Angiogenesis最新文献

{"title":"ACVR1/ALK2-p21 signaling axis modulates proliferation of the venous endothelium in the retinal vasculature","authors":"Boryeong Pak,&nbsp;Minjung Kim,&nbsp;Orjin Han,&nbsp;Heon-Woo Lee,&nbsp;Alexandre Dubrac,&nbsp;Woosoung Choi,&nbsp;Jee Myung Yang,&nbsp;Kevin Boyé,&nbsp;Heewon Cho,&nbsp;Kathryn M. Citrin,&nbsp;Injune Kim,&nbsp;Anne Eichmann,&nbsp;Victoria L. Bautch,&nbsp;Suk-Won Jin","doi":"10.1007/s10456-024-09936-6","DOIUrl":"10.1007/s10456-024-09936-6","url":null,"abstract":"<div><p>The proliferation of the endothelium is a highly coordinated process to ensure the emergence, expansion, and homeostasis of the vasculature. While Bone Morphogenetic Protein (BMP) signaling fine-tunes the behaviors of endothelium in health and disease, how BMP signaling influences the proliferation of endothelium and therefore, modulates angiogenesis remains largely unknown. Here, we evaluated the role of Activin A Type I Receptor (ACVR1/ALK2), a key BMP receptor in the endothelium, in modulating the proliferation of endothelial cells. We show that ACVR1/ALK2 is a key modulator for the proliferation of endothelium in the retinal vessels. Loss of endothelial ALK2 leads to a significant reduction in endothelial proliferation and results in fewer branches/endothelial cells in the retinal vessels. Interestingly, venous endothelium appears to be more susceptible to ALK2 deletion. Mechanistically, ACVR1/ALK2 inhibits the expression of CDKN1A/p21, a critical negative regulator of cell cycle progression, in a SMAD1/5-dependent manner, thereby enabling the venous endothelium to undergo active proliferation by suppressing CDKN1A/p21. Taken together, our findings show that BMP signaling mediated by ACVR1/ALK2 provides a critical yet previously underappreciated input to modulate the proliferation of venous endothelium, thereby fine-tuning the context of angiogenesis in health and disease.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 4","pages":"765 - 777"},"PeriodicalIF":9.2,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490534","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":"Botulinum neurotoxin serotype A inhibited ocular angiogenesis through modulating glial activation via SOCS3","authors":"Austin T. Gregg,&nbsp;Tianxi Wang,&nbsp;Manon Szczepan,&nbsp;Enton Lam,&nbsp;Hitomi Yagi,&nbsp;Katherine Neilsen,&nbsp;Xingyan Wang,&nbsp;Lois E. H. Smith,&nbsp;Ye Sun","doi":"10.1007/s10456-024-09935-7","DOIUrl":"10.1007/s10456-024-09935-7","url":null,"abstract":"<div><h3>Background</h3><p>Pathological angiogenesis causes significant vision loss in neovascular age-related macular degeneration and other retinopathies with neovascularization (NV). Neuronal/glial-vascular interactions influence the release of angiogenic and neurotrophic factors. We hypothesized that botulinum neurotoxin serotype A (BoNT/A) modulates pathological endothelial cell proliferation through glial cell activation and growth factor release.</p><h3>Methods</h3><p>A laser-induced choroidal NV (CNV) was employed to investigate the anti-angiogenic effects of BoNT/A. Fundus fluorescence angiography, immunohistochemistry, and real-time PCR were used to assess BoNT/A efficacy in inhibiting CNV and the molecular mechanisms underlying this inhibition. Neuronal and glial suppressor of cytokine signaling 3 (SOCS3) deficient mice were used to investigate the molecular mechanisms of BoNT/A in inhibiting CNV via SOCS3.</p><h3>Findings</h3><p>In laser-induced CNV mice with intravitreal BoNT/A treatment, CNV lesions decreased &gt; 30%; vascular leakage and retinal glial activation were suppressed; and <i>Socs3</i> mRNA expression was induced while vascular endothelial growth factor A (<i>Vegfa</i>) mRNA expression was suppressed. The protective effects of BoNT/A on CNV development were diminished in mice lacking neuronal/glial SOCS3.</p><h3>Conclusion</h3><p>BoNT/A suppressed laser-induced CNV and glial cell activation, in part through SOCS3 induction in neuronal/glial cells. BoNT/A treatment led to a decrease of pro-angiogenic factors, including VEGFA, highlighting the potential of BoNT/A as a therapeutic intervention for pathological angiogenesis in retinopathies.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 4","pages":"753 - 764"},"PeriodicalIF":9.2,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-024-09935-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449363","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: Human iPSC and CRISPR targeted gene knock-in strategy for studying the somatic TIE2L914F mutation in endothelial cells","authors":"Bojana Lazovic,&nbsp;Hoang-Tuan Nguyen,&nbsp;Mohammadhassan Ansarizadeh,&nbsp;Leif Wigge,&nbsp;Franziska Kohl,&nbsp;Songyuan Li,&nbsp;Miguel Carracedo,&nbsp;Jere Kettunen,&nbsp;Luc Krimpenfort,&nbsp;Ramy Elgendy,&nbsp;Kati Richter,&nbsp;Laknee De Silva,&nbsp;Bilada Bilican,&nbsp;Prateek Singh,&nbsp;Pratik Saxena,&nbsp;Lars Jakobsson,&nbsp;Xuechong Hong,&nbsp;Lauri Eklund,&nbsp;Ryan Hicks","doi":"10.1007/s10456-024-09932-w","DOIUrl":"10.1007/s10456-024-09932-w","url":null,"abstract":"","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 3","pages":"543 - 544"},"PeriodicalIF":9.2,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449364","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":"A C-type lectin from Bothrops jararacussu venom reprograms endothelial cell biology","authors":"Federico G. Baudou,&nbsp;Nancy L. Charó,&nbsp;Marco A. Scheidegger,&nbsp;Juan C. Stupirski,&nbsp;Juan M. Pérez Sáez,&nbsp;María F. Troncoso,&nbsp;Mora Massaro,&nbsp;Adolfo R. de Roodt,&nbsp;Mauricio C. De Marzi,&nbsp;Mirta Schattner,&nbsp;Gabriel A. Rabinovich","doi":"10.1007/s10456-024-09931-x","DOIUrl":"10.1007/s10456-024-09931-x","url":null,"abstract":"<div><p>Snake venoms are intricate mixtures of enzymes and bioactive factors that induce a range of detrimental effects in afflicted hosts. Certain Viperids, including <i>Bothrops jararacussu</i>, harbor C-type lectins (CTLs) known for their modulation of a variety of host cellular responses. In this study, we isolated and purified BjcuL, a CTL from <i>B. jararacussu</i> venom and investigated its impact on endothelial cell behavior, contrasting it with human galectin-1 (Gal-1), a prototype member of the galectin family with shared β-galactoside-binding activity. We found that BjcuL binds to human dermal microvascular endothelial cells (HMECs) in a concentration- and carbohydrate-dependent fashion and reprograms the function of these cells, favoring a pro-inflammatory and pro-coagulant endothelial phenotype. In light of the quest for universal antagonists capable of mitigating the harmful consequences of snake venoms, BjcuL emerges as a promising target to be blocked in order to regulate pathological endothelial cell responses.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 4","pages":"583 - 586"},"PeriodicalIF":9.2,"publicationDate":"2024-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327066","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":"Breathing new life into tissue engineering: exploring cutting-edge vascularization strategies for skin substitutes","authors":"M. Zohaib Iqbal,&nbsp;Mahrukh Riaz,&nbsp;Thomas Biedermann,&nbsp;Agnes S. Klar","doi":"10.1007/s10456-024-09928-6","DOIUrl":"10.1007/s10456-024-09928-6","url":null,"abstract":"<div><p>Tissue-engineered skin substitutes (TESS) emerged as a new therapeutic option to improve skin transplantation. However, establishing an adequate and rapid vascularization in TESS is a critical factor for their clinical application and successful engraftment in patients. Therefore, several methods have been applied to improve the vascularization of skin substitutes including (i) modifying the structural and physicochemical properties of dermal scaffolds; (ii) activating biological scaffolds with growth factor-releasing systems or gene vectors; and (iii) developing prevascularized skin substitutes by loading scaffolds with capillary-forming cells. This review provides a detailed overview of the most recent and important developments in the vascularization strategies for skin substitutes. On the one hand, we present cell-based approaches using stem cells, microvascular fragments, adipose tissue derived stromal vascular fraction, endothelial cells derived from blood and skin as well as other pro-angiogenic stimulation methods. On the other hand, we discuss how distinct 3D bioprinting techniques and microfluidics, miRNA manipulation, cell sheet engineering and photosynthetic scaffolds like GelMA, can enhance skin vascularization for clinical applications. Finally, we summarize and discuss the challenges and prospects of the currently available vascularization techniques that may serve as a steppingstone to a mainstream application of skin tissue engineering.</p><h3>Graphical abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 4","pages":"587 - 621"},"PeriodicalIF":9.2,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-024-09928-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141260354","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":"Lactate secreted by glycolytic conjunctival melanoma cells attracts and polarizes macrophages to drive angiogenesis in zebrafish xenografts","authors":"Jie Yin,&nbsp;Gabriel Forn-Cuní,&nbsp;Akshaya Mahalakshmi Surendran,&nbsp;Bruno Lopes-Bastos,&nbsp;Niki Pouliopoulou,&nbsp;Martine J. Jager,&nbsp;Sylvia E Le Dévédec,&nbsp;Quanchi Chen,&nbsp;B. Ewa Snaar-Jagalska","doi":"10.1007/s10456-024-09930-y","DOIUrl":"10.1007/s10456-024-09930-y","url":null,"abstract":"<div><p>Conjunctival melanoma (CoM) is a rare but potentially lethal cancer of the eye, with limited therapeutic option for metastases. A better understanding how primary CoM disseminate to form metastases is urgently needed in order to develop novel therapies. Previous studies indicated that primary CoM tumors express Vascular Endothelial Growth Factor (VEGF) and may recruit pro-tumorigenic M2-like macrophages. However, due to a lack of proper models, the expected role of angiogenesis in the metastatic dissemination of CoM is still unknown. We show that cells derived from two CoM cell lines induce a strong angiogenic response when xenografted in zebrafish larvae. CoM cells are highly glycolytic and secrete lactate, which recruits and polarizes human and zebrafish macrophages towards a M2-like phenotype. These macrophages elevate the levels of proangiogenic factors such as VEGF, TGF-β, and IL-10 in the tumor microenvironment to induce an angiogenic response towards the engrafted CoM cells in vivo. Chemical ablation of zebrafish macrophages or inhibition of glycolysis in CoM cells terminates this response, suggesting that attraction of lactate-dependent macrophages into engrafted CoM cells drives angiogenesis and serves as a possible dissemination mechanism for glycolytic CoM cells.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 4","pages":"703 - 717"},"PeriodicalIF":9.2,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-024-09930-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141260363","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":"Differential endothelial cell cycle status in postnatal retinal vessels revealed using a novel PIP-FUCCI reporter and zonation analysis","authors":"Ziqing Liu,&nbsp;Natalie T. Tanke,&nbsp;Alexandra Neal,&nbsp;Tianji Yu,&nbsp;Tershona Branch,&nbsp;Arya Sharma,&nbsp;Jean G. Cook,&nbsp;Victoria L. Bautch","doi":"10.1007/s10456-024-09920-0","DOIUrl":"10.1007/s10456-024-09920-0","url":null,"abstract":"<div><p>Cell cycle regulation is critical to blood vessel formation and function, but how the endothelial cell cycle integrates with vascular regulation is not well-understood, and available dynamic cell cycle reporters do not precisely distinguish all cell cycle stage transitions in vivo. Here we characterized a recently developed improved cell cycle reporter (PIP-FUCCI) that precisely delineates S phase and the S/G2 transition. Live image analysis of primary endothelial cells revealed predicted temporal changes and well-defined stage transitions. A new inducible mouse cell cycle reporter allele was selectively expressed in postnatal retinal endothelial cells upon Cre-mediated activation and predicted endothelial cell cycle status. We developed a semi-automated zonation program to define endothelial cell cycle status in spatially defined and developmentally distinct retinal areas and found predicted cell cycle stage differences in arteries, veins, and remodeled and angiogenic capillaries. Surprisingly, the predicted dearth of S-phase proliferative tip cells relative to stalk cells at the vascular front was accompanied by an unexpected enrichment for endothelial tip and stalk cells in G2, suggesting G2 stalling as a contribution to tip-cell arrest and dynamics at the front. Thus, this improved reporter precisely defines endothelial cell cycle status in vivo and reveals novel G2 regulation that may contribute to unique aspects of blood vessel network expansion. </p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 4","pages":"681 - 689"},"PeriodicalIF":9.2,"publicationDate":"2024-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-024-09920-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141096831","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":"Human atherosclerotic plaque transcriptomics reveals endothelial beta-2 spectrin as a potential regulator a leaky plaque microvasculature phenotype","authors":"Timo Rademakers,&nbsp;Marco Manca,&nbsp;Han Jin,&nbsp;Tanguy Orban,&nbsp;Ljubica Matic Perisic,&nbsp;Hubertus J. M. Frissen,&nbsp;Frank Rühle,&nbsp;Petra Hautvast,&nbsp;Jos van Rijssel,&nbsp;Kim van Kuijk,&nbsp;Barend M. E. Mees,&nbsp;Carine J. Peutz-Kootstra,&nbsp;Sylvia Heeneman,&nbsp;Mat J. A. P. Daemen,&nbsp;Gerard Pasterkamp,&nbsp;Monika Stoll,&nbsp;Marc A. M. J. van Zandvoort,&nbsp;Ulf Hedin,&nbsp;Franck Dequiedt,&nbsp;Jaap D. van Buul,&nbsp;Judith C. Sluimer,&nbsp;Erik A. L. Biessen","doi":"10.1007/s10456-024-09921-z","DOIUrl":"10.1007/s10456-024-09921-z","url":null,"abstract":"<div><p>The presence of atherosclerotic plaque vessels is a critical factor in plaque destabilization. This may be attributable to the leaky phenotype of these microvessels, although direct proof for this notion is lacking. In this study, we investigated molecular and cellular patterns of stable and hemorrhaged human plaque to identify novel drivers of intraplaque vessel dysfunction. From transcriptome data of a human atherosclerotic lesion cohort, we reconstructed a co-expression network, identifying a gene module strongly and selectively correlated with both plaque microvascular density and inflammation. Spectrin Beta Non-Erythrocytic 1 (<i>sptbn1</i>) was identified as one of the central hubs of this module (along with <i>zeb1</i> and <i>dock1</i>) and was selected for further study based on its predominant endothelial expression. Silencing of <i>sptbn1</i> enhanced leukocyte transmigration and vascular permeability in vitro, characterized by an increased number of focal adhesions and reduced junctional VE-cadherin. In vivo, <i>sptbn1</i> knockdown in zebrafish impaired the development of the caudal vein plexus. Mechanistically, increased substrate stiffness was associated with <i>sptbn1</i> downregulation in endothelial cells in vitro and in human vessels. Plaque SPTBN1 mRNA and protein expression were found to correlate with an enhanced presence of intraplaque hemorrhage and future cardiovascular disease (CVD) events during follow-up. In conclusion, we identify SPTBN1 as a central hub gene in a gene program correlating with plaque vascularisation. SPTBN1 was regulated by substrate stiffness in vitro while silencing blocked vascular development in vivo, and compromised barrier function in vitro. Together, SPTBN1 is identified as a new potential regulator of the leaky phenotype of atherosclerotic plaque microvessels.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 3","pages":"461 - 474"},"PeriodicalIF":9.2,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080492","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":"Generation and characterisation of scalable and stable human pluripotent stem cell-derived microvascular-like endothelial cells for cardiac applications","authors":"Qasim A. Majid,&nbsp;Bishwa R. Ghimire,&nbsp;Bela Merkely,&nbsp;Anna M. Randi,&nbsp;Sian E. Harding,&nbsp;Virpi Talman,&nbsp;Gábor Földes","doi":"10.1007/s10456-024-09929-5","DOIUrl":"10.1007/s10456-024-09929-5","url":null,"abstract":"<div><p>Coronary microvascular disease (CMD) and its progression towards major adverse coronary events pose a significant health challenge. Accurate in vitro investigation of CMD requires a robust cell model that faithfully represents the cells within the cardiac microvasculature. Human pluripotent stem cell-derived endothelial cells (hPSC-ECs) offer great potential; however, they are traditionally derived via differentiation protocols that are not readily scalable and are not specified towards the microvasculature. Here, we report the development and comprehensive characterisation of a scalable 3D protocol enabling the generation of phenotypically stable cardiac hPSC-microvascular-like ECs (hPSC-CMVECs) and cardiac pericyte-like cells. These were derived by growing vascular organoids within 3D stirred tank bioreactors and subjecting the emerging 3D hPSC-ECs to high-concentration VEGF-A treatment (3DV). Not only did this promote phenotypic stability of the 3DV hPSC-ECs; single cell-RNA sequencing (scRNA-seq) revealed the pronounced expression of cardiac endothelial- and microvascular-associated genes. Further, the generated mural cells attained from the vascular organoid exhibited markers characteristic of cardiac pericytes. Thus, we present a suitable cell model for investigating the cardiac microvasculature as well as the endothelial-dependent and -independent mechanisms of CMD. Moreover, owing to their phenotypic stability, cardiac specificity, and high angiogenic potential, the cells described within would also be well suited for cardiac tissue engineering applications.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 3","pages":"561 - 582"},"PeriodicalIF":9.2,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141074609","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":"Human iPSC and CRISPR targeted gene knock-in strategy for studying the somatic TIE2L914F mutation in endothelial cells","authors":"Bojana Lazovic,&nbsp;Hoang-Tuan Nguyen,&nbsp;Mohammadhassan Ansarizadeh,&nbsp;Leif Wigge,&nbsp;Franziska Kohl,&nbsp;Songyuan Li,&nbsp;Miguel Carracedo,&nbsp;Jere Kettunen,&nbsp;Luc Krimpenfort,&nbsp;Ramy Elgendy,&nbsp;Kati Richter,&nbsp;Laknee De Silva,&nbsp;Bilada Bilican,&nbsp;Prateek Singh,&nbsp;Pratik Saxena,&nbsp;Lars Jakobsson,&nbsp;Xuechong Hong,&nbsp;Lauri Eklund,&nbsp;Ryan Hicks","doi":"10.1007/s10456-024-09925-9","DOIUrl":"10.1007/s10456-024-09925-9","url":null,"abstract":"<div><p>Induced pluripotent stem cell (iPSC) derived endothelial cells (iECs) have emerged as a promising tool for studying vascular biology and providing a platform for modelling various vascular diseases, including those with genetic origins. Currently, primary ECs are the main source for disease modelling in this field. However, they are difficult to edit and have a limited lifespan. To study the effects of targeted mutations on an endogenous level, we generated and characterized an iPSC derived model for venous malformations (VMs). CRISPR-Cas9 technology was used to generate a novel human iPSC line with an amino acid substitution L914F in the TIE2 receptor, known to cause VMs. This enabled us to study the differential effects of VM causative mutations in iECs in multiple in vitro models and assess their ability to form vessels in vivo. The analysis of TIE2 expression levels in TIE2^L914F iECs showed a significantly lower expression of TIE2 on mRNA and protein level, which has not been observed before due to a lack of models with endogenous edited TIE2^L914F and sparse patient data. Interestingly, the TIE2 pathway was still significantly upregulated and TIE2 showed high levels of phosphorylation. TIE2^L914F iECs exhibited dysregulated angiogenesis markers and upregulated migration capability, while proliferation was not affected. Under shear stress TIE2^L914F iECs showed reduced alignment in the flow direction and a larger cell area than TIE2^WT iECs. In summary, we developed a novel TIE2^L914F iPSC-derived iEC model and characterized it in multiple in vitro models. The model can be used in future work for drug screening for novel treatments for VMs.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 3","pages":"523 - 542"},"PeriodicalIF":9.2,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141069657","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}