{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:46:32Z","timestamp":1753890392048,"version":"3.41.2"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T00:00:00Z","timestamp":1690416000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>During development, apoptosis removes redundant cells and ensures proper organ morphogenesis. Necrosis is long known as an adult-bound inflammatory and pathologic cell death. Whether there exists physiological necrosis during early development has been speculated but yet clearly demonstrated. Here, we report evidence of necroptosis, a type of programmed necrosis, specifically in perivascular cells of cerebral cortex and skin at the early stage of development. Phosphorylated Mixed Lineage Kinase Domain-Like protein (MLKL), a key molecule in executing necroptosis, co-expressed with blood endothelial marker CD31 and venous-lymphatic progenitor marker Sox18. Depletion of <jats:italic>Mlkl<\/jats:italic> did not affect the formation of blood vessel network but increased the differentiation of venous-lymphatic lineage cells in postnatal cerebral cortex and skin. Consistently, significant enhancement of cerebrospinal fluid diffusion and lymphatic drainage was found in brain and skin of <jats:italic>Mlkl<\/jats:italic>-deficient mice. Under hypobaric hypoxia induced cerebral edema and inflammation induced skin edema, <jats:italic>Mlkl<\/jats:italic> mutation significantly attenuated brain-blood-barrier damage and edema formation. Our data, for the first time, demonstrated the presence of physiological vascular-associated necroptosis and its potential involvement in the development of venous-lymphatic vessels.<\/jats:p>","DOI":"10.3389\/fcell.2023.1229788","type":"journal-article","created":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T09:02:06Z","timestamp":1690448526000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Evidence for developmental vascular-associated necroptosis and its contribution to venous-lymphatic endothelial differentiation"],"prefix":"10.3389","volume":"11","author":[{"given":"Han","family":"Meng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Youyi","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuqian","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Fan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuyang","family":"Yi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyu","family":"Meng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengfei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fanfan","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengxi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yazhou","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.devcel.2006.11.012","article-title":"A morphologically conserved nonapoptotic program promotes linker cell death in Caenorhabditis elegans","volume":"12","author":"Abraham","year":"2007","journal-title":"Dev. Cell."},{"key":"B2","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1161\/01.RES.0000182903.16652.d7","article-title":"Endothelial\/pericyte interactions","volume":"97","author":"Armulik","year":"2005","journal-title":"Circ. Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"104987","DOI":"10.1016\/j.isci.2022.104987","article-title":"The glymphatic system: Current understanding and modeling","volume":"25","author":"Bohr","year":"2022","journal-title":"iScience"},{"key":"B4","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1002\/cne.10411","article-title":"Ultrastructure of retinal ganglion cell death after axotomy in chick embryos","volume":"453","author":"Borsello","year":"2002","journal-title":"J. Comp. Neurol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/ncb2883","article-title":"Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis","volume":"16","author":"Cai","year":"2014","journal-title":"Nat. Cell. Biol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1007\/s12264-021-00772-y","article-title":"Digoxin ameliorates glymphatic transport and cognitive impairment in a mouse model of chronic cerebral hypoperfusion","volume":"38","author":"Cao","year":"2022","journal-title":"Neurosci. Bull."},{"key":"B7","doi-asserted-by":"publisher","first-page":"2125","DOI":"10.1007\/s00018-016-2188-z","article-title":"Developmental checkpoints guarded by regulated necrosis","volume":"73","author":"Dillon","year":"2016","journal-title":"Cell. Mol. Life Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s13024-016-0081-8","article-title":"Reactive astrocytes undergo M1 microglia\/macrohpages-induced necroptosis in spinal cord injury","volume":"11","author":"Fan","year":"2016","journal-title":"Mol. Neurodegener."},{"key":"B9","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.molcel.2011.09.003","article-title":"RIPK-Dependent necrosis and its regulation by caspases: A mystery in five acts","volume":"44","author":"Green","year":"2011","journal-title":"Mol. Cell."},{"key":"B10","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1038\/s41586-020-2129-8","article-title":"Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation","volume":"580","author":"Jiao","year":"2020","journal-title":"Nature"},{"key":"B11","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1038\/nature09857","article-title":"RIP3 mediates the embryonic lethality of caspase-8-deficient mice","volume":"471","author":"Kaiser","year":"2011","journal-title":"Nature"},{"key":"B12","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1007\/s10456-015-9479-0","article-title":"Decline of lymphatic vessel density and function in murine skin during aging","volume":"18","author":"Karaman","year":"2015","journal-title":"Angiogenesis"},{"key":"B13","doi-asserted-by":"publisher","first-page":"708","DOI":"10.2353\/ajpath.2006.051200","article-title":"Lymphangiogenic growth factor responsiveness is modulated by postnatal lymphatic vessel maturation","volume":"169","author":"Karpanen","year":"2006","journal-title":"Am. J. Pathol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1146\/annurev-cellbio-100617-062608","article-title":"Development and cell Biology of the blood-brain barrier","volume":"35","author":"Langen","year":"2019","journal-title":"Annu. Rev. Cell. Dev. Biol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1007\/s10456-021-09785-7","article-title":"Vascular endothelial cell specification in health and disease","volume":"24","author":"Marziano","year":"2021","journal-title":"Angiogenesis"},{"key":"B16","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1038\/35037734","article-title":"Apoptosis in development","volume":"407","author":"Meier","year":"2000","journal-title":"Nature"},{"key":"B17","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.celrep.2019.03.034","article-title":"Lysosomal machinery drives extracellular acidification to direct non-apoptotic cell death","volume":"27","author":"Mondragon","year":"2019","journal-title":"Cell. Rep."},{"key":"B18","doi-asserted-by":"publisher","first-page":"2955","DOI":"10.1016\/j.celrep.2019.02.050","article-title":"PDGF-B is required for development of the glymphatic system","volume":"26","author":"Munk","year":"2019","journal-title":"Cell. Rep."},{"key":"B19","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1146\/annurev-immunol-032713-120240","article-title":"Microglia development and function","volume":"32","author":"Nayak","year":"2014","journal-title":"Annu. Rev. Immunol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/j.tcb.2015.01.001","article-title":"RIPK1 and RIPK3: Critical regulators of inflammation and cell death","volume":"25","author":"Newton","year":"2015","journal-title":"Trends Cell. Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1038\/s41586-019-1752-8","article-title":"Activity of caspase-8 determines plasticity between cell death pathways","volume":"575","author":"Newton","year":"2019","journal-title":"Nature"},{"key":"B22","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1038\/nature09852","article-title":"Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis","volume":"471","author":"Oberst","year":"2011","journal-title":"Nature"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1161\/ATVBAHA.119.313640","article-title":"Loss of MLKL (mixed lineage kinase domain-like protein) decreases necrotic core but increases macrophage lipid accumulation in atherosclerosis","volume":"40","author":"Rasheed","year":"2020","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1016\/S1474-4422(18)30318-1","article-title":"The glymphatic pathway in neurological disorders","volume":"17","author":"Rasmussen","year":"2018","journal-title":"Lancet Neurol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1101\/gad.312561.118","article-title":"Necroptosis in development and diseases","volume":"32","author":"Shan","year":"2018","journal-title":"Genes. Dev."},{"key":"B26","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1016\/j.immuni.2013.10.004","article-title":"Origins and functional specialization of macrophages and of conventional and monocyte-derived dendritic cells in mouse skin","volume":"39","author":"Tamoutounour","year":"2013","journal-title":"Immunity"},{"key":"B27","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/j.tim.2021.11.011","article-title":"Viral manipulation of host cell necroptosis and pyroptosis","volume":"30","author":"Verdonck","year":"2022","journal-title":"Trends Microbiol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"mjac036","DOI":"10.1093\/jmcb\/mjac036","article-title":"NRF1-mediated microglial activation triggers high-altitude cerebral edema","volume":"14","author":"Wang","year":"2022","journal-title":"J. Mol. Cell. Biol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1038\/nrm.2016.149","article-title":"Necroptosis in development, inflammation and disease","volume":"18","author":"Weinlich","year":"2017","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1038\/cr.2013.91","article-title":"Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis","volume":"23","author":"Wu","year":"2013","journal-title":"Cell. Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.immuni.2017.06.001","article-title":"MLKL, the protein that mediates necroptosis, also regulates endosomal trafficking and extracellular vesicle generation","volume":"47","author":"Yoon","year":"2017","journal-title":"Immunity"},{"key":"B32","doi-asserted-by":"publisher","first-page":"4759","DOI":"10.7150\/thno.54072","article-title":"Mlkl: Functions beyond serving as the executioner of necroptosis","volume":"11","author":"Zhan","year":"2021","journal-title":"Theranostics"},{"key":"B33","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/j.lfs.2018.03.057","article-title":"Characterizing the glymphatic influx by utilizing intracisternal infusion of fluorescently conjugated cadaverine","volume":"201","author":"Zhang","year":"2018","journal-title":"Life Sci."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2023.1229788\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T09:02:11Z","timestamp":1690448531000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2023.1229788\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,27]]},"references-count":33,"alternative-id":["10.3389\/fcell.2023.1229788"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2023.1229788","relation":{},"ISSN":["2296-634X"],"issn-type":[{"type":"electronic","value":"2296-634X"}],"subject":[],"published":{"date-parts":[[2023,7,27]]},"article-number":"1229788"}}