{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T13:25:03Z","timestamp":1786973103714,"version":"build-2736575974"},"reference-count":65,"publisher":"Springer Science and Business Media LLC","issue":"18","license":[{"start":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T00:00:00Z","timestamp":1754870400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T00:00:00Z","timestamp":1754870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U22A20335"],"award-info":[{"award-number":["U22A20335"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31970149"],"award-info":[{"award-number":["31970149"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["EMBO Rep"],"published-print":{"date-parts":[[2025,9,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hemorrhage is a major pathological manifestation of certain viral infections, such as severe fever with thrombocytopenia syndrome (SFTS), Ebola, Crimean-Congo hemorrhagic fever and Dengue. SFTS is an emerging viral hemorrhagic fever caused by the SFTS virus (SFTSV). Hemorrhage and angiogenesis dysfunction are key manifestations of SFTSV infection but the underlying mechanisms remain unclear. Here, we demonstrate that SFTSV infection increases soluble vascular endothelial growth factor-receptor 1 (sVEGFR1) secretion from monocytes\/macrophages. Increased sVEGFR1 in the serum of SFTS patients is positively correlated with disease severity. Moreover, we show that SFTSV induces sVEGFR1 upregulation via early growth response gene 1 (EGR1), of which VEGFR1 is a downstream target. Serum from SFTS patients containing high levels of sVEGFR1 inhibit angiogenesis, which can be reversed by removal of sVEGFR1. Treatment of SFTSV-infected animals with sVEGFR1 neutralizing antibodies improves angiogenesis and prevents blood vessel leaks in vivo. In conclusion, we show that SFTSV infection induces sVEGFR1 secretion through EGR1 upregulation, thereby contributing to hemorrhage.<\/jats:p>","DOI":"10.1038\/s44319-025-00541-2","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T14:44:19Z","timestamp":1754923459000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["sVEGFR1 up-regulation via EGR1 impairs vascular repair in SFTSV-induced hemorrhage"],"prefix":"10.1038","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5839-112X","authenticated-orcid":false,"given":"Na","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9111-3139","authenticated-orcid":false,"given":"Jing","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2337-0580","authenticated-orcid":false,"given":"Yating","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0402-2122","authenticated-orcid":false,"given":"Mengmeng","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linjing","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7032-0590","authenticated-orcid":false,"given":"Shengwei","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6306-717X","authenticated-orcid":false,"given":"Qiao","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yurong","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2048-6608","authenticated-orcid":false,"given":"Bingxin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7473-2181","authenticated-orcid":false,"given":"Ruining","family":"Lyu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8745-4555","authenticated-orcid":false,"given":"Jin","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0672-948X","authenticated-orcid":false,"given":"Zhiwei","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,11]]},"reference":[{"key":"541_CR1","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1089\/vbz.2012.1061","volume":"13","author":"E Akinci","year":"2013","unstructured":"Akinci E, Bodur H, Leblebicioglu H (2013) Pathogenesis of Crimean-Congo hemorrhagic fever. Vector Borne Zoonotic Dis 13:429\u2013437","journal-title":"Vector Borne Zoonotic Dis"},{"key":"541_CR2","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nprot.2011.435","volume":"7","author":"M Baker","year":"2011","unstructured":"Baker M, Robinson SD, Lechertier T, Barber PR, Tavora B, D\u2019Amico G, Jones DT, Vojnovic B, Hodivala-Dilke K (2011) Use of the mouse aortic ring assay to study angiogenesis. Nat Protoc 7:89\u2013104","journal-title":"Nat Protoc"},{"key":"541_CR3","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1002\/jmv.23666","volume":"85","author":"M Bakir","year":"2013","unstructured":"Bakir M, Bakir S, Sari I, Celik VK, Gozel MG, Engin A (2013) Evaluation of the relationship between serum levels of VEGF and sVEGFR1 with mortality and prognosis in patients with Crimean-Congo hemorrhagic fever. J Med Virol 85:1794\u20131801","journal-title":"J Med Virol"},{"key":"541_CR4","doi-asserted-by":"crossref","first-page":"438","DOI":"10.21037\/atm.2016.08.53","volume":"4","author":"H Bosshart","year":"2016","unstructured":"Bosshart H, Heinzelmann M (2016) THP-1 cells as a model for human monocytes. Ann Transl Med 4:438","journal-title":"Ann Transl Med"},{"key":"541_CR5","doi-asserted-by":"crossref","first-page":"e1007625","DOI":"10.1371\/journal.ppat.1007625","volume":"15","author":"CH Chao","year":"2019","unstructured":"Chao CH, Wu WC, Lai YC, Tsai PJ, Perng GC, Lin YS, Yeh TM (2019) Dengue virus nonstructural protein 1 activates platelets via Toll-like receptor 4, leading to thrombocytopenia and hemorrhage. PLoS Pathog 15:e1007625","journal-title":"PLoS Pathog"},{"key":"541_CR6","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.virol.2019.10.016","volume":"539","author":"B Dahal","year":"2020","unstructured":"Dahal B, Lin SC, Carey BD, Jacobs JL, Dinman JD, van Hoek ML, Adams AA, Kehn-Hall K (2020) EGR1 upregulation following Venezuelan equine encephalitis virus infection is regulated by ERK and PERK pathways contributing to cell death. Virology 539:121\u2013128","journal-title":"Virology"},{"key":"541_CR7","volume":"2011","author":"S Denic","year":"2011","unstructured":"Denic S, Janbeih J, Nair S, Conca W, Tariq WU, Al-Salam S (2011) Acute thrombocytopenia, leucopenia, and multiorgan dysfunction: the first case of SFTS Bunyavirus outside China? Case Rep. Infect Dis 2011:204056","journal-title":"Case Rep. Infect Dis"},{"key":"541_CR8","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.immuni.2004.10.011","volume":"21","author":"TD Eubank","year":"2004","unstructured":"Eubank TD, Roberts R, Galloway M, Wang Y, Cohn DE, Marsh CB (2004) GM-CSF induces expression of soluble VEGF receptor-1 from human monocytes and inhibits angiogenesis in mice. Immunity 21:831\u2013842","journal-title":"Immunity"},{"key":"541_CR9","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1016\/j.jtha.2023.02.006","volume":"21","author":"L Fang","year":"2023","unstructured":"Fang L, Yu S, Tian X, Fu W, Su L, Chen Z, Yan C, He J, Hong J, Lian W et al (2023) Severe fever with thrombocytopenia syndrome virus replicates in platelets and enhances platelet activation. J Thromb Haemost 21:1336\u20131351","journal-title":"J Thromb Haemost"},{"key":"541_CR10","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/S0140-6736(10)60667-8","volume":"377","author":"H Feldmann","year":"2011","unstructured":"Feldmann H, Geisbert TW (2011) Ebola haemorrhagic fever. Lancet 377:849\u2013862","journal-title":"Lancet"},{"key":"541_CR11","doi-asserted-by":"crossref","first-page":"e1505","DOI":"10.1371\/journal.pntd.0001505","volume":"6","author":"T Furuta","year":"2012","unstructured":"Furuta T, Murao LA, Lan NT, Huy NT, Huong VT, Thuy TT, Tham VD, Nga CT, Ha TT, Ohmoto Y et al (2012) Association of mast cell-derived VEGF and proteases in Dengue shock syndrome. PLoS Negl Trop Dis 6:e1505","journal-title":"PLoS Negl Trop Dis"},{"key":"541_CR12","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1093\/cid\/cir776","volume":"54","author":"Z Gai","year":"2012","unstructured":"Gai Z, Liang M, Zhang Y, Zhang S, Jin C, Wang SW, Sun L, Zhou N, Zhang Q, Sun Y et al (2012) Person-to-person transmission of severe fever with thrombocytopenia syndrome bunyavirus through blood contact. Clin Infect Dis 54:249\u2013252","journal-title":"Clin Infect Dis"},{"key":"541_CR13","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1038\/sj.bjc.6602824","volume":"93","author":"S Garvin","year":"2005","unstructured":"Garvin S, Nilsson UW, Dabrosin C (2005) Effects of oestradiol and tamoxifen on VEGF, soluble VEGFR-1, and VEGFR-2 in breast cancer and endothelial cells. Br J Cancer 93:1005\u20131010","journal-title":"Br J Cancer"},{"key":"541_CR14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11262-018-1611-y","volume":"55","author":"NN Gaudreault","year":"2019","unstructured":"Gaudreault NN, Indran SV, Balaraman V, Wilson WC, Richt JA (2019) Molecular aspects of Rift Valley fever virus and the emergence of reassortants. Virus Genes 55:1\u201311","journal-title":"Virus Genes"},{"key":"541_CR15","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1016\/j.idc.2019.08.003","volume":"33","author":"M Iannetta","year":"2019","unstructured":"Iannetta M, Di Caro A, Nicastri E, Vairo F, Masanja H, Kobinger G, Mirazimi A, Ntoumi F, Zumla A, Ippolito G (2019) Viral hemorrhagic fevers other than Ebola and Lassa. Infect Dis Clin North Am 33:977\u20131002","journal-title":"Infect Dis Clin North Am"},{"key":"541_CR16","doi-asserted-by":"crossref","DOI":"10.1016\/j.antiviral.2024.105916","volume":"227","author":"N Jiang","year":"2024","unstructured":"Jiang N, He Y, Wu J, You Q, Zhang R, Cheng M, Liu B, Cai Y, Lyu R, Wu Z (2024) 6-Thioguanine inhibits severe fever with thrombocytopenia syndrome virus through suppression of EGR1. Antivir Res 227:105916","journal-title":"Antivir Res"},{"key":"541_CR17","doi-asserted-by":"crossref","first-page":"5557","DOI":"10.1182\/blood-2009-05-220434","volume":"114","author":"E Jin","year":"2009","unstructured":"Jin E, Liu J, Suehiro J, Yuan L, Okada Y, Nikolova-Krstevski V, Yano K, Janes L, Beeler D, Spokes KC et al (2009) Differential roles for ETS, CREB, and EGR binding sites in mediating VEGF receptor 1 expression in vivo. Blood 114:5557\u20135566","journal-title":"Blood"},{"key":"541_CR18","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/S0140-6736(16)00502-X","volume":"387","author":"O Karimi","year":"2016","unstructured":"Karimi O, Goorhuis A, Schinkel J, Codrington J, Vreden SGS, Vermaat JS, Stijnis C, Grobusch MP (2016) Thrombocytopenia and subcutaneous bleedings in a patient with Zika virus infection. Lancet 387:939\u2013940","journal-title":"Lancet"},{"key":"541_CR19","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.febslet.2007.01.020","volume":"581","author":"JH Kim","year":"2007","unstructured":"Kim JH, Kim WS, Kang JH, Lim HY, Ko YH, Park C (2007) Egr-1, a new downstream molecule of Epstein-Barr virus latent membrane protein 1. FEBS Lett 581:623\u2013628","journal-title":"FEBS Lett"},{"key":"541_CR20","first-page":"1892","volume":"19","author":"KH Kim","year":"2013","unstructured":"Kim KH, Yi J, Kim G, Choi SJ, Jun KI, Kim NH, Choe PG, Kim NJ, Lee JK, Oh MD (2013) Severe fever with thrombocytopenia syndrome, South Korea, 2012. Emerg Infect Dis 19:1892\u20131894","journal-title":"Emerg Infect Dis"},{"key":"541_CR21","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.3390\/v14061210","volume":"14","author":"CW Lehman","year":"2022","unstructured":"Lehman CW, Smith A, Kelly J, Jacobs JL, Dinman JD, Kehn-Hall K (2022) EGR1 upregulation during encephalitic viral infections contributes to inflammation and cell death. Viruses 14:1210","journal-title":"Viruses"},{"key":"541_CR22","volume":"37","author":"H Li","year":"2021","unstructured":"Li H, Li X, Lv S, Peng X, Cui N, Yang T, Yang Z, Yuan C, Yuan Y, Yao J et al (2021a) Single-cell landscape of peripheral immune responses to fatal SFTS. Cell Rep 37:110039","journal-title":"Cell Rep"},{"key":"541_CR23","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1016\/S1473-3099(18)30293-7","volume":"18","author":"H Li","year":"2018","unstructured":"Li H, Lu QB, Xing B, Zhang SF, Liu K, Du J, Li XK, Cui N, Yang ZD, Wang LY et al (2018a) Epidemiological and clinical features of laboratory-diagnosed severe fever with thrombocytopenia syndrome in China, 2011-17: a prospective observational study. Lancet Infect Dis 18:1127\u20131137","journal-title":"Lancet Infect Dis"},{"key":"541_CR24","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1080\/1040841X.2020.1847037","volume":"47","author":"J Li","year":"2021","unstructured":"Li J, Li S, Yang L, Cao P, Lu J (2021b) Severe fever with thrombocytopenia syndrome virus: a highly lethal bunyavirus. Crit Rev Microbiol 47:112\u2013125","journal-title":"Crit Rev Microbiol"},{"key":"541_CR25","volume":"11","author":"XK Li","year":"2017","unstructured":"Li XK, Yang ZD, Du J, Xing B, Cui N, Zhang PH, Li H, Zhang XA, Lu QB, Liu W (2017) Endothelial activation and dysfunction in severe fever with thrombocytopenia syndrome. PLoS Negl Trop Dis 11:e0005746","journal-title":"PLoS Negl Trop Dis"},{"key":"541_CR26","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.virol.2018.05.001","volume":"520","author":"XK Li","year":"2018","unstructured":"Li XK, Zhang SF, Xu W, Xing B, Lu QB, Zhang PH, Li H, Zhang L, Zhang WC, Chen WW et al (2018b) Vascular endothelial injury in severe fever with thrombocytopenia syndrome caused by the novel bunyavirus. Virology 520:11\u201320","journal-title":"Virology"},{"key":"541_CR27","volume":"23","author":"S Liang","year":"2023","unstructured":"Liang S, Li Z, Zhang N, Wang X, Qin Y, Xie W, Bao C, Hu J (2023) Epidemiological and spatiotemporal analysis of severe fever with thrombocytopenia syndrome in Eastern China, 2011-2021. BMC Public Health 23:508","journal-title":"BMC Public Health"},{"key":"541_CR28","volume":"23","author":"X Liu","year":"2023","unstructured":"Liu X (2023) macrophage and sVEGFR1. BMC Cancer 23:259","journal-title":"BMC Cancer"},{"key":"541_CR29","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1016\/j.vaccine.2015.01.051","volume":"33","author":"QB Lu","year":"2015","unstructured":"Lu QB, Cui N, Hu JG, Chen WW, Xu W, Li H, Zhang XA, Ly H, Liu W, Cao WC (2015) Characterization of immunological responses in patients with severe fever with thrombocytopenia syndrome: a cohort study in China. Vaccine 33:1250\u20131255","journal-title":"Vaccine"},{"key":"541_CR30","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1056\/NEJMoa1203378","volume":"367","author":"LK McMullan","year":"2012","unstructured":"McMullan LK, Folk SM, Kelly AJ, MacNeil A, Goldsmith CS, Metcalfe MG, Batten BC, Albarino CG, Zaki SR, Rollin PE et al (2012) A new phlebovirus associated with severe febrile illness in Missouri. N Engl J Med 367:834\u2013841","journal-title":"N Engl J Med"},{"key":"541_CR31","first-page":"455","volume":"59","author":"CS Melincovici","year":"2018","unstructured":"Melincovici CS, Bosca AB, Susman S, Marginean M, Mihu C, Istrate M, Moldovan IM, Roman AL, Mihu CM (2018) Vascular endothelial growth factor (VEGF)\u2014key factor in normal and pathological angiogenesis. Rom J Morphol Embryol 59:455\u2013467","journal-title":"Rom J Morphol Embryol"},{"key":"541_CR32","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.coi.2015.06.003","volume":"36","author":"I Messaoudi","year":"2015","unstructured":"Messaoudi I, Basler CF (2015) Immunological features underlying viral hemorrhagic fevers. Curr Opin Immunol 36:38\u201346","journal-title":"Curr Opin Immunol"},{"key":"541_CR33","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1128\/JVI.79.4.2087-2096.2005","volume":"79","author":"H Nakata","year":"2005","unstructured":"Nakata H, Maeda K, Miyakawa T, Shibayama S, Matsuo M, Takaoka Y, Ito M, Koyanagi Y, Mitsuya H (2005) Potent anti-R5 human immunodeficiency virus type 1 effects of a CCR5 antagonist, AK602\/ONO4128\/GW873140, in a novel human peripheral blood mononuclear cell nonobese diabetic-SCID, interleukin-2 receptor gamma-chain-knocked-out AIDS mouse model. J Virol 79:2087\u20132096","journal-title":"J Virol"},{"key":"541_CR34","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1146\/annurev-pathol-020712-164041","volume":"8","author":"S Paessler","year":"2013","unstructured":"Paessler S, Walker DH (2013) Pathogenesis of the viral hemorrhagic fevers. Annu Rev Pathol 8:411\u2013440","journal-title":"Annu Rev Pathol"},{"key":"541_CR35","first-page":"e02583","volume":"12","author":"A Park","year":"2021","unstructured":"Park A, Park SJ, Jung KL, Kim SM, Kim EH, Kim YI, Foo SS, Kim S, Kim SG, Yu KM et al (2021) Molecular signatures of inflammatory profile and B-cell function in patients with severe fever with thrombocytopenia syndrome. mBio 12:e02583\u201320","journal-title":"mBio"},{"key":"541_CR36","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.ijid.2015.12.009","volume":"43","author":"C Peng","year":"2016","unstructured":"Peng C, Wang H, Zhang W, Zheng X, Tong Q, Jie S, Yang D, Zhou Y (2016) Decreased monocyte subsets and TLR4-mediated functions in patients with acute severe fever with thrombocytopenia syndrome (SFTS). Int J Infect Dis 43:37\u201342","journal-title":"Int J Infect Dis"},{"key":"541_CR37","doi-asserted-by":"crossref","first-page":"8388","DOI":"10.1128\/JVI.00612-12","volume":"86","author":"B Qu","year":"2012","unstructured":"Qu B, Qi X, Wu X, Liang M, Li C, Cardona CJ, Xu W, Tang F, Li Z, Wu B et al (2012) Suppression of the interferon and NF-kappaB responses by severe fever with thrombocytopenia syndrome virus. J Virol 86:8388\u20138401","journal-title":"J Virol"},{"key":"541_CR38","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.virol.2008.02.021","volume":"375","author":"L Romagnoli","year":"2008","unstructured":"Romagnoli L, Sariyer IK, Tung J, Feliciano M, Sawaya BE, Del Valle L, Ferrante P, Khalili K, Safak M, White MK (2008) Early growth response-1 protein is induced by JC virus infection and binds and regulates the JC virus promoter. Virology 375:331\u2013341","journal-title":"Virology"},{"key":"541_CR39","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/j.jiac.2018.07.009","volume":"24","author":"M Saijo","year":"2018","unstructured":"Saijo M (2018) Pathophysiology of severe fever with thrombocytopenia syndrome and development of specific antiviral therapy. J Infect Chemother 24:773\u2013781","journal-title":"J Infect Chemother"},{"key":"541_CR40","doi-asserted-by":"crossref","first-page":"91425","DOI":"10.18632\/oncotarget.20648","volume":"8","author":"R Sarkar","year":"2017","unstructured":"Sarkar R, Verma SC (2017) Egr-1 regulates RTA transcription through a cooperative involvement of transcriptional regulators. Oncotarget 8:91425\u201391444","journal-title":"Oncotarget"},{"key":"541_CR41","doi-asserted-by":"crossref","first-page":"e248","DOI":"10.1016\/j.ijid.2008.11.028","volume":"13","author":"RC Seet","year":"2009","unstructured":"Seet RC, Chow AW, Quek AM, Chan YH, Lim EC (2009) Relationship between circulating vascular endothelial growth factor and its soluble receptors in adults with dengue virus infection: a case-control study. Int J Infect Dis 13:e248\u2013253","journal-title":"Int J Infect Dis"},{"key":"541_CR42","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s10456-006-9055-8","volume":"9","author":"M Shibuya","year":"2006","unstructured":"Shibuya M (2006) Vascular endothelial growth factor receptor-1 (VEGFR-1\/Flt-1): a dual regulator for angiogenesis. Angiogenesis 9:225\u2013230. discussion 231","journal-title":"Angiogenesis"},{"key":"541_CR43","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1093\/jb\/mvs136","volume":"153","author":"M Shibuya","year":"2013","unstructured":"Shibuya M (2013) Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J Biochem 153:13\u201319","journal-title":"J Biochem"},{"key":"541_CR44","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s12985-017-0686-8","volume":"14","author":"K Shimizu","year":"2017","unstructured":"Shimizu K, Koma T, Yoshimatsu K, Tsuda Y, Isegawa Y, Arikawa J (2017) Appearance of renal hemorrhage in adult mice after inoculation of patient-derived hantavirus. Virol J 14:13","journal-title":"Virol J"},{"key":"541_CR45","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1056\/NEJMra1110265","volume":"366","author":"CP Simmons","year":"2012","unstructured":"Simmons CP, Farrar JJ, Nguyen VV, Wills B (2012) Dengue. N Engl J Med 366:1423\u20131432","journal-title":"N Engl J Med"},{"key":"541_CR46","volume":"9","author":"P Song","year":"2018","unstructured":"Song P, Zheng N, Liu Y, Tian C, Wu X, Ma X, Chen D, Zou X, Wang G, Wang H et al (2018) Deficient humoral responses and disrupted B-cell immunity are associated with fatal SFTSV infection. Nat Commun 9:3328","journal-title":"Nat Commun"},{"key":"541_CR47","volume":"7","author":"J Sun","year":"2017","unstructured":"Sun J, Lu L, Wu H, Yang J, Ren J, Liu Q (2017) The changing epidemiological characteristics of severe fever with thrombocytopenia syndrome in China, 2011-2016. Sci Rep 7:9236","journal-title":"Sci Rep"},{"key":"541_CR48","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1172\/JCI129171","volume":"130","author":"T Suzuki","year":"2020","unstructured":"Suzuki T, Sato Y, Sano K, Arashiro T, Katano H, Nakajima N, Shimojima M, Kataoka M, Takahashi K, Wada Y et al (2020) Severe fever with thrombocytopenia syndrome virus targets B cells in lethal human infections. J Clin Invest 130:799\u2013812","journal-title":"J Clin Invest"},{"key":"541_CR49","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1056\/NEJMc1414992","volume":"372","author":"J Agua-Agum","year":"2015","unstructured":"Team WHOER, Agua-Agum J, Ariyarajah A, Aylward B, Blake IM, Brennan R, Cori A, Donnelly CA, Dorigatti I, Dye C et al (2015) West African Ebola epidemic after one year-slowing but not yet under control. N. Engl J Med 372:584\u2013587","journal-title":"N. Engl J Med"},{"key":"541_CR50","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.3201\/eid2505.181463","volume":"25","author":"XC Tran","year":"2019","unstructured":"Tran XC, Yun Y, Van An L, Kim SH, Thao NTP, Man PKC, Yoo JR, Heo ST, Cho NH, Lee KH (2019) Endemic severe fever with thrombocytopenia syndrome, Vietnam. Emerg Infect Dis 25:1029\u20131031","journal-title":"Emerg Infect Dis"},{"key":"541_CR51","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1097\/01.CCM.0000275273.56547.B8","volume":"35","author":"PN Tsao","year":"2007","unstructured":"Tsao PN, Chan FT, Wei SC, Hsieh WS, Chou HC, Su YN, Chen CY, Hsu WM, Hsieh FJ, Hsu SM (2007) Soluble vascular endothelial growth factor receptor-1 protects mice in sepsis. Crit Care Med 35:1955\u20131960","journal-title":"Crit Care Med"},{"key":"541_CR52","doi-asserted-by":"crossref","first-page":"3387","DOI":"10.1182\/blood.V95.11.3387","volume":"95","author":"F Vidal","year":"2000","unstructured":"Vidal F, Aragones J, Alfranca A, de, Landazuri MO (2000) Up-regulation of vascular endothelial growth factor receptor Flt-1 after endothelial denudation: role of transcription factor Egr-1. Blood 95:3387\u20133395","journal-title":"Blood"},{"key":"541_CR53","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1186\/s12929-022-00889-w","volume":"29","author":"SH Wang","year":"2022","unstructured":"Wang SH, Cheng JY, Tsai HH, Lo TC, Hung JT, Lin CC, Lee CW, Ho YH, Kuo HH, Yu AL et al (2022) Conformational alteration in glycan induces phospholipase Cbeta1 activation and angiogenesis. J Biomed Sci 29:105","journal-title":"J Biomed Sci"},{"key":"541_CR54","volume":"12","author":"Y Wang","year":"2021","unstructured":"Wang Y, Han S, Ran R, Li A, Liu H, Liu M, Duan Y, Zhang X, Zhao Z, Song S et al (2021) A longitudinal sampling study of transcriptomic and epigenetic profiles in patients with thrombocytopenia syndrome. Nat Commun 12:5629","journal-title":"Nat Commun"},{"key":"541_CR55","doi-asserted-by":"crossref","first-page":"1878","DOI":"10.3201\/eid2608.200135","volume":"26","author":"AM Win","year":"2020","unstructured":"Win AM, Nguyen YTH, Kim Y, Ha NY, Kang JG, Kim H, San B, Kyaw O, Htike WW, Choi DO et al (2020) Genotypic heterogeneity of Orientia tsutsugamushi in scrub typhus patients and thrombocytopenia syndrome co-infection, Myanmar. Emerg Infect Dis 26:1878\u20131881","journal-title":"Emerg Infect Dis"},{"key":"541_CR56","volume":"13","author":"LM Wong","year":"2022","unstructured":"Wong LM, Li D, Tang Y, Mendez-Lagares G, Thompson 3rd GR, Hartigan-O\u2019Connor DJ, Dandekar S, Jiang G (2022) Human immunodeficiency virus-1 latency reversal via the induction of early growth response protein 1 to bypass protein kinase C agonist-associated immune activation. Front Microbiol 13:836831","journal-title":"Front Microbiol"},{"key":"541_CR57","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1016\/j.ajpath.2015.04.013","volume":"185","author":"WK Wu","year":"2015","unstructured":"Wu WK, Georgiadis A, Copland DA, Liyanage S, Luhmann UF, Robbie SJ, Liu J, Wu J, Bainbridge JW, Bates DO et al (2015) IL-4 regulates specific Arg-1(+) macrophage sFlt-1-mediated inhibition of angiogenesis. Am J Pathol 185:2324\u20132335","journal-title":"Am J Pathol"},{"key":"541_CR58","doi-asserted-by":"crossref","first-page":"e136855","DOI":"10.1172\/jci.insight.136855","volume":"5","author":"X Wu","year":"2020","unstructured":"Wu X, Li Y, Huang B, Ma X, Zhu L, Zheng N, Xu S, Nawaz W, Xu C, Wu Z (2020) A single-domain antibody inhibits SFTSV and mitigates virus-induced pathogenesis in vivo. JCI Insight 5:e136855","journal-title":"JCI Insight"},{"key":"541_CR59","doi-asserted-by":"crossref","first-page":"e1009587","DOI":"10.1371\/journal.ppat.1009587","volume":"17","author":"S Xu","year":"2021","unstructured":"Xu S, Jiang N, Nawaz W, Liu B, Zhang F, Liu Y, Wu X, Wu Z (2021) Infection of humanized mice with a novel phlebovirus presented pathogenic features of severe fever with thrombocytopenia syndrome. PLoS Pathog 17:e1009587","journal-title":"PLoS Pathog"},{"key":"541_CR60","doi-asserted-by":"crossref","first-page":"8559","DOI":"10.1128\/JVI.00505-12","volume":"86","author":"HW Yao","year":"2012","unstructured":"Yao HW, Chen SH, Li C, Tung YY, Chen SH (2012) Suppression of transcription factor early growth response 1 reduces herpes simplex virus 1-induced corneal disease in mice. J Virol 86:8559\u20138567","journal-title":"J Virol"},{"key":"541_CR61","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1056\/NEJMoa1010095","volume":"364","author":"XJ Yu","year":"2011","unstructured":"Yu XJ, Liang MF, Zhang SY, Liu Y, Li JD, Sun YL, Zhang L, Zhang QF, Popov VL, Li C et al (2011) Fever with thrombocytopenia associated with a novel bunyavirus in China. N Engl J Med 364:1523\u20131532","journal-title":"N Engl J Med"},{"key":"541_CR62","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.3389\/fimmu.2019.01095","volume":"10","author":"L Zhang","year":"2019","unstructured":"Zhang L, Fu Y, Wang H, Guan Y, Zhu W, Guo M, Zheng N, Wu Z (2019) Severe fever with thrombocytopenia syndrome virus-induced macrophage differentiation is regulated by miR-146. Front Immunol 10:1095","journal-title":"Front Immunol"},{"key":"541_CR63","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1093\/cid\/cir804","volume":"54","author":"YZ Zhang","year":"2012","unstructured":"Zhang YZ, He YW, Dai YA, Xiong Y, Zheng H, Zhou DJ, Li J, Sun Q, Luo XL, Cheng YL et al (2012) Hemorrhagic fever caused by a novel Bunyavirus in China: pathogenesis and correlates of fatal outcome. Clin Infect Dis 54:527\u2013533","journal-title":"Clin Infect Dis"},{"key":"541_CR64","doi-asserted-by":"crossref","first-page":"287","DOI":"10.14336\/AD.2016.0920","volume":"8","author":"G Zhao","year":"2017","unstructured":"Zhao G, Cheng XW, Piao L, Hu L, Lei Y, Yang G, Inoue A, Ogasawara S, Wu H, Hao CN et al (2017) The soluble VEGF receptor sFlt-1 contributes to impaired neovascularization in aged mice. Aging Dis 8:287\u2013300","journal-title":"Aging Dis"},{"key":"541_CR65","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.3201\/eid2607.190611","volume":"26","author":"A Zohaib","year":"2020","unstructured":"Zohaib A, Zhang J, Saqib M, Athar MA, Hussain MH, Chen J, Sial AU, Tayyab MH, Batool M, Khan S et al (2020) Serologic evidence of severe fever with thrombocytopenia syndrome virus and related viruses in Pakistan. Emerg Infect Dis 26:1513\u20131516","journal-title":"Emerg Infect Dis"}],"container-title":["EMBO Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1038\/s44319-025-00541-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1038\/s44319-025-00541-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1038\/s44319-025-00541-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:34:11Z","timestamp":1786970051000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1038\/s44319-025-00541-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,11]]},"references-count":65,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2025,9,23]]}},"alternative-id":["541"],"URL":"https:\/\/doi.org\/10.1038\/s44319-025-00541-2","relation":{},"ISSN":["1469-221X","1469-3178"],"issn-type":[{"value":"1469-221X","type":"print"},{"value":"1469-3178","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,11]]},"assertion":[{"value":"17 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 July 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 July 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 August 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosure and competing interests statement"}}],"article-number":"10"}}