{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T01:21:39Z","timestamp":1788916899317,"version":"build-2803163510"},"reference-count":43,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T00:00:00Z","timestamp":1643241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kanzawa Medical Research Foundation","award":["2019"],"award-info":[{"award-number":["2019"]}]},{"name":"Seiichi Imai Memorial Foundatio","award":["2020"],"award-info":[{"award-number":["2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fetal growth restriction (FGR) is a major cause of poor perinatal outcomes. Although several studies have been conducted to improve the prognosis of FGR in infants, no effective intrauterine treatment method has been established. This study aimed to use tadalafil, a phosphodiesterase 5 inhibitor (PDE5) inhibitor, as a novel intrauterine treatment and conducted several basic and clinical studies. The study investigated the effects of tadalafil on placental mTOR signaling. Tadalafil was administered to mice with L-NG-nitroarginine methyl ester (L-NAME)-induced FGR and associated preeclampsia (PE). Placental phosphorylated mTOR (p-mTOR) signaling was assessed by fluorescent immunohistochemical staining and Western blotting. The expression of p-mTOR was significantly decreased in mice with FGR on 13 days post coitum (d.p.c.) but recovered to the same level as that of the control on 17 d.p.c. following tadalafil treatment. The results were similar for 4E-binding protein 1 (4E-BP1) and S6 ribosomal (S6R) protein, which act downstream in the mTOR signaling pathway. We demonstrate that the tadalafil treatment of FGR in mice improved placental mTOR signaling to facilitate fetal growth. Our study provides the key mechanistic detail about the mode of action of tadalafil and thus would be helpful for future clinical studies on FGR.<\/jats:p>","DOI":"10.3390\/ijms23031474","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T22:00:56Z","timestamp":1643320856000},"page":"1474","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Tadalafil Treatment of Mice with Fetal Growth Restriction and Preeclampsia Improves Placental mTOR Signaling"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8373-1567","authenticated-orcid":false,"given":"Kayo","family":"Tanaka","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Mie University School of Medicine, Edobashi, Tsu 5148507, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1760-691X","authenticated-orcid":false,"given":"Hiroaki","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Mie University School of Medicine, Edobashi, Tsu 5148507, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryota","family":"Tachibana","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Mie University School of Medicine, Edobashi, Tsu 5148507, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kento","family":"Yoshikawa","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Mie University School of Medicine, Edobashi, Tsu 5148507, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Kawamura","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Mie University School of Medicine, Edobashi, Tsu 5148507, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sho","family":"Takakura","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Mie University School of Medicine, Edobashi, Tsu 5148507, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5994-7416","authenticated-orcid":false,"given":"Hiroki","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Mie University School of Medicine, Edobashi, Tsu 5148507, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1489-4810","authenticated-orcid":false,"given":"Tomoaki","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Mie University School of Medicine, Edobashi, Tsu 5148507, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1097\/00003081-200606000-00008","article-title":"Perinatal outcome and later implications of intrauterine growth restriction","volume":"49","author":"Pallotto","year":"2006","journal-title":"Clin Obstet Gynecol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s40748-016-0041-x","article-title":"Early onset fetal growth restriction","volume":"3","author":"Brunelli","year":"2017","journal-title":"Matern Health Neonatol Perinatol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Heinonen, K., R\u00e4ikk\u00f6nen, K., Pesonen, A.K., Andersson, S., Kajantie, E., Eriksson, J.G., Wolke, D., and Lano, A. 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