Angiogenesis最新文献

{"title":"The vascular gene Apold1 is dispensable for normal development but controls angiogenesis under pathological conditions","authors":"Zheng Fan,&nbsp;Raphaela Ardicoglu,&nbsp;Aashil A. Batavia,&nbsp;Ruslan Rust,&nbsp;Lukas von Ziegler,&nbsp;Rebecca Waag,&nbsp;Jing Zhang,&nbsp;Thibaut Desgeorges,&nbsp;Oliver Sturman,&nbsp;Hairuo Dang,&nbsp;Rebecca Weber,&nbsp;Martin Roszkowski,&nbsp;Andreas E. Moor,&nbsp;Martin E. Schwab,&nbsp;Pierre-Luc Germain,&nbsp;Johannes Bohacek,&nbsp;Katrien De Bock","doi":"10.1007/s10456-023-09870-z","DOIUrl":"10.1007/s10456-023-09870-z","url":null,"abstract":"<div><p>The molecular mechanisms of angiogenesis have been intensely studied, but many genes that control endothelial behavior and fate still need to be described. Here, we characterize the role of <i>Apold1</i> (Apolipoprotein L domain containing 1) in angiogenesis in vivo and in vitro. Single-cell analyses reveal that - across tissues - the expression of <i>Apold1</i> is restricted to the vasculature and that <i>Apold1</i> expression in endothelial cells (ECs) is highly sensitive to environmental factors. Using <i>Apold1</i>^{<i>−/−</i>} mice, we find that <i>Apold1</i> is dispensable for development and does not affect postnatal retinal angiogenesis nor alters the vascular network in adult brain and muscle. However, when exposed to ischemic conditions following photothrombotic stroke as well as femoral artery ligation, <i>Apold1</i>^{<i>−/−</i>}<i> mice</i> display dramatic impairments in recovery and revascularization. We also find that human tumor endothelial cells express strikingly higher levels of <i>Apold1</i> and that <i>Apold1</i> deletion in mice stunts the growth of subcutaneous B16 melanoma tumors, which have smaller and poorly perfused vessels. Mechanistically, <i>Apold1</i> is activated in ECs upon growth factor stimulation as well as in hypoxia, and <i>Apold1</i> intrinsically controls EC proliferation but not migration. Our data demonstrate that <i>Apold1</i> is a key regulator of angiogenesis in pathological settings, whereas it does not affect developmental angiogenesis, thus making it a promising candidate for clinical investigation.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"26 3","pages":"385 - 407"},"PeriodicalIF":9.8,"publicationDate":"2023-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-023-09870-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10212428","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}

{"title":"Nectins and Nectin-like molecules drive vascular development and barrier function","authors":"Doryssa Hermans,&nbsp;Carla Rodriguez-Mogeda,&nbsp;Hannelore Kemps,&nbsp;Annelies Bronckaers,&nbsp;Helga E. de Vries,&nbsp;Bieke Broux","doi":"10.1007/s10456-023-09871-y","DOIUrl":"10.1007/s10456-023-09871-y","url":null,"abstract":"<div><p>Angiogenesis, barriergenesis, and immune cell migration are all key physiological events that are dependent on the functional characteristics of the vascular endothelium. The protein family of Nectins and Nectin-like molecules (Necls) is a group of cell adhesion molecules that are widely expressed by different endothelial cell types. The family includes four Nectins (Nectin-1 to -4) and five Necls (Necl-1 to -5) that either interact with each other by forming homo- and heterotypical interactions or bind to ligands expressed within the immune system. Nectin and Necl proteins are mainly described to play a role in cancer immunology and in the development of the nervous system. However, Nectins and Necls are underestimated players in the formation of blood vessels, their barrier properties, and in guiding transendothelial migration of leukocytes. This review summarizes their role in supporting the endothelial barrier through their function in angiogenesis, cell–cell junction formation, and immune cell migration. In addition, this review provides a detailed overview of the expression patterns of Nectins and Necls in the vascular endothelium.\u0000</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"26 3","pages":"349 - 362"},"PeriodicalIF":9.8,"publicationDate":"2023-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9785458","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}

{"title":"Modeling angiogenesis in the human brain in a tissue-engineered post-capillary venule","authors":"Nan Zhao,&nbsp;Sarah Kulkarni,&nbsp;Sophia Zhang,&nbsp;Raleigh M. Linville,&nbsp;Tracy D. Chung,&nbsp;Zhaobin Guo,&nbsp;John J. Jamieson,&nbsp;Danielle Norman,&nbsp;Lily Liang,&nbsp;Alexander F. Pessell,&nbsp;Peter Searson","doi":"10.1007/s10456-023-09868-7","DOIUrl":"10.1007/s10456-023-09868-7","url":null,"abstract":"<div><p>Angiogenesis plays an essential role in embryonic development, organ remodeling, wound healing, and is also associated with many human diseases. The process of angiogenesis in the brain during development is well characterized in animal models, but little is known about the process in the mature brain. Here, we use a tissue-engineered post-capillary venule (PCV) model incorporating stem cell derived induced brain microvascular endothelial-like cells (iBMECs) and pericyte-like cells (iPCs) to visualize the dynamics of angiogenesis. We compare angiogenesis under two conditions: in response to perfusion of growth factors and in the presence of an external concentration gradient. We show that both iBMECs and iPCs can serve as tip cells leading angiogenic sprouts. More importantly, the growth rate for iPC-led sprouts is about twofold higher than for iBMEC-led sprouts. Under a concentration gradient, angiogenic sprouts show a small directional bias toward the high growth factor concentration. Overall, pericytes exhibited a broad range of behavior, including maintaining quiescence, co-migrating with endothelial cells in sprouts, or leading sprout growth as tip cells.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"26 2","pages":"203 - 216"},"PeriodicalIF":9.8,"publicationDate":"2023-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-023-09868-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9953512","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}

{"title":"Loss of GLTSCR1 causes congenital heart defects by regulating NPPA transcription","authors":"Fengyan Han,&nbsp;Beibei Yang,&nbsp;Yan Chen,&nbsp;Lu Liu,&nbsp;Xiaoqing Cheng,&nbsp;Jiaqi Huang,&nbsp;Ke Zhou,&nbsp;Dandan Zhang,&nbsp;Enping Xu,&nbsp;Maode Lai,&nbsp;Bingjian Lv,&nbsp;Hongqiang Cheng,&nbsp;Honghe Zhang","doi":"10.1007/s10456-023-09869-6","DOIUrl":"10.1007/s10456-023-09869-6","url":null,"abstract":"<div><p>Precise and specific spatiotemporal domains of gene expression regulation are critical for embryonic development. Recent studies have identified GLTSCR1 as a gene transcriptional elongation regulator in cancer research. However, the function of GLTSCR1, especially in embryonic development, remains poorly understood. Here, we found that GLTSCR1 was essential for cardiac development because Gltscr1 knockout (Gltscr1^−/−) led to embryonic lethality in mice with severe congenital heart defects (CHDs). Ventricular septal defect and double outflow right ventricular were also observed in neural crest cells with conditional deletion of Gltscr1, which were associated with neonatal lethality in mice. Mechanistically, GLTSCR1 deletion promoted NPPA expression by coordinating the CHD risk G allele of rs56153133 in the NPPA enhancer and releasing the transcription factor ZNF740-binding site on the NPPA promoter. These findings demonstrated that GLTSCR1 acts as a candidate CHD-related gene.\u0000</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"26 2","pages":"217 - 232"},"PeriodicalIF":9.8,"publicationDate":"2023-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-023-09869-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9634733","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}

{"title":"Endothelial hyperactivation of mutant MAP3K3 induces cerebral cavernous malformation enhanced by PIK3CA GOF mutation","authors":"Ran Huo,&nbsp;Yingxi Yang,&nbsp;Yingfan Sun,&nbsp;Qiuxia Zhou,&nbsp;Shaozhi Zhao,&nbsp;Zongchao Mo,&nbsp;Hongyuan Xu,&nbsp;Jie Wang,&nbsp;Jiancong Weng,&nbsp;Yuming Jiao,&nbsp;Junze Zhang,&nbsp;Qiheng He,&nbsp;Shuo Wang,&nbsp;Jizong Zhao,&nbsp;Jiguang Wang,&nbsp;Yong Cao","doi":"10.1007/s10456-023-09866-9","DOIUrl":"10.1007/s10456-023-09866-9","url":null,"abstract":"<div><p>Cerebral cavernous malformations (CCMs) refer to a common vascular abnormality that affects up to 0.5% of the population. A somatic gain-of-function mutation in <i>MAP3K3</i> (p.I441M) was recently reported in sporadic CCMs, frequently accompanied by somatic activating <i>PIK3CA</i> mutations in diseased endothelium. However, the molecular mechanisms of these driver genes remain elusive. In this study, we performed whole-exome sequencing and droplet digital polymerase chain reaction to analyze CCM lesions and the matched blood from sporadic patients. 44 of 94 cases harbored mutations in <i>KRIT1</i>/<i>CCM2</i> or <i>MAP3K3</i>, of which 75% were accompanied by <i>PIK3CA</i> mutations (<i>P</i> = 0.006). AAV-BR1-mediated brain endothelial-specific <i>MAP3K3</i>^I441M overexpression induced CCM-like lesions throughout the brain and spinal cord in adolescent mice. Interestingly, over half of lesions disappeared at adulthood. Single-cell RNA sequencing found significant enrichment of the apoptosis pathway in a subset of brain endothelial cells in <i>MAP3K3</i>^I441M mice compared to controls. We then demonstrated that <i>MAP3K3</i>^I441M overexpression activated p38 signaling that is associated with the apoptosis of endothelial cells in vitro and in vivo. In contrast, the mice simultaneously overexpressing <i>PIK3CA</i> and <i>MAP3K3</i> mutations had an increased number of CCM-like lesions and maintained these lesions for a longer time compared to those with only <i>MAP3K3</i>^I441M. Further in vitro and in vivo experiments showed that activating PI3K signaling increased proliferation and alleviated apoptosis of endothelial cells. By using AAV-BR1, we found that <i>MAP3K3</i>^I441M mutation can provoke CCM-like lesions in mice and the activation of PI3K signaling significantly enhances and maintains these lesions, providing a preclinical model for the further mechanistic and therapeutic study of CCMs.\u0000</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"26 2","pages":"295 - 312"},"PeriodicalIF":9.8,"publicationDate":"2023-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-023-09866-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10022729","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}

{"title":"Endothelial cells require functional FLVCR1a during developmental and adult angiogenesis","authors":"Sara Petrillo,&nbsp;F. De Giorgio,&nbsp;F. Bertino,&nbsp;F. Garello,&nbsp;V. Bitonto,&nbsp;D. L. Longo,&nbsp;S. Mercurio,&nbsp;G. Ammirata,&nbsp;A. L. Allocco,&nbsp;V. Fiorito,&nbsp;D. Chiabrando,&nbsp;F. Altruda,&nbsp;E. Terreno,&nbsp;P. Provero,&nbsp;L. Munaron,&nbsp;T. Genova,&nbsp;A. Nóvoa,&nbsp;A. R. Carlos,&nbsp;S. Cardoso,&nbsp;M. Mallo,&nbsp;M. P. Soares,&nbsp;E. Tolosano","doi":"10.1007/s10456-023-09865-w","DOIUrl":"10.1007/s10456-023-09865-w","url":null,"abstract":"<div><p>The Feline Leukemia Virus Subgroup C Receptor 1a (FLVCR1a) is a transmembrane heme exporter essential for embryonic vascular development. However, the exact role of FLVCR1a during blood vessel development remains largely undefined. Here, we show that FLVCR1a is highly expressed in angiogenic endothelial cells (ECs) compared to quiescent ECs. Consistently, ECs lacking FLVCR1a give rise to structurally and functionally abnormal vascular networks in multiple models of developmental and pathologic angiogenesis. Firstly, zebrafish embryos without FLVCR1a displayed defective intersegmental vessels formation. Furthermore, endothelial-specific <i>Flvcr1a</i> targeting in mice led to a reduced radial expansion of the retinal vasculature associated to decreased EC proliferation. Moreover, <i>Flvcr1a</i> null retinas showed defective vascular organization and loose attachment of pericytes. Finally, adult neo-angiogenesis is severely affected in murine models of tumor angiogenesis. Tumor blood vessels lacking <i>Flvcr1a</i> were disorganized and dysfunctional. Collectively, our results demonstrate the critical role of FLVCR1a as a regulator of developmental and pathological angiogenesis identifying FLVCR1a as a potential therapeutic target in human diseases characterized by aberrant neovascularization.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"26 3","pages":"365 - 384"},"PeriodicalIF":9.8,"publicationDate":"2023-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-023-09865-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10213785","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}

{"title":"Retraction Note: Cancer-derived exosomal miR-221-3p promotes angiogenesis by targeting THBS2 in cervical squamous cell carcinoma","authors":"Xiang-Guang Wu,&nbsp;Chen-Fei Zhou,&nbsp;Yan-Mei Zhang,&nbsp;Rui-Ming Yan,&nbsp;Wen-Fei Wei,&nbsp;Xiao-Jing Chen,&nbsp;Hong-Yan Yi,&nbsp;Luo-Jiao Liang,&nbsp;Liang-sheng Fan,&nbsp;Li Liang,&nbsp;Sha Wu,&nbsp;Wei Wang","doi":"10.1007/s10456-022-09864-3","DOIUrl":"10.1007/s10456-022-09864-3","url":null,"abstract":"","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"26 1","pages":"201 - 201"},"PeriodicalIF":9.8,"publicationDate":"2022-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10670593","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}

{"title":"Proinflammatory activity of VEGF-targeted treatment through reversal of tumor endothelial cell anergy","authors":"Patrycja Nowak-Sliwinska,&nbsp;Judy R. van Beijnum,&nbsp;Christian J. Griffioen,&nbsp;Zowi R. Huinen,&nbsp;Nadine Grima Sopesens,&nbsp;Ralph Schulz,&nbsp;Samir V. Jenkins,&nbsp;Ruud P. M. Dings,&nbsp;Floris H. Groenendijk,&nbsp;Elisabeth J. M. Huijbers,&nbsp;Victor L. J. L. Thijssen,&nbsp;Eric Jonasch,&nbsp;Florry A. Vyth-Dreese,&nbsp;Ekaterina S. Jordanova,&nbsp;Axel Bex,&nbsp;René Bernards,&nbsp;Tanja D. de Gruijl,&nbsp;Arjan W. Griffioen","doi":"10.1007/s10456-022-09863-4","DOIUrl":"10.1007/s10456-022-09863-4","url":null,"abstract":"<div><h3>Purpose</h3><p>Ongoing angiogenesis renders the tumor endothelium unresponsive to inflammatory cytokines and interferes with adhesion of leukocytes, resulting in escape from immunity. This process is referred to as tumor endothelial cell anergy. We aimed to investigate whether anti-angiogenic agents can overcome endothelial cell anergy and provide pro-inflammatory conditions.</p><h3>Experimental design</h3><p>Tissues of renal cell carcinoma (RCC) patients treated with VEGF pathway-targeted drugs and control tissues were subject to RNAseq and immunohistochemical profiling of the leukocyte infiltrate. Analysis of adhesion molecule regulation in cultured endothelial cells, in a preclinical model and in human tissues was performed and correlated to leukocyte infiltration.</p><h3>Results</h3><p>It is shown that treatment of RCC patients with the drugs sunitinib or bevacizumab overcomes tumor endothelial cell anergy. This treatment resulted in an augmented inflammatory state of the tumor, characterized by enhanced infiltration of all major leukocyte subsets, including T cells, regulatory T cells, macrophages of both M1- and M2-like phenotypes and activated dendritic cells. In vitro, exposure of angiogenic endothelial cells to anti-angiogenic drugs normalized ICAM-1 expression. In addition, a panel of tyrosine kinase inhibitors was shown to increase transendothelial migration of both non-adherent and monocytic leukocytes. In primary tumors of RCC patients, ICAM-1 expression was found to be significantly increased in both the sunitinib and bevacizumab-treated groups. Genomic analysis confirmed the correlation between increased immune cell infiltration and ICAM-1 expression upon VEGF-targeted treatment.</p><h3>Conclusion</h3><p>The results support the emerging concept that anti-angiogenic therapy can boost immunity and show how immunotherapy approaches can benefit from combination with anti-angiogenic compounds.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"26 2","pages":"279 - 293"},"PeriodicalIF":9.8,"publicationDate":"2022-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-022-09863-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10149120","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}

{"title":"Endothelial Rap1B mediates T-cell exclusion to promote tumor growth: a novel mechanism underlying vascular immunosuppression","authors":"Guru Prasad Sharma,&nbsp;Ramoji Kosuru,&nbsp;Sribalaji Lakshmikanthan,&nbsp;Shikan Zheng,&nbsp;Yao Chen,&nbsp;Robert Burns,&nbsp;Gang Xin,&nbsp;Weiguo Cui,&nbsp;Magdalena Chrzanowska","doi":"10.1007/s10456-022-09862-5","DOIUrl":"10.1007/s10456-022-09862-5","url":null,"abstract":"<div><p>Overcoming vascular immunosuppression: lack of endothelial cell (EC) responsiveness to inflammatory stimuli in the proangiogenic environment of tumors, is essential for successful cancer immunotherapy. The mechanisms through which Vascular Endothelial Growth Factor A(VEGF-A) modulates tumor EC response to exclude T-cells are not well understood. Here, we demonstrate that EC-specific deletion of small GTPase Rap1B, previously implicated in normal angiogenesis, restricts tumor growth in endothelial-specific Rap1B-knockout (Rap1B^i<b>Δ</b>EC) mice. EC-specific Rap1B deletion inhibits angiogenesis, but also leads to an altered tumor microenvironment with increased recruitment of leukocytes and increased activity of tumor CD8⁺ T-cells. Depletion of CD8⁺ T-cells restored tumor growth in Rap1B^i<b>Δ</b>EC mice. Mechanistically, global transcriptome and functional analyses indicated upregulation of signaling by a tumor cytokine, TNF-α, and increased NF-κB transcription in Rap1B-deficient ECs. Rap1B-deficiency led to elevated proinflammatory chemokine and Cell Adhesion Molecules (CAMs) expression in TNF-α stimulated ECs. Importantly, CAM expression was elevated in tumor ECs from Rap1B^i<b>Δ</b>EC mice. Significantly, Rap1B deletion prevented VEGF-A-induced immunosuppressive downregulation of CAM expression, demonstrating that Rap1B is essential for VEGF-A-suppressive signaling. Thus, our studies identify a novel endothelial-endogenous mechanism underlying VEGF-A-dependent desensitization of EC to proinflammatory stimuli. Significantly, they identify EC Rap1B as a potential novel vascular target in cancer immunotherapy.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"26 2","pages":"265 - 278"},"PeriodicalIF":9.8,"publicationDate":"2022-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-022-09862-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9823615","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}

{"title":"Notch1 and Notch4 core binding domain peptibodies exhibit distinct ligand-binding and anti-angiogenic properties","authors":"Timothy Sargis,&nbsp;Seock-Won Youn,&nbsp;Krishna Thakkar,&nbsp;L. A. Naiche,&nbsp;Na Yoon Paik,&nbsp;Kostandin V. Pajcini,&nbsp;Jan K. Kitajewski","doi":"10.1007/s10456-022-09861-6","DOIUrl":"10.1007/s10456-022-09861-6","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"26 2","pages":"249 - 263"},"PeriodicalIF":9.8,"publicationDate":"2022-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-022-09861-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9579009","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}