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The pathophysiological mechanisms mediating this relationship are currently unknown, and one potential candidate is the anti-angiogenic factor soluble Fms-like tyrosine kinase 1 (sFlt-1), which is highly elevated in PE. While sFlt-1 can impair angiogenesis via inhibition of VEGFA signalling, it is unclear whether it can directly affect neuronal development independently of its effects on the vasculature. To test this hypothesis, the current study differentiated the human neural progenitor cell (NPC) line ReNcell\u00ae VM into a mixed culture of mature neurons and glia, and exposed them to sFlt-1 during development. Outcomes measured were neurite growth, cytotoxicity, mRNA expression of nestin, MBP, GFAP, and \u03b2III-tubulin, and neurosphere differentiation. sFlt-1 induced a significant reduction in neurite growth and this effect was timing- and dose-dependent up to 100 ng\/ml, with no effect on cytotoxicity. sFlt-1 (100 ng\/ml) also reduced \u03b2III-tubulin mRNA and neuronal differentiation of neurospheres. Undifferentiated NPCs and mature neurons\/glia expressed VEGFA and VEGFR-2, required for endogenous autocrine and paracrine VEGFA signalling, while sFlt-1 treatment prevented the neurogenic effects of exogenous VEGFA. Overall, these data provide the first experimental evidence for a direct effect of sFlt-1 on neurite growth and neuronal differentiation in human neurons through inhibition of VEGFA signalling, clarifying our understanding of the potential role of sFlt-1 as a mechanism by which PE can affect neuronal development.<\/jats:p>","DOI":"10.1042\/bsr20240562","type":"journal-article","created":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T07:01:35Z","timestamp":1714719695000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["sFlt-1 impairs neurite growth and neuronal differentiation in SH-SY5Y cells and human neurons"],"prefix":"10.1042","volume":"44","author":[{"given":"Aaron","family":"Barron","sequence":"first","affiliation":[{"name":"1Department of Anatomy and Neuroscience, University College, Cork, Ireland"},{"name":"2Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland"},{"name":"3FinnBrain Birth Cohort Study, Turku Brain and Mind Centre, Department of Clinical Medicine, University of Turku, Turku, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Barrett","sequence":"additional","affiliation":[{"name":"1Department of Anatomy and Neuroscience, University College, Cork, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jetro\u00a0J.","family":"Tuulari","sequence":"additional","affiliation":[{"name":"3FinnBrain Birth Cohort Study, Turku Brain and Mind Centre, Department of Clinical Medicine, University of Turku, Turku, Finland"},{"name":"4Department of Psychiatry and Turku Brain and Mind Centre, University of Turku and Turku University Hospital, Turku, Finland"},{"name":"5Turku Collegium for Science, Medicine and Technology, University of Turku, Turku, Finland"},{"name":"6Centre for Population Health Research, University of Turku, Turku University Hospital, Turku, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linnea","family":"Karlsson","sequence":"additional","affiliation":[{"name":"3FinnBrain Birth Cohort Study, Turku Brain and Mind Centre, Department of Clinical Medicine, University of Turku, Turku, Finland"},{"name":"6Centre for Population Health Research, University of Turku, Turku University Hospital, Turku, Finland"},{"name":"7Department of Clinical Medicine, Paediatrics and Adolescent Medicine, Turku University Hospital and University of Turku, Turku, Finland"},{"name":"8Department of Clinical Medicine, Unit of Public Health, University of Turku, Turku, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hasse","family":"Karlsson","sequence":"additional","affiliation":[{"name":"3FinnBrain Birth Cohort Study, Turku Brain and Mind Centre, Department of Clinical Medicine, University of Turku, Turku, Finland"},{"name":"4Department of Psychiatry and Turku Brain and Mind Centre, University of Turku and Turku University Hospital, Turku, Finland"},{"name":"6Centre for Population Health Research, University of Turku, Turku University Hospital, Turku, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9514-9021","authenticated-orcid":false,"given":"Cathal\u00a0M.","family":"McCarthy","sequence":"additional","affiliation":[{"name":"2Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5149-0933","authenticated-orcid":false,"given":"Gerard\u00a0W.","family":"O'Keeffe","sequence":"additional","affiliation":[{"name":"1Department of Anatomy and Neuroscience, University College, Cork, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2024,5,17]]},"reference":[{"key":"2024051707310203100_B1","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.preghy.2021.09.008","article-title":"The 2021 International Society for the Study of Hypertension in Pregnancy classification, diagnosis & management recommendations for international practice","volume":"27","author":"Magee","year":"2022","journal-title":"Pregnancy Hypertension"},{"key":"2024051707310203100_B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ejogrb.2013.05.005","article-title":"Global and regional estimates of preeclampsia and eclampsia: a systematic review","volume":"170","author":"Abalos","year":"2013","journal-title":"Eur. 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