Angiogenesis最新文献

{"title":"Genetic deletion of microRNA-15a/16-1 in pericytes stimulates cerebral angiogenesis and promotes functional recovery after ischemic stroke","authors":"Ping Sun,&nbsp;Yang Xu,&nbsp;Tianqing Xiong,&nbsp;Shun Li,&nbsp;Na Qiu,&nbsp;Chao Zhou,&nbsp;Jiefei Wang,&nbsp;Alexander Chang,&nbsp;Uma R. Chandran,&nbsp;Ke-Jie Yin","doi":"10.1007/s10456-025-09987-3","DOIUrl":"10.1007/s10456-025-09987-3","url":null,"abstract":"<div><p>Stroke is a leading cause of mortality and disability globally. Despite advancements in acute stroke therapies, patient outcomes with ischemic stroke remain suboptimal. Understanding its molecular mechanisms is crucial for developing effective treatments. Angiogenesis actively contributes to post-stroke functional recovery and improves long-term survival in stroke patients. Pericytes are essential for maintaining vascular stability and promoting angiogenesis. We hypothesized that microRNA-15a/16-1 in pericytes significantly modulates post-stroke angiogenesis and neurological recovery. Using a pericyte-specific miR-15a/16-1 conditional knockout (cKO) mouse model, we found that genetic deletion of miR-15a/16-1 in pericytes enhances angiogenesis, promotes cerebral blood flow recovery, and improves sensorimotor and cognitive outcomes following ischemic stroke. Mechanistically, RNA sequencing identified several novel targets of miR-15a/16-1, including Pappa2, Fgf9, Islr, and Ccr2. Interestingly, Pappa2, Fgf9, and Islr function as secreted proteins. Luciferase reporter assays demonstrated that miR-15a/16-1 directly binds and suppresses Pappa2, Fgf9, Islr, and Ccr2 activity in cultured pericytes. In vivo and in vitro assays further confirmed that miR-15a/16-1 silencing in pericytes significantly elevates the protein levels of Pappa2, Fgf9, Islr, and Ccr2 and enhances endothelial cell proliferation, migration, and tube formation under ischemic conditions. These findings suggest that targeting miR-15a/16-1 in pericytes offers a promising therapeutic strategy for enhancing stroke recovery by promoting neurovascular repair and reducing brain damage.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"28 3","pages":""},"PeriodicalIF":9.2,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315769","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":"Diversity of extracellular vesicle sources in atherosclerosis: role and therapeutic application","authors":"Yuan Zhang,&nbsp;Wendiao Zhang,&nbsp;Zhiwen Wu,&nbsp;Yong Chen","doi":"10.1007/s10456-025-09983-7","DOIUrl":"10.1007/s10456-025-09983-7","url":null,"abstract":"<div><p>Extracellular vesicles (EVs) are phospholipid bilayer membrane structures secreted by cells and widely present in blood or body fluids, playing critical roles in cell communication and homeostasis. Increasing evidence has implicated EVs dysfunction in the pathogenesis of various cardiovascular diseases (CVD), including atherosclerosis (AS), ischemic heart disease, heart failure, aortic lesions, and valvular lesions. Using EVs derived from diseases or multiple tissue types to illuminate the functional mechanisms of EVs will promote pathological studies and drug development. EVs including exosomes, microvesicles, and apoptotic bodies, play key roles in the cellular physiological processes linked to AS, notably the recently developed engineering strategies applied to EVs have provided a new avenue for elucidating the mechanisms underlying the development and pathology of AS. To help researchers develop robust and reproducible methods that recapitulate in-vivo signatures of EVs to study AS development and pathology, this review summarized the current methods used to isolate or generate EVs and provided opinions on the use of EVs for disease and functional studies through collecting EVs derived from different kinds of cells or diseases in AS, which are the aspects that have not been generalized in previous reviews. In essence, EVs and their derivatives offer a novel approach to understanding the complex etiology of AS, and serve as a substantial basis for the discovery of potential diagnostic biomarkers and therapeutic targets.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"28 3","pages":""},"PeriodicalIF":9.2,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301034","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":"An endothelial specific mouse model for the capillary malformation mutation Gnaq p.R183Q","authors":"Patrick Smits,&nbsp;Leanna Marrs,&nbsp;Yu Sheng Cheng,&nbsp;Michal Ad,&nbsp;Sana Nasim,&nbsp;David Zurakowski,&nbsp;Joyce Bischoff,&nbsp;Arin K. Greene","doi":"10.1007/s10456-025-09986-4","DOIUrl":"10.1007/s10456-025-09986-4","url":null,"abstract":"<div><p>Capillary malformation (CM) is a congenital, non-hereditary lesion composed of enlarged and tortuous blood vessels. CM is associated with a somatic p.R183Q activating mutation in the Guanine nucleotide-binding protein G(q) subunit alpha (<i>GNAQ</i>) gene in endothelial cells (EC). Cutaneous CMs are present in 1/300 infants and in 55–70% of CM cases soft tissue overgrowth is observed. Pharmacotherapy for CM does not exist. Here we report a conditional mouse model allowing the simultaneous tissue specific expression of GNAQ p.R183Q and Green Fluorescent Protein (GFP) from the <i>Rosa26</i> (R26) locus (<i>R26</i>^{<i>GT − Gnaq−GFP</i>}). We show that expression of GNAQ p.R183Q in ECs results in vascular malformations with features similar to human CM lesions. GNAQ p.R183Q expression during embryonic development (<i>Tg-Cadherin5Cre (Tg-Cdh5Cre))</i> resulted in a severe vascular phenotype, lethal by embryonic (E) 16.5. Sporadic induction of mutant GNAQ expression in ECs at postnatal (P) day 1 (<i>Tg-Cdh5CreER)</i> led to tortuous and enlarged blood vessels, most noticeable in the intestines. GNAQ p.R183Q/GFP expressing ECs co-localized with lesions and displayed increased proliferation. Mutant ECs had abnormal mural cell coverage and abnormal pericellular extracellular matrix deposition, which was confirmed in human CM samples. Similar to human CM they displayed strong expression of the tip cell marker Endothelial cell-specific molecule 1 (ESM1) and increased Angiopoietin 2 (ANGPT2) expression. In conclusion, GNAQ p.R183Q expression in mouse ECs causes vascular malformations supporting the mutation’s causality for CM. The lesions recapitulate multiple features of human CM, making the mouse model suitable for the preclinical testing of future CM pharmacotherapy.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"28 3","pages":""},"PeriodicalIF":9.2,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265137","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":"High-throughput differentiation of human blood vessel organoids reveals overlapping and distinct functions of the cerebral cavernous malformation proteins","authors":"Dariush Skowronek,&nbsp;Robin A. Pilz,&nbsp;Valeriia V. Saenko,&nbsp;Lara Mellinger,&nbsp;Debora Singer,&nbsp;Silvia Ribback,&nbsp;Anja Weise,&nbsp;Kevin Claaßen,&nbsp;Christian Büttner,&nbsp;Emily M. Brockmann,&nbsp;Christian A. Hübner,&nbsp;Thiha Aung,&nbsp;Silke Haerteis,&nbsp;Sander Bekeschus,&nbsp;Arif B. Ekici,&nbsp;Ute Felbor,&nbsp;Matthias Rath","doi":"10.1007/s10456-025-09985-5","DOIUrl":"10.1007/s10456-025-09985-5","url":null,"abstract":"<div><p>Cerebral cavernous malformations (CCMs) are clusters of thin-walled enlarged blood vessels in the central nervous system that are prone to recurrent hemorrhage and can occur in both sporadic and familial forms. The familial form results from loss-of-function variants in the <i>CCM1</i>, <i>CCM2</i>, or <i>CCM3</i> gene. Despite a better understanding of CCM pathogenesis in recent years, it is still unclear why <i>CCM3</i> mutations often lead to a more aggressive phenotype than <i>CCM1</i> or <i>CCM2</i> variants. By combining high-throughput differentiation of blood vessel organoids from human induced pluripotent stem cells (hiPSCs) with a <i>CCM1</i>, <i>CCM2</i>, or <i>CCM3</i> knockout, single-cell RNA sequencing, and high-content imaging, we uncovered both shared and distinct functions of the CCM proteins. While there was a significant overlap of differentially expressed genes in fibroblasts across all three knockout conditions, inactivation of <i>CCM1</i>, <i>CCM2</i>, or <i>CCM3</i> also led to specific gene expression patterns in neuronal, mesenchymal, and endothelial cell populations, respectively. Taking advantage of the different fluorescent labels of the hiPSCs, we could also visualize the abnormal expansion of <i>CCM1</i> and <i>CCM3</i> knockout cells when differentiated together with wild-type cells into mosaic blood vessel organoids. In contrast, <i>CCM2</i> knockout cells showed even reduced proliferation. These observations may help to explain the less severe clinical course in individuals with a pathogenic variant in <i>CCM2</i> and to decode the molecular and cellular heterogeneity in CCM disease. Finally, the excellent scalability of blood vessel organoid differentiation in a 96-well format further supports their use in high-throughput drug discovery and other biomedical research studies.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"28 3","pages":""},"PeriodicalIF":9.2,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144233007","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":"Polysialic acid regulates glomerular microvasculature formation by interaction with VEGF-A188 in mice","authors":"Kristina M. Niculovic,&nbsp;Manuel M. Vicente,&nbsp;Vanessa Wittek,&nbsp;Elina Kats,&nbsp;Iris Albers,&nbsp;Kerstin Flächsig-Schulz,&nbsp;Ulrike Peters-Bernard,&nbsp;Anna-Carina Weiss,&nbsp;Hauke Thiesler,&nbsp;Laura S. Dräger,&nbsp;Manuel H. Taft,&nbsp;Anne Jörns,&nbsp;Hans Bakker,&nbsp;Herbert Hildebrandt,&nbsp;Martina Mühlenhoff,&nbsp;Birgit Weinhold,&nbsp;Markus Abeln,&nbsp;Anja K. Münster-Kühnel","doi":"10.1007/s10456-025-09984-6","DOIUrl":"10.1007/s10456-025-09984-6","url":null,"abstract":"<div><p>Vascular endothelial growth factor A (VEGF-A) is a key signalling protein that stimulates blood vessel development and repair. Its tight control is essential for organ development and tissue homeostasis. However, the complex regulatory network for balanced bioavailability of VEGF-A is not fully understood. Here, we assessed the role of the glycocalyx component polysialic acid (polySia) for kidney development and its potential interactions with VEGF-A isoforms, in vitro and in vivo, using mouse models of polySia deficiency. PolySia acts as negative regulator of cell adhesion, but also may interact with extracellular components. In murine kidney, polySia was identified on nephron progenitor and endothelial cell subsets in developing nephrons with declining expression during maturation. Loss of polySia in <i>Ncam</i>^{<i>−/−</i>} mice revealed the neural cell adhesion molecule NCAM as major protein carrier. Both polysialyltransferase-negative and <i>Ncam</i>^{<i>−/−</i>} mice displayed impaired glomerular microvasculature development with reduced endothelial cell numbers, reminiscent to the phenotype of mice with impaired VEGF-A signalling. In vitro, immobilized polySia specifically interacted with the VEGF-A188 isoform demonstrating an isoform-specific direct interaction. Single cell RNA sequencing data analysis of newborn mouse kidneys implicated activation of VEGF-A-signalling in polysialyltransferase-positive endothelial cells. Consistently, loss of polySia resulted in diminished VEGFR2 activation in perinatal kidney and human endothelial cells. At transcriptional level, the expression of polysialyltransferases and known polySia carrier proteins is conserved in human developing kidney. Together, these data demonstrate a direct impact of polySia on VEGF-A signalling with the perspective that polysialylation could be a therapeutic target to ameliorate microvasculature repair after renal injury.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"28 3","pages":""},"PeriodicalIF":9.2,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-025-09984-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144125699","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 endothelial colony forming cells (ECFCs) require endothelial protein C receptor (EPCR) for cell cycle progression and angiogenic activity","authors":"Sarah E. J. Chambers,&nbsp;Jasenka Guduric-Fuchs,&nbsp;Edoardo Pedrini,&nbsp;Pietro M. Bertelli,&nbsp;Chutima Charoensuk,&nbsp;Elisa Peixoto,&nbsp;Varun Pathak,&nbsp;Hamza I. Alhamdan,&nbsp;Ruoxiao Xie,&nbsp;Anna Krasnodembskaya,&nbsp;Judith Lechner,&nbsp;Alan W. Stitt,&nbsp;Reinhold J. Medina","doi":"10.1007/s10456-025-09982-8","DOIUrl":"10.1007/s10456-025-09982-8","url":null,"abstract":"<div><p>Vascular repair and regeneration are critical for tissue homeostasis. Endothelial colony forming cells (ECFCs) are vessel-resident progenitors with vasoreparative capacity and they offer an important avenue for allogeneic cytotherapy to achieve perfusion of ischemic tissues. Endothelial Protein C Receptor (EPCR) has been proposed as a marker for vascular endothelial stem cells, but its precise role in ECFC biology remains unknown. The current study has investigated the biological relevance of EPCR in ECFC function. Our data show that over 95% of ECFCs exhibit high EPCR expression. These levels surpassing CD34 and CD157, positions EPCR as a new robust ECFC immunophenotypic marker, alongside established markers CD31 and CD105. Functionally, depleting EPCR expression in ECFCs significantly diminished angiogenic activity, including proliferation, migration and tube formation. This knockdown also altered normal ECFC barrier function. Transcriptomic analysis indicated that knockdown of EPCR led to enrichment of gene signatures for cell cycle, TGF beta, and focal adhesion kinases. G1 cell cycle arrest was confirmed in ECFCs with depleted EPCR. Mechanistically, EPCR knockdown led to increased release of TGFβ2 and SMAD2/3 activation, coupled with increased p21, decreased pFAK, and increased transgelin. Additionally, we showed that quiescent ECFCs showed significantly lower EPCR expression when compared to proliferating ECFCs. In agreement with this, cell sorting experiments demonstrated that ECFCs with the highest EPCR expression exhibited the highest clonogenic capacity. In summary, our findings highlight that EPCR expression in ECFCs is critical for their angiogenic activity, by modulating cell cycle progression.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"28 3","pages":""},"PeriodicalIF":9.2,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-025-09982-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144117670","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":"Acute aortic dissection in a patient with Hereditary Hemorrhagic Telangiectasia associated with Juvenile Polyposis due to SMAD4 mutation: case report and literature review","authors":"Catalina Pezzoto,&nbsp;Ana Braslavsky,&nbsp;Carolina Vázquez,&nbsp;Candelaria Serrano,&nbsp;Marcelo Serra","doi":"10.1007/s10456-025-09981-9","DOIUrl":"10.1007/s10456-025-09981-9","url":null,"abstract":"<div><h3>Objective</h3><p>We present a novel case of concurrent Hereditary Hemorrhagic Telangiectasia-Juvenile Polyposis Syndrome (HHT-JP), resulting in a fatal aortic dissection. Given rarity of the case, we aimed to perform a comprehensive review of the existing literature to better characterize this clinical complication in this population.</p><h3>Methods</h3><p>We conducted a literature review on HHT-JP syndrome using PubMed, focusing on English-language articles published between 2010 and 2024, specifically case reports and small series. Search terms \"Hereditary Hemorrhagic Telangiectasia\", “Osler-Weber-Rendu syndrome” and \"Juvenile Polyposis\" were used. Exclusion criteria included population studies lacking detailed individual characteristics related to Hereditary Hemorrhagic Telangiectasia (HHT) or Juvenile Polyposis (JP). Duplicate articles were removed, and data were extracted on patient demographics, clinical presentations, diagnostic criteria (Curaçao criteria for HHT, Jass criteria for JP), treatments, and outcomes.</p><h3>Results</h3><p>Fifty-six individuals with the MADH4 mutation met the inclusion criteria and were compared to our patient. The age range of the total cohort of fifty-six participants spanned from 6 to 66 years, with a distribution between men and women. The typical clinical presentation of HHT-JP was observed in most cases. Notably, only one patient from previous literature exhibited aortic dissection, aligning with our patient's presentation. Additionally, three other patients had aortic aneurysms. Musculoskeletal and other cardiovascular anomalies were also identified and described.</p><h3>Discussion</h3><p>While aortic aneurysms prevail in HHT-JP syndrome, aortic dissection cases are extremely rare. This case highlights the need for vigilant screening to identify aortic anomalies in this specific patient subset, emphasizing the severe complications associated with this syndrome combination.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"28 3","pages":""},"PeriodicalIF":9.2,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143896768","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":"SDF-1α mRNA therapy in peripheral artery disease","authors":"Tinghong Zhang,&nbsp;Binqiang Zhu,&nbsp;Shijie Deng,&nbsp;Jinling Qin,&nbsp;Jingyuan Zhang,&nbsp;Shu Meng","doi":"10.1007/s10456-025-09979-3","DOIUrl":"10.1007/s10456-025-09979-3","url":null,"abstract":"<div><p>Stromal cell-derived factor-1 alpha (SDF-1α) is a promising target for therapeutic angiogenesis in ischemic diseases such as peripheral artery disease (PAD). However, the clinical application of SDF-1α protein or plasmid-based gene therapy is unsuccessful. mRNA therapy has shown great promise in protein replacement. Here, we developed DOPE-lipid nanoparticles (LNPs) encapsulating SDF-1α mRNA (LNP@SDF-1α) for efficient gene delivery. In vitro, LNP@SDF-1α treatment of human umbilical vein endothelial cells (HUVECs) significantly enhanced endothelial migration, tube formation, and increased monocyte adhesion, demonstrating robust pro-angiogenic activity. In vivo, LNP@SDF-1α transfected HUVECs showed enhanced angiogenic capacity in a murine Matrigel plug model. Furthermore, in a mouse hindlimb ischemia model, intramuscular injection of LNP@SDF-1α into ischemic limbs accelerated blood flow recovery, as assessed by laser speckle contrast imaging. Immunofluorescence staining revealed a marked increase in capillary and arteriole densities in treated tissues. Angiogenic protein profiling demonstrated an upregulation of pro-angiogenic factors, including VEGF and Ang-1, and a downregulation of anti-angiogenic factors. No significant toxicity was observed in major organs, indicating the safety of this approach. Our study demonstrates that SDF-1α mRNA therapy, delivered via DOPE-LNPs, significantly promotes vascular regeneration in ischemic tissues by enhancing angiogenesis and arteriogenesis, thereby restoring blood perfusion. This approach presents a promising therapeutic option for PAD and suggests broader applications of mRNA-based therapies for ischemic diseases.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"28 3","pages":""},"PeriodicalIF":9.2,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-025-09979-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143896775","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":"The VEGF decoy receptor soluble Fms-like tyrosine kinase 1 binds to macrophages","authors":"Cleo C. L. van Aanhold,&nbsp;Qing Yong,&nbsp;Lisa Landman,&nbsp;Samiksha Sardana,&nbsp;Anouk B. Bouwmeester,&nbsp;Kyra L. Dijkstra,&nbsp;Ron Wolterbeek,&nbsp;Hailiang Mei,&nbsp;Rayman T. N. Tjokrodirijo,&nbsp;Arnoud H. de Ru,&nbsp;Peter A. van Veelen,&nbsp;Jan A. Bruijn,&nbsp;Cees van Kooten,&nbsp;Hans J. Baelde","doi":"10.1007/s10456-025-09980-w","DOIUrl":"10.1007/s10456-025-09980-w","url":null,"abstract":"<div><h3>Background</h3><p>Soluble Fms-like Tyrosine kinase-1 (sFLT1) is a native inhibitor of VEGF, best known for its antiangiogenic effects in preeclampsia. sFLT1 also reduces chronic inflammation and promotes tissue repair. In experimental diabetic nephropathy, we previously found that sFLT1 ameliorates kidney fibrosis and reduces the infiltration of macrophages. How sFLT1 regulates inflammation is still incompletely understood. Based on the direct association of sFLT1 with various cell types, we here studied whether sFLT1 interacts with macrophages to modulate inflammation.</p><h3>Methods</h3><p>Using various macrophage cell lines, sFLT1 cell surface binding was detected with flow cytometry. Enzyme studies, mass spectrometry and RNAseq were employed to identify potential sFLT1 cell surface interactors and effects of sFLT1 on macrophage signaling.</p><h3>Results</h3><p>Soluble FLT1 binds to primary macrophages, THP-1 and RAW264.7 macrophages in vitro. Alternative activation with IL-4 increases sFLT1 binding in THP-1 macrophages, whereas proinflammatory activation with IFN-γ and LPS decreases binding. Binding of sFLT1 depends on heparan sulphates, and colocalizes with the membrane heparin sulfate proteoglycan neuropilin-1. Incubation with sFLT1 reduces the gene expression of chemokine receptors.</p><h3>Conclusion</h3><p>Our results show that sFLT1, while typically associated with angiogenesis, also directly interacts with macrophages. Alternative activation of macrophages by IL-4 strongly increases binding of sFLT1 to the cell surface membrane, possibly via the VEGF co-receptor neuropilin-1. Considering sFLT1’s anti-inflammatory effects in animal studies, our findings indicate a novel function for sFLT1 to directly control anti-inflammatory macrophage function. </p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"28 3","pages":""},"PeriodicalIF":9.2,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-025-09980-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143896772","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":"Mixed lineage kinase (MLK) controls tumor development and angiogenesis","authors":"Shashi Kant,&nbsp;Amada D. Caliz,&nbsp;Hyung-Jin Yoo,&nbsp;Gaganpreet Kaur,&nbsp;Heather Learnard,&nbsp;Hassan A. Khalil,&nbsp;Roger J. Davis,&nbsp;John F. Jr. Keaney","doi":"10.1007/s10456-025-09978-4","DOIUrl":"10.1007/s10456-025-09978-4","url":null,"abstract":"<div><p>Cancer is among the leading causes of death in the USA and worldwide. Solid tumors require the formation of new blood vessels (angiogenesis) for their growth. The endothelium plays a crucial role in angiogenesis and tumor progression. Hypoxic stress generated by tumors can activate stress kinases such as mixed lineage kinases (MLKs). Publicly available datasets on lung adenocarcinoma, along with our experimental findings, indicate that MLK2 and MLK3 are expressed in human lung tumors. In this study, using three distinct mouse models of tumor development, we demonstrated that MLK2 (<i>MAP3K10</i>) and MLK3 (<i>MAP3K11</i>) are essential for tumor growth and angiogenesis. Furthermore, MLK2 and MLK3 are highly expressed in the endothelium and are necessary for endothelial proliferation, migration, and angiogenesis. In the endothelium, MLKs regulate the expression of angiogenic growth factors and metalloproteinases, including <i>Pgf</i>,<i> Vegfa</i>,<i> Angptl4</i>,<i> Adam8</i>,<i> and Mmp9</i>. Additionally, the MLK family of kinases acts through the long noncoding RNA (lncRNA) <i>H19</i> to control the expression of these pro-angiogenic factors in the endothelium. Collectively, these findings suggest that the MLK-H19 axis coordinates endothelial function, angiogenesis, and tumor growth.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"28 3","pages":""},"PeriodicalIF":9.2,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143896774","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}