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Excessive soluble fms-like tyrosine kinase 1 (sFlt1) that antagonizes VEGF has been implicated in the pathogenesis of PE. VEGF increases the expression of endothelial nitric oxide synthase (eNOS) and activates it. <jats:italic>eNOS<\/jats:italic> polymorphisms that cause reduced NO production are associated with PE. The aim of this study was to clarify the role on hepatic function by excess sFlt1 in the absence of <jats:italic>eNOS<\/jats:italic> gene product. We first overexpressed sFlt1 using adenovirus in <jats:italic>eNOS<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> and <jats:italic>eNOS<\/jats:italic><jats:sup>+\/+<\/jats:sup> mice. Excessive sFlt1 and lack of <jats:italic>eNOS<\/jats:italic> synergistically increased plasma levels of liver transaminases, exacerbated infiltration of inflammatory cells, elevated expression levels of cytokines in the liver, and aggravated oxidative stress and coagulation abnormalities. Lack of <jats:italic>eNOS<\/jats:italic> in the presence of excess sFlt1 also induced thrombocytopenia, whereas <jats:italic>eNOS<\/jats:italic><jats:sup>+\/+<\/jats:sup> mice with excess sFlt1 alone showed no or modest liver phenotype. Taken together, excessive sFlt1 and lack of <jats:italic>eNOS<\/jats:italic> synergistically induce hepatic dysfunction and thrombocytopenia, suggesting a novel role for VEGF and nitric oxide signaling in hepatocyte-endothelial cross-talk in health and in liver injury states.<\/jats:p>","DOI":"10.1038\/s41598-017-18260-7","type":"journal-article","created":{"date-parts":[[2018,1,2]],"date-time":"2018-01-02T18:59:09Z","timestamp":1514919549000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Hepatic dysfunction and thrombocytopenia induced by excess sFlt1 in mice lacking endothelial nitric oxide synthase"],"prefix":"10.1038","volume":"8","author":[{"given":"Yuji","family":"Oe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mieko","family":"Ko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomofumi","family":"Fushima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emiko","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. Ananth","family":"Karumanchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junichi","family":"Sugawara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadayoshi","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuyuki","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,1,8]]},"reference":[{"key":"18260_CR1","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1038\/nrm1911","volume":"7","author":"AK Olsson","year":"2006","unstructured":"Olsson, A. K., Dimberg, A., Kreuger, J. & Claesson-Welsh, L. VEGF receptor signalling - in control of vascular function. 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