BMP10蛋白而非BMP9蛋白的给药可预防BMP9/10dKO和内皮特异性Eng-iKO小鼠的视网膜AVM。这些数据表明,BMP10对于形成合适的动静脉网络是必不可少的,而BMP9对BMP10的损失具有有限的补偿功能。我们认为BMP10是与HHT发病机制相关的ENG-ALK1信号通路的最相关的生理配体。
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引用次数: 4
Tissue-resident glial cells associate with tumoral vasculature and promote cancer progression 组织侧胶质细胞与肿瘤血管系统相关并促进癌症进展
IF 9.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-10-01 DOI: 10.1007/s10456-022-09858-1
Beatriz G. S. Rocha, Caroline C. Picoli, Bryan O. P. Gonçalves, Walison N. Silva, Alinne C. Costa, Michele M. Moraes, Pedro A. C. Costa, Gabryella S. P. Santos, Milla R. Almeida, Luciana M. Silva, Youvika Singh, Marcelo Falchetti, Gabriela D. A. Guardia, Pedro P. G. Guimarães, Remo C. Russo, Rodrigo R. Resende, Mauro C. X. Pinto, Jaime H. Amorim, Vasco A. C. Azevedo, Alexandre Kanashiro, Helder I. Nakaya, Edroaldo L. Rocha, Pedro A. F. Galante, Akiva Mintz, Paul S. Frenette, Alexander Birbrair

Cancer cells are embedded within the tissue and interact dynamically with its components during cancer progression. Understanding the contribution of cellular components within the tumor microenvironment is crucial for the success of therapeutic applications. Here, we reveal the presence of perivascular GFAP+/Plp1+ cells within the tumor microenvironment. Using in vivo inducible Cre/loxP mediated systems, we demonstrated that these cells derive from tissue-resident Schwann cells. Genetic ablation of endogenous Schwann cells slowed down tumor growth and angiogenesis. Schwann cell-specific depletion also induced a boost in the immune surveillance by increasing tumor-infiltrating anti-tumor lymphocytes, while reducing immune-suppressor cells. In humans, a retrospective in silico analysis of tumor biopsies revealed that increased expression of Schwann cell-related genes within melanoma was associated with improved survival. Collectively, our study suggests that Schwann cells regulate tumor progression, indicating that manipulation of Schwann cells may provide a valuable tool to improve cancer patients’ outcomes.

癌症细胞嵌入组织中,并在癌症进展过程中与其成分动态相互作用。了解肿瘤微环境中细胞成分的贡献对于治疗应用的成功至关重要。在这里,我们揭示了肿瘤微环境中血管周围GFAP+/Plp1+细胞的存在。使用体内诱导型Cre/loxP介导的系统,我们证明这些细胞来源于组织固有的施旺细胞。内源性施旺细胞的基因消融减缓了肿瘤生长和血管生成。雪旺细胞特异性耗竭还通过增加肿瘤浸润的抗肿瘤淋巴细胞,同时减少免疫抑制细胞,诱导免疫监测的增强。在人类中,一项对肿瘤活检的回顾性计算机分析显示,黑色素瘤中施旺细胞相关基因表达的增加与生存率的提高有关。总之,我们的研究表明,施旺细胞调节肿瘤进展,这表明施旺细胞的操作可能为改善癌症患者的预后提供有价值的工具。
{"title":"Tissue-resident glial cells associate with tumoral vasculature and promote cancer progression","authors":"Beatriz G. S. Rocha,&nbsp;Caroline C. Picoli,&nbsp;Bryan O. P. Gonçalves,&nbsp;Walison N. Silva,&nbsp;Alinne C. Costa,&nbsp;Michele M. Moraes,&nbsp;Pedro A. C. Costa,&nbsp;Gabryella S. P. Santos,&nbsp;Milla R. Almeida,&nbsp;Luciana M. Silva,&nbsp;Youvika Singh,&nbsp;Marcelo Falchetti,&nbsp;Gabriela D. A. Guardia,&nbsp;Pedro P. G. Guimarães,&nbsp;Remo C. Russo,&nbsp;Rodrigo R. Resende,&nbsp;Mauro C. X. Pinto,&nbsp;Jaime H. Amorim,&nbsp;Vasco A. C. Azevedo,&nbsp;Alexandre Kanashiro,&nbsp;Helder I. Nakaya,&nbsp;Edroaldo L. Rocha,&nbsp;Pedro A. F. Galante,&nbsp;Akiva Mintz,&nbsp;Paul S. Frenette,&nbsp;Alexander Birbrair","doi":"10.1007/s10456-022-09858-1","DOIUrl":"10.1007/s10456-022-09858-1","url":null,"abstract":"<div><p>Cancer cells are embedded within the tissue and interact dynamically with its components during cancer progression. Understanding the contribution of cellular components within the tumor microenvironment is crucial for the success of therapeutic applications. Here, we reveal the presence of perivascular GFAP+/Plp1+ cells within the tumor microenvironment. Using in vivo inducible Cre/loxP mediated systems, we demonstrated that these cells derive from tissue-resident Schwann cells. Genetic ablation of endogenous Schwann cells slowed down tumor growth and angiogenesis. Schwann cell-specific depletion also induced a boost in the immune surveillance by increasing tumor-infiltrating anti-tumor lymphocytes, while reducing immune-suppressor cells. In humans, a retrospective in silico analysis of tumor biopsies revealed that increased expression of Schwann cell-related genes within melanoma was associated with improved survival. Collectively, our study suggests that Schwann cells regulate tumor progression, indicating that manipulation of Schwann cells may provide a valuable tool to improve cancer patients’ outcomes.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10729602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 2
Correction: RNA m6A methylation promotes the formation of vasculogenic mimicry in hepatocellular carcinoma via Hippo pathway 更正:RNA m6A甲基化通过Hippo途径促进肝细胞癌血管生成拟态的形成
IF 9.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-09-30 DOI: 10.1007/s10456-022-09857-2
Kailiang Qiao, Yantao Liu, Zheng Xu, Haohao Zhang, Heng Zhang, Chao Zhang, Zhi Chang, Xinyan Lu, Zhongwei Li, Ce Luo, Yanrong Liu, Cheng Yang, Tao Sun
{"title":"Correction: RNA m6A methylation promotes the formation of vasculogenic mimicry in hepatocellular carcinoma via Hippo pathway","authors":"Kailiang Qiao,&nbsp;Yantao Liu,&nbsp;Zheng Xu,&nbsp;Haohao Zhang,&nbsp;Heng Zhang,&nbsp;Chao Zhang,&nbsp;Zhi Chang,&nbsp;Xinyan Lu,&nbsp;Zhongwei Li,&nbsp;Ce Luo,&nbsp;Yanrong Liu,&nbsp;Cheng Yang,&nbsp;Tao Sun","doi":"10.1007/s10456-022-09857-2","DOIUrl":"10.1007/s10456-022-09857-2","url":null,"abstract":"","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2022-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10663738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 8
Correction: A novel lymphatic pattern promotes metastasis of cervical cancer in a hypoxic tumour-associated macrophage-dependent manner 更正:一种新的淋巴模式以缺氧肿瘤相关巨噬细胞依赖的方式促进癌症的转移
IF 9.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-09-10 DOI: 10.1007/s10456-022-09854-5
Xiao-Jing Chen, Wen-Fei Wei, Zi-Ci Wang, Nisha Wang, Chu-Hong Guo, Chen-Fei Zhou, Luo-Jiao Liang, Sha Wu, Li Liang, Wei Wang
{"title":"Correction: A novel lymphatic pattern promotes metastasis of cervical cancer in a hypoxic tumour-associated macrophage-dependent manner","authors":"Xiao-Jing Chen,&nbsp;Wen-Fei Wei,&nbsp;Zi-Ci Wang,&nbsp;Nisha Wang,&nbsp;Chu-Hong Guo,&nbsp;Chen-Fei Zhou,&nbsp;Luo-Jiao Liang,&nbsp;Sha Wu,&nbsp;Li Liang,&nbsp;Wei Wang","doi":"10.1007/s10456-022-09854-5","DOIUrl":"10.1007/s10456-022-09854-5","url":null,"abstract":"","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2022-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-022-09854-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10686825","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: 18
Correction: Celecoxib and octreotide synergistically ameliorate portal hypertension via inhibition of angiogenesis in cirrhotic rats 更正:塞来昔布和奥曲肽通过抑制肝硬化大鼠的血管生成协同改善门静脉高压
IF 9.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-09-10 DOI: 10.1007/s10456-022-09855-4
Jin-Hang Gao, Shi-Lei Wen, Shi Feng, Wen-Juan Yang, Yao-Yao Lu, Huan Tong, Rui Liu, Shi-Hang Tang, Zhi-Yin Huang, Ying-Mei Tang, Jin-Hui Yang, Hui-Qi Xie, Cheng-Wei Tang
{"title":"Correction: Celecoxib and octreotide synergistically ameliorate portal hypertension via inhibition of angiogenesis in cirrhotic rats","authors":"Jin-Hang Gao,&nbsp;Shi-Lei Wen,&nbsp;Shi Feng,&nbsp;Wen-Juan Yang,&nbsp;Yao-Yao Lu,&nbsp;Huan Tong,&nbsp;Rui Liu,&nbsp;Shi-Hang Tang,&nbsp;Zhi-Yin Huang,&nbsp;Ying-Mei Tang,&nbsp;Jin-Hui Yang,&nbsp;Hui-Qi Xie,&nbsp;Cheng-Wei Tang","doi":"10.1007/s10456-022-09855-4","DOIUrl":"10.1007/s10456-022-09855-4","url":null,"abstract":"","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2022-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-022-09855-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10686822","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
MicroRNA-375 repression of Kruppel-like factor 5 improves angiogenesis in diabetic critical limb ischemia MicroRNA-375对Kruppel样因子5的抑制改善糖尿病危重肢体缺血的血管生成
IF 9.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-09-08 DOI: 10.1007/s10456-022-09856-3
Michael G. McCoy, Anurag Jamaiyar, Grasiele Sausen, Henry S. Cheng, Daniel Pérez-Cremades, Rulin Zhuang, Jingshu Chen, Philip P. Goodney, Mark A. Creager, Marc S. Sabatine, Marc P. Bonaca, Mark W. Feinberg

Peripheral artery disease (PAD) is an occlusive disease of limb arteries. Critical limb ischemia (CLI) is an advanced form of PAD that is prognostically worse in subjects with diabetes and can result in limb loss, gangrene, and death, although the underlying signaling mechanisms that contribute to its development remain poorly understood. By comparing plasma samples from diabetic humans with PAD and mouse models of PAD, we identified miR-375 to be significantly downregulated in humans and mice during progression to CLI. Overexpression of miR-375 was pro-angiogenic in endothelial cells in vitro and induced endothelial migration, proliferation, sprouting, and vascular network formation, whereas miR-375 inhibition conferred anti-angiogenic effects. Intramuscular delivery of miR-375 improved blood flow recovery to diabetic mouse hindlimbs following femoral artery ligation (FAL) and improved neovessel growth and arteriogenesis in muscle tissues. Using RNA-sequencing and prediction algorithms, Kruppel-like factor 5 (KLF5) was identified as a direct target of miR-375 and siRNA knockdown of KLF5 phenocopied the effects of miR-375 overexpression in vitro and in vivo through regulatory changes in NF-kB signaling. Together, a miR-375-KLF5-NF-kB signaling axis figures prominently as a potential therapeutic pathway in the development CLI in diabetes.

外周动脉疾病(PAD)是一种肢体动脉闭塞性疾病。严重肢体缺血(CLI)是PAD的一种高级形式,在糖尿病患者中预后更差,可能导致肢体丧失、坏疽和死亡,尽管导致其发展的潜在信号机制尚不清楚。通过比较糖尿病患者的血浆样本与PAD和PAD小鼠模型,我们发现miR-375在人类和小鼠中向CLI的进展过程中显著下调。miR-375的过表达在体外内皮细胞中促血管生成,并诱导内皮迁移、增殖、出芽和血管网络形成,而miR-375抑制则具有抗血管生成作用。miR-375的肌内递送改善了股动脉结扎(FAL)后糖尿病小鼠后肢的血流恢复,并改善了肌肉组织中的新生血管生长和动脉生成。使用RNA测序和预测算法,Kruppel样因子5(KLF5)被鉴定为miR-375的直接靶点,KLF5的siRNA敲除通过NF-kB信号传导的调节变化在体外和体内表型复制了miR-375过表达的影响。总之,miR-375-KLF5-NF-kB信号轴在糖尿病CLI的发展中是一种潜在的治疗途径。
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引用次数: 10
Protein disulfide isomerase A1 as a novel redox sensor in VEGFR2 signaling and angiogenesis 蛋白二硫化物异构酶A1作为VEGFR2信号传导和血管生成中的一种新型氧化还原传感器
IF 9.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-08-19 DOI: 10.1007/s10456-022-09852-7
Sheela Nagarkoti, Young-Mee Kim, Dipankar Ash, Archita Das, Eric Vitriol, Tracy-Ann Read, Seock-Won Youn, Varadarajan Sudhahar, Malgorzata McMenamin, Yali Hou, Harriet Boatwright, Ruth Caldwell, David W. Essex, Jaehyung Cho, Tohru Fukai, Masuko Ushio-Fukai

VEGFR2 signaling in endothelial cells (ECs) is regulated by reactive oxygen species (ROS) derived from NADPH oxidases (NOXs) and mitochondria, which plays an important role in postnatal angiogenesis. However, it remains unclear how highly diffusible ROS signal enhances VEGFR2 signaling and reparative angiogenesis. Protein disulfide isomerase A1 (PDIA1) functions as an oxidoreductase depending on the redox environment. We hypothesized that PDIA1 functions as a redox sensor to enhance angiogenesis. Here we showed that PDIA1 co-immunoprecipitated with VEGFR2 or colocalized with either VEGFR2 or an early endosome marker Rab5 at the perinuclear region upon stimulation of human ECs with VEGF. PDIA1 silencing significantly reduced VEGF-induced EC migration, proliferation and spheroid sprouting via inhibiting VEGFR2 signaling. Mechanistically, VEGF stimulation rapidly increased Cys-OH formation of PDIA1 via the NOX4–mitochondrial ROS axis. Overexpression of “redox-dead” mutant PDIA1 with replacement of the active four Cys residues with Ser significantly inhibited VEGF-induced PDIA1–CysOH formation and angiogenic responses via reducing VEGFR2 phosphorylation. Pdia1+/− mice showed impaired angiogenesis in developmental retina and Matrigel plug models as well as ex vivo aortic ring sprouting model. Study using hindlimb ischemia model revealed that PDIA1 expression was markedly increased in angiogenic ECs of ischemic muscles, and that ischemia-induced limb perfusion recovery and neovascularization were impaired in EC-specific Pdia1 conditional knockout mice. These results suggest that PDIA1 can sense VEGF-induced H2O2 signal via CysOH formation to promote VEGFR2 signaling and angiogenesis in ECs, thereby enhancing postnatal angiogenesis. The oxidized PDIA1 is a potential therapeutic target for treatment of ischemic vascular diseases.

内皮细胞(EC)中的VEGFR2信号传导受到来自NADPH氧化酶(NOx)和线粒体的活性氧(ROS)的调节,后者在出生后血管生成中起着重要作用。然而,目前尚不清楚高扩散性ROS信号如何增强VEGFR2信号传导和修复性血管生成。蛋白质二硫化物异构酶A1(PDIA1)根据氧化还原环境起氧化还原酶的作用。我们假设PDIA1起氧化还原传感器的作用,以增强血管生成。在这里,我们发现在用VEGF刺激人内皮细胞时,PDIA1在核周区域与VEGFR2共免疫沉淀,或与VEGF FR2或早期内体标记物Rab5共定位。PDIA1沉默通过抑制VEGFR2信号传导显著降低VEGF诱导的EC迁移、增殖和球体发芽。从机制上讲,VEGF刺激通过NOX4-线粒体ROS轴快速增加了PDIA1的Cys-OH形成。用Ser取代活性四个Cys残基的“氧化还原死亡”突变体PDIA1的过表达通过减少VEGFR2磷酸化显著抑制VEGF诱导的PDIA1–CysOH的形成和血管生成反应。Pdia1+/-小鼠在发育中的视网膜和Matrigel栓塞模型以及离体主动脉环发芽模型中表现出血管生成受损。使用后肢缺血模型的研究表明,在缺血肌肉的血管生成内皮细胞中,PDIA1的表达显著增加,并且在EC特异性PDIA1条件敲除小鼠中,缺血诱导的肢体灌注恢复和新生血管形成受损。这些结果表明,PDIA1可以通过CysOH的形成来感知VEGF诱导的H2O2信号,以促进内皮细胞中的VEGFR2信号和血管生成,从而增强出生后的血管生成。氧化的PDIA1是治疗缺血性血管疾病的潜在治疗靶点。
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引用次数: 3
Endothelial cell expression of mutant Map2k1 causes vascular malformations in mice 突变型Map2k1的内皮细胞表达导致小鼠血管畸形
IF 9.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-08-16 DOI: 10.1007/s10456-022-09853-6
Patrick J. Smits, Christopher L. Sudduth, Dennis J. Konczyk, Yu Sheng Cheng, Matthew P. Vivero, Harry P. W. Kozakewich, Matthew L. Warman, Arin K. Greene

Extracranial arteriovenous malformation (AVM) is a congenital vascular anomaly causing disfigurement, bleeding, ulceration, and pain. Most lesions are associated with somatic MAP2K1 activating mutations in endothelial cells (ECs). The purpose of this study was to determine if EC expression of mutant activated MAP2K1 is sufficient to produce vascular malformations in mice. We generated mice with a ROSA26 allele containing a lox-stop-lox gene trap (GT), Map2k1 cDNA with an activating p.K57N missense mutation, an internal ribosomal entry site, and green fluorescent protein cDNA (R26GT−Map2k1−GFP). We expressed mutant MAP2K1 and GFP in ECs of fetal and newborn mice using Tg-Cdh5Cre or Tg-Cdh5CreER alleles. Tg-Cdh5Cre+/−;R26GT−Map2k1−GFP/+ animals that express mutant MAP2K1 in ECs in utero developed diffuse vascular abnormalities and died by embryonic (E) day 16.5. Tg-Cdh5CreER+/−;R26GT−Map2k1−GFP/+ animals in which mutant MAP2K1 expression was induced in ECs by tamoxifen at postnatal (P) day 1 developed vascular malformations in the brain, ear, and intestines by P23. The lesions consisted of abnormal networks of blood vessels containing recombined and non-recombined ECs. In conclusion, expression of MAP2K1 p.K57N is sufficient to cause vascular malformations in mice. This model can be used to study the malformation process and for pre-clinical pharmacologic studies.

颅外动静脉畸形(AVM)是一种先天性血管畸形,可导致畸形、出血、溃疡和疼痛。大多数病变与内皮细胞(EC)中体细胞MAP2K1激活突变有关。本研究的目的是确定突变激活的MAP2K1的EC表达是否足以在小鼠中产生血管畸形。我们产生了具有ROSA26等位基因的小鼠,该等位基因包含lox-stop lox基因陷阱(GT)、具有激活p.K57N错义突变的Map2k1 cDNA、内部核糖体进入位点和绿色荧光蛋白cDNA(R26GT−Map2k1−GFP)。我们使用Tg-Cdh5Cre或Tg-Cdh5CreER等位基因在胎儿和新生儿小鼠的EC中表达突变的MAP2K1和GFP。Tg-Cdh5Cr+/−;R26GT−Map2k1−GFP/+在子宫内皮细胞中表达突变Map2k1的动物出现弥漫性血管异常,并在胚胎(E)第16.5天死亡。Tg-Cdh5受体+/−;R26GT−Map2k1−GFP/+动物在出生后(P)第1天,三苯氧胺在内皮细胞中诱导突变Map2k1表达,P23导致大脑、耳朵和肠道出现血管畸形。病变由包含重组和非重组内皮细胞的异常血管网络组成。总之,MAP2K1 p.K57N的表达足以引起小鼠的血管畸形。该模型可用于研究畸形过程和临床前药理学研究。
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引用次数: 6
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Angiogenesis
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