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Our previous research suggested an association between elevated SERPINA5 levels and PE features. This study investigated whether SERPINA5 could be a potential therapeutic target for PE. We established PE-like features in pregnant rats using L-NAME (75 mg\/kg\/d) treatment. Adenoviruses carrying overexpressed or suppressed SERPINA5 genes were intravenously injected into these PE rats on the fifth and seventh days of pregnancy. We evaluated the rats\u2019 systolic blood pressure, urine protein concentration, and placental and fetal metrics and histology. Placental gene expression following SERPINA5 overexpression was evaluated using mRNA sequencing. The L-NAME-induced PE rat model observed a significant increase in placental and peripheral SERPINA5 levels. The overexpression of SERPINA5 exacerbated L-NAME-induced hypertension and proteinuria in pregnant rats. A histology examination revealed a smaller placental junctional zone in L-NAME + overexpressing rats. Placental gene expression analysis in the L-NAME + overexpressing group indicated increased coagulation activation. L-NAME-induced hypertension and proteinuria were mitigated when SERPINA5 expression was suppressed. Additionally, placental development was improved in the SERPINA5-suppressed group. Our findings suggested that SERPINA5 may worsen L-NAME-induced PE-like features by promoting the activation of the coagulation cascade. Therefore, reducing SERPINA5 expression could potentially serve as a therapeutic strategy for PE.<\/jats:p>","DOI":"10.3390\/biom13121792","type":"journal-article","created":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T03:58:02Z","timestamp":1702526282000},"page":"1792","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Improvement in Clinical Features of L-NAME-Induced Preeclampsia-like Rats through Reduced SERPINA5 Expression"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4258-1363","authenticated-orcid":false,"given":"Shanshui","family":"Zeng","sequence":"first","affiliation":[{"name":"Department of Laboratory, Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University, Guangzhou 510623, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zimeng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Laboratory, Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University, Guangzhou 510623, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaye","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Laboratory, Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University, Guangzhou 510623, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Laboratory, Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University, Guangzhou 510623, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4646-0067","authenticated-orcid":false,"given":"Min","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Laboratory, Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University, Guangzhou 510623, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6303-4193","authenticated-orcid":false,"given":"Hongling","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Laboratory, Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University, Guangzhou 510623, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2560-9216","authenticated-orcid":false,"given":"Yan","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Laboratory, Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University, Guangzhou 510623, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,14]]},"reference":[{"key":"ref_1","unstructured":"(2019). ACOG Practice Bulletin No. 202: Gestational Hypertension and Pre-eclampsia. Obstet. Gynecol., 133, 1."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"l2381","DOI":"10.1136\/bmj.l2381","article-title":"Pre-eclampsia: Pathophysiology and clinical implications","volume":"366","author":"Burton","year":"2019","journal-title":"BMJ"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/S0140-6736(15)00070-7","article-title":"Pre-eclampsia","volume":"387","author":"Mol","year":"2016","journal-title":"Lancet Lond. Engl."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1093\/eurheartj\/ehy863","article-title":"Does pregnancy complication history improve cardiovascular disease risk prediction? Findings from the HUNT study in Norway","volume":"40","author":"Markovitz","year":"2019","journal-title":"Eur. Heart J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1053\/j.semperi.2011.09.011","article-title":"Maternal mortality from pre-eclampsia\/eclampsia","volume":"36","author":"Ghulmiyyah","year":"2012","journal-title":"Semin. Perinatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1161\/CIRCULATIONAHA.118.036748","article-title":"Cardiovascular Disease-Related Morbidity and Mortality in Women With a History of Pregnancy Complications","volume":"139","author":"Grandi","year":"2019","journal-title":"Circulation"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1001\/jama.2016.18315","article-title":"Pre-eclampsia Screening: Evidence Report and Systematic Review for the US Preventive Services Task Force","volume":"317","author":"Henderson","year":"2017","journal-title":"JAMA"},{"key":"ref_8","first-page":"4108271","article-title":"Early- and Late-Onset Preeclampsia: A Comprehensive Cohort Study of Laboratory and Clinical Findings according to the New ISHHP Criteria","volume":"2019","author":"Babczyk","year":"2019","journal-title":"Int. J. Hypertens."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.ccl.2019.04.008","article-title":"Hypertensive Disorders of Pregnancy","volume":"37","author":"Shah","year":"2019","journal-title":"Cardiol. Clin."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Zeng, S., Han, M., Jiang, M., Liu, F., Hu, Y., Long, Y., Zhu, C., Zeng, F., Gan, Q., and Ye, W. (2021). Serum complement proteomics reveal biomarkers for hypertension disorder of pregnancy and the potential role of Clusterin. Reprod. Biol. Endocrinol. RBE, 19.","DOI":"10.1186\/s12958-021-00742-z"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1080\/19336918.2015.1120397","article-title":"Intrauterine trophoblast migration: A comparative view of humans and rodents","volume":"10","author":"Silva","year":"2016","journal-title":"Cell Adhes. Migr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jri.2019.07.004","article-title":"The two-stage placental model of pre-eclampsia: An update","volume":"134\u2013135","author":"Staff","year":"2019","journal-title":"J. Reprod. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"S32","DOI":"10.1016\/j.placenta.2008.11.009","article-title":"The two stage model of pre-eclampsia: Variations on the theme","volume":"30","author":"Roberts","year":"2009","journal-title":"Placenta"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/s41586-022-04410-z","article-title":"Early prediction of pre-eclampsia in pregnancy with cell-free RNA","volume":"602","author":"Moufarrej","year":"2022","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Zhang, Y., Zhao, L., Shi, J., and Yang, H. (2021). Plasma SerpinA5 in conjunction with uterine artery pulsatility index and clinical risk factor for the early prediction of pre-eclampsia. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0258541"},{"key":"ref_16","first-page":"14","article-title":"SERPINA5 may promote the development of pre-eclampsia by disruption of the uPA\/uPAR pathway","volume":"251","author":"Long","year":"2023","journal-title":"Transl. Res. J. Lab. Clin. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1016\/0002-9378(93)90299-X","article-title":"Inhibition of nitric oxide synthesis in rats during pregnancy produces signs similar to those of pre-eclampsia","volume":"169","author":"Yallampalli","year":"1993","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/S1734-1140(12)70846-0","article-title":"L-NAME in the cardiovascular system-nitric oxide synthase activator?","volume":"64","year":"2012","journal-title":"Pharmacol. Rep. PR"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.ejogrb.2011.03.005","article-title":"Sildenafil citrate decreases sFlt-1 and sEng in pregnant l-NAME treated Sprague\u2013Dawley rats","volume":"157","author":"Ramesar","year":"2011","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"S973","DOI":"10.1016\/j.ajog.2020.10.025","article-title":"Animal models of pre-eclampsia: Investigating pathophysiology and therapeutic targets","volume":"226","author":"Bakrania","year":"2022","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1038\/hr.2009.12","article-title":"Effect of L-NAME-induced hypertension on melatonin receptors and melatonin levels in the pineal gland and the peripheral organs of rats","volume":"32","author":"Benova","year":"2009","journal-title":"Hypertens. Res. Off. J. Jpn Soc. Hypertens."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.placenta.2020.06.015","article-title":"Effect and mechanism of prophylactic use of tadalafil during pregnancy on l-NAME-induced preeclampsia-like rats","volume":"99","author":"Li","year":"2020","journal-title":"Placenta"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.placenta.2020.09.012","article-title":"CircSFXN1 regulates the behaviour of trophoblasts and likely mediates pre-eclampsia","volume":"101","author":"Zhang","year":"2020","journal-title":"Placenta"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e12","DOI":"10.1002\/imt2.12","article-title":"Majorbio Cloud: A one-stop, comprehensive bioinformatic platform for multiomics analyses","volume":"1","author":"Ren","year":"2022","journal-title":"IMeta"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.bbrc.2021.10.064","article-title":"Role of clusterin in the regulation of trophoblast development and pre-eclampsia","volume":"583","author":"Zeng","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1681\/ASN.2014030233","article-title":"Deficiency of fibroblast growth factor-inducible 14 (Fn14) preserves the filtration barrier and ameliorates lupus nephritis","volume":"26","author":"Xia","year":"2015","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1161\/01.HYP.0000250831.52876.cb","article-title":"Expressional and epigenetic alterations of placental serine protease inhibitors: SERPINA3 is a potential marker of preeclampsia","volume":"49","author":"Chelbi","year":"2007","journal-title":"Hypertension"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.semcdb.2016.10.007","article-title":"Cell penetrating SERPINA5 (ProteinC inhibitor, PCI): More questions than answers","volume":"62","author":"Yang","year":"2017","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/5584_2017_60","article-title":"Regulation of the Extracellular SERPINA5 (Protein C Inhibitor) Penetration Through Cellular Membranes","volume":"966","author":"Yang","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1161\/HYPERTENSIONAHA.116.07293","article-title":"Unsupervised Placental Gene Expression Profiling Identifies Clinically Relevant Subclasses of Human Preeclampsia","volume":"68","author":"Leavey","year":"2016","journal-title":"Hypertension"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1080\/019262302753559614","article-title":"Pregnancy dating in the rat: Placental morphology and maternal blood parameters","volume":"30","author":"Flik","year":"2002","journal-title":"Toxicol. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4642","DOI":"10.1073\/pnas.1919563117","article-title":"Bisphenol A and bisphenol S disruptions of the mouse placenta and potential effects on the placenta-brain axis","volume":"117","author":"Mao","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"R62","DOI":"10.1152\/ajpregu.00377.2014","article-title":"The Dahl salt-sensitive rat is a spontaneous model of superimposed pre-eclampsia","volume":"309","author":"Gillis","year":"2015","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1172\/JCI17189","article-title":"Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in pre-eclampsia","volume":"111","author":"Maynard","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1007\/s00418-007-0330-6","article-title":"Intracellular localization of protein C inhibitor (PCI) and urinary plasminogen activator in renal tubular epithelial cells from humans and human PCI gene transgenic mice","volume":"128","author":"Song","year":"2007","journal-title":"Histochem. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/S0014-5793(98)00613-9","article-title":"Molecular cloning, tissue distribution and androgen regulation of rat protein C inhibitor","volume":"429","author":"Wakita","year":"1998","journal-title":"FEBS Lett."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Han, C., Huang, P., Lyu, M., and Dong, J. (2020). Oxidative Stress and Preeclampsia-Associated Prothrombotic State. Antioxidants, 9.","DOI":"10.3390\/antiox9111139"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1016\/S0049-3848(19)30359-7","article-title":"The role of haemostasis in placenta-mediated complications","volume":"181","author":"Gris","year":"2019","journal-title":"Thromb. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/s41581-019-0119-6","article-title":"Pre-eclampsia: Pathogenesis, novel diagnostics and therapies","volume":"15","author":"Phipps","year":"2019","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Rana, S., Cerdeira, A.S., Wenger, J., Salahuddin, S., Lim, K.-H., Ralston, S.J., Thadhani, R.I., and Karumanchi, S.A. (2012). Plasma Concentrations of Soluble Endoglin versus Standard Evaluation in Patients with Suspected Pre-eclampsia. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0048259"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e90","DOI":"10.1161\/ATVBAHA.118.310367","article-title":"Recent Highlights of ATVB Thrombotic regulation from the endothelial cell perspectives","volume":"38","author":"Wang","year":"2018","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/modpathol.2010.214","article-title":"Loss of SerpinA5 protein expression is associated with advanced-stage serous ovarian tumors","volume":"24","author":"Bijsmans","year":"2011","journal-title":"Mod. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1002\/ijc.22773","article-title":"Protein C inhibitor inhibits breast cancer cell growth, metastasis and angiogenesis independently of its protease inhibitory activity","volume":"121","author":"Asanuma","year":"2007","journal-title":"Int. J. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1111\/j.1538-7836.2008.03181.x","article-title":"The multi-functional serpin, protein C inhibitor: Beyond thrombosis and hemostasis","volume":"6","author":"Suzuki","year":"2008","journal-title":"J. Thromb. Haemost. JTH"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1016\/j.thromres.2015.03.026","article-title":"Host protein C inhibitor inhibits tumor growth, but promotes tumor metastasis, which is closely correlated with hypercoagulability","volume":"135","author":"Akita","year":"2015","journal-title":"Thromb. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1055\/s-0031-1276583","article-title":"Protein C inhibitor","volume":"37","author":"Meijers","year":"2011","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_47","first-page":"CD004659","article-title":"Antiplatelet agents for preventing pre-eclampsia and its complications","volume":"2","author":"Duley","year":"2007","journal-title":"Cochrane Database Syst. Rev."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/12\/1792\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:38:33Z","timestamp":1760132313000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/12\/1792"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,14]]},"references-count":47,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["biom13121792"],"URL":"https:\/\/doi.org\/10.3390\/biom13121792","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,14]]}}}