Angiogenesis最新文献

{"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}

{"title":"Inflammation and vascular remodeling in COVID-19 hearts","authors":"Christopher Werlein,&nbsp;Maximilian Ackermann,&nbsp;Helge Stark,&nbsp;Harshit R. Shah,&nbsp;Alexandar Tzankov,&nbsp;Jasmin Dinonne Haslbauer,&nbsp;Saskia von Stillfried,&nbsp;Roman David Bülow,&nbsp;Ali El-Armouche,&nbsp;Stephan Kuenzel,&nbsp;Jan Lukas Robertus,&nbsp;Marius Reichardt,&nbsp;Axel Haverich,&nbsp;Anne Höfer,&nbsp;Lavinia Neubert,&nbsp;Edith Plucinski,&nbsp;Peter Braubach,&nbsp;Stijn Verleden,&nbsp;Tim Salditt,&nbsp;Nikolaus Marx,&nbsp;Tobias Welte,&nbsp;Johann Bauersachs,&nbsp;Hans-Heinrich Kreipe,&nbsp;Steven J. Mentzer,&nbsp;Peter Boor,&nbsp;Stephen M. Black,&nbsp;Florian Länger,&nbsp;Mark Kuehnel,&nbsp;Danny Jonigk","doi":"10.1007/s10456-022-09860-7","DOIUrl":"10.1007/s10456-022-09860-7","url":null,"abstract":"<div><p>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 (<i>n</i> = 16), lymphocytic non-influenza myocarditis cases (<i>n</i> = 8), and non-inflamed heart tissue (<i>n</i> = 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.\u0000</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"26 2","pages":"233 - 248"},"PeriodicalIF":9.8,"publicationDate":"2022-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-022-09860-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9978542","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":"BMP10 functions independently from BMP9 for the development of a proper arteriovenous network","authors":"Hyunwoo Choi,&nbsp;Bo-Gyeong Kim,&nbsp;Yong Hwan Kim,&nbsp;Se-Jin Lee,&nbsp;Young Jae Lee,&nbsp;S. Paul Oh","doi":"10.1007/s10456-022-09859-0","DOIUrl":"10.1007/s10456-022-09859-0","url":null,"abstract":"<div><p>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 <i>Bmp10</i> conditional knockout mouse strain. We examined whether global <i>Bmp10</i>-inducible knockout (iKO) mice develop AVMs at neonatal and adult stages in comparison with control, <i>Bmp9</i>-KO, and <i>Bmp9/10</i>-double KO (dKO) mice. <i>Bmp10</i>-iKO and <i>Bmp9/10</i>-dKO mice showed AVMs in developing retina, postnatal brain, and adult wounded skin, while <i>Bmp9</i>-KO did not display any noticeable vascular defects. <i>Bmp10</i> deficiency resulted in increased proliferation and size of endothelial cells in AVM vessels. The impaired neurovascular integrity in the brain and retina of <i>Bmp10</i>-iKO and <i>Bmp9/10</i>-dKO mice was detected. <i>Bmp9/10</i>-dKO mice exhibited the lethality and vascular malformation similar to <i>Bmp10</i>-iKO mice, but their phenotypes were more pronounced. Administration of BMP10 protein, but not BMP9 protein, prevented retinal AVM in <i>Bmp9/10</i>-dKO and endothelial-specific <i>Eng</i>-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.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"26 1","pages":"167 - 186"},"PeriodicalIF":9.8,"publicationDate":"2022-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-022-09859-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10741264","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":"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":"26 1","pages":"129 - 166"},"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}

{"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":"26 1","pages":"197 - 199"},"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}

{"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":"26 1","pages":"187 - 191"},"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}

{"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":"26 1","pages":"193 - 196"},"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}

{"title":"MicroRNA-375 repression of Kruppel-like factor 5 improves angiogenesis in diabetic critical limb ischemia","authors":"Michael G. McCoy,&nbsp;Anurag Jamaiyar,&nbsp;Grasiele Sausen,&nbsp;Henry S. Cheng,&nbsp;Daniel Pérez-Cremades,&nbsp;Rulin Zhuang,&nbsp;Jingshu Chen,&nbsp;Philip P. Goodney,&nbsp;Mark A. Creager,&nbsp;Marc S. Sabatine,&nbsp;Marc P. Bonaca,&nbsp;Mark W. Feinberg","doi":"10.1007/s10456-022-09856-3","DOIUrl":"10.1007/s10456-022-09856-3","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"26 1","pages":"107 - 127"},"PeriodicalIF":9.8,"publicationDate":"2022-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-022-09856-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10729597","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":"Protein disulfide isomerase A1 as a novel redox sensor in VEGFR2 signaling and angiogenesis","authors":"Sheela Nagarkoti,&nbsp;Young-Mee Kim,&nbsp;Dipankar Ash,&nbsp;Archita Das,&nbsp;Eric Vitriol,&nbsp;Tracy-Ann Read,&nbsp;Seock-Won Youn,&nbsp;Varadarajan Sudhahar,&nbsp;Malgorzata McMenamin,&nbsp;Yali Hou,&nbsp;Harriet Boatwright,&nbsp;Ruth Caldwell,&nbsp;David W. Essex,&nbsp;Jaehyung Cho,&nbsp;Tohru Fukai,&nbsp;Masuko Ushio-Fukai","doi":"10.1007/s10456-022-09852-7","DOIUrl":"10.1007/s10456-022-09852-7","url":null,"abstract":"<div><p>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 <i>Cys-OH</i> 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.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"26 1","pages":"77 - 96"},"PeriodicalIF":9.8,"publicationDate":"2022-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9918675/pdf/nihms-1842367.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9620053","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 cell expression of mutant Map2k1 causes vascular malformations in mice","authors":"Patrick J. Smits,&nbsp;Christopher L. Sudduth,&nbsp;Dennis J. Konczyk,&nbsp;Yu Sheng Cheng,&nbsp;Matthew P. Vivero,&nbsp;Harry P. W. Kozakewich,&nbsp;Matthew L. Warman,&nbsp;Arin K. Greene","doi":"10.1007/s10456-022-09853-6","DOIUrl":"10.1007/s10456-022-09853-6","url":null,"abstract":"<div><p>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 <i>ROSA26</i> allele containing a lox-stop-lox gene trap (GT), <i>Map2k1</i> cDNA with an activating p.K57N missense mutation, an internal ribosomal entry site, and green fluorescent protein cDNA (<i>R26</i>^{<i>GT−Map2k1−GFP</i>}). We expressed mutant MAP2K1 and GFP in ECs of fetal and newborn mice using <i>Tg-Cdh5Cre</i> or <i>Tg-Cdh5CreER</i> alleles. <i>Tg-Cdh5Cre</i>^+/−<i>;R26</i>^{<i>GT−Map2k1−GFP/</i>+} animals that express mutant MAP2K1 in ECs in utero developed diffuse vascular abnormalities and died by embryonic (E) day 16.5. <i>Tg-Cdh5CreER</i>^+/−<i>;R26</i>^{<i>GT−Map2k1−GFP/</i>+} 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.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"26 1","pages":"97 - 105"},"PeriodicalIF":9.8,"publicationDate":"2022-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-022-09853-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10741220","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}