Notch signaling pathway regulates the progression of fetal growth restriction through mediating immune dysfunction

Ye,Liyan; Zheng,Xiujuan; Yang,Yali; Lyu,Ying

doi:10.3892/br.2025.1989

Notch signaling pathway regulates the progression of fetal growth restriction through mediating immune dysfunction

Authors:
- Liyan Ye
- Xiujuan Zheng
- Yali Yang
- Ying Lyu
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Affiliations: Department of Obstetrics, Jinhua Maternal and Child Health Hospital, Jinhua, Zhejiang 321000, P.R. China
Published online on: May 6, 2025 https://doi.org/10.3892/br.2025.1989
Article Number: 111
Copyright: © Ye et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Fetal growth restriction (FGR) is associated with an increased risk of neonatal morbidity and mortality, as well as the development of metabolic syndrome in adulthood. The present study investigated the regulatory mechanisms of Notch signaling in FGR progression. The expression levels of Notch1 and Jagged1 were determined using reverse transcription‑quantitative PCR, western blotting, immunofluorescence staining and immunohistochemistry (IHC). ELISA was used to measure the concentrations of IL‑10, IL‑17 and IL‑35 in serum and placental samples. ELISA and western blotting determined the inflammation‑ and angiogenesis‑related cytokine levels. Th17, Treg and macrophage levels were determined using IHC and flow cytometry. Additionally, hematoxylin & eosin staining and TUNEL assay assessed placenta histology and trophoblast cell apoptosis. Significant trophoblast apoptosis was observed in the placenta of FGR pregnancies. The expression of Notch1 and Jagged1 in peripheral blood mononuclear cells and placental tissues of FGR pregnancies was significantly lower than in the control group. The FGR group exhibited a remarkable inflammation, anti‑angiogenesis and immune dysfunction. In conclusion, the Notch signaling pathway mediates immune balance to regulate the development of FGR. These findings offer the potential for advancing innovative predictive, diagnostic and therapeutic approaches for FGR.

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1	Damhuis SE, Ganzevoort W and Gordijn SJ: Abnormal fetal growth: small for gestational age, fetal growth restriction, large for gestational age: Definitions and epidemiology. Obstet Gynecol Clin North Am. 48:267–279. 2021.PubMed/NCBI View Article : Google Scholar
2	Gupta N and Khajuria A: Histomorphological features of placenta in pregnancy complicated with intrauterine growth retardation. JK Sci. 18:21–25. 2016.
3	Nardozza LMM, Caetano ACR, Zamarian ACP, Mazzola JB, Silva CP, Marçal VMG, Lobo TF, Peixoto AB and Araujo Júnior E: Fetal growth restriction: Current knowledge. Arch Gynecol Obstet. 295:1061–1077. 2017.PubMed/NCBI View Article : Google Scholar
4	Turner S, Posthumus AG, Steegers EAP, AlMakoshi A, Sallout B, Rifas-Shiman SL, Oken E, Kumwenda B, Alostad F, Wright-Corker C, et al: Household income, fetal size and birth weight: An analysis of eight populations. J Epidemiol Community Health. 76:629–636. 2022.PubMed/NCBI View Article : Google Scholar
5	González-Fernández D, Muralidharan O, Neves PA and Bhutta ZA: Associations of maternal nutritional status and supplementation with fetal, newborn, and infant outcomes in low-income and middle-income settings: An overview of reviews. Nutrients. 16(3725)2024.PubMed/NCBI View Article : Google Scholar
6	Dudink I, Hüppi PS, Sizonenko SV, Castillo-Melendez M, Sutherland AE, Allison BJ and Miller SL: Altered trajectory of neurodevelopment associated with fetal growth restriction. Exp Neurol. 347(113885)2022.PubMed/NCBI View Article : Google Scholar
7	Della Gatta AN, Aceti A, Spinedi SF, Martini S, Corvaglia L, Sansavini A, Zuccarini M, Lenzi J, Seidenari A, Dionisi C, et al: Neurodevelopmental outcomes of very preterm infants born following early foetal growth restriction with absent end-diastolic umbilical flow. Eur J Pediatr. 182:4467–4476. 2023.PubMed/NCBI View Article : Google Scholar
8	Rock CR, White TA, Piscopo BR, Sutherland AE, Miller SL, Camm EJ and Allison BJ: Cardiovascular and cerebrovascular implications of growth restriction: Mechanisms and potential treatments. Int J Mol Sci. 22(7555)2021.PubMed/NCBI View Article : Google Scholar
9	Bezemer RE, Schoots MH, Timmer A, Scherjon SA, Erwich JJHM, van Goor H, Gordijn SJ and Prins JR: Altered levels of decidual immune cell subsets in fetal growth restriction, stillbirth, and placental pathology. Front Immunol. 11(1898)2020.PubMed/NCBI View Article : Google Scholar
10	Muskavitch MA: Delta-notch signaling and Drosophila cell fate choice. Dev Biol. 166:415–430. 1994.PubMed/NCBI View Article : Google Scholar
11	Siebel C and Lendahl U: Notch signaling in development, tissue homeostasis, and disease. Physiol Rev. 97:1235–1294. 2017.PubMed/NCBI View Article : Google Scholar
12	Kopan R and Ilagan MX: The canonical Notch signaling pathway: Unfolding the activation mechanism. Cell. 137:216–233. 2009.PubMed/NCBI View Article : Google Scholar
13	Afshar Y, Miele L and Fazleabas AT: Notch1 is regulated by chorionic gonadotropin and progesterone in endometrial stromal cells and modulates decidualization in primates. Endocrinology. 153:2884–2896. 2012.PubMed/NCBI View Article : Google Scholar
14	Hunkapiller NM, Gasperowicz M, Kapidzic M, Plaks V, Maltepe E, Kitajewski J, Cross JC and Fisher SJ: A role for Notch signaling in trophoblast endovascular invasion and in the pathogenesis of pre-eclampsia. Development. 138:2987–2998. 2011.PubMed/NCBI View Article : Google Scholar
15	Sahin Z, Acar N, Ozbey O, Ustunel I and Demir R: Distribution of Notch family proteins in intrauterine growth restriction and hypertension complicated human term placentas. Acta Histochem. 113:270–276. 2011.PubMed/NCBI View Article : Google Scholar
16	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
17	Chen YH, Liu ZB, Ma L, Zhang ZC, Fu L, Yu Z, Chen W, Song YP, Wang P, Wang H and Xu X: Gestational vitamin D deficiency causes placental insufficiency and fetal intrauterine growth restriction partially through inducing placental inflammation. J Steroid Biochem Mol Biol. 203(105733)2020.PubMed/NCBI View Article : Google Scholar
18	Hong J and Kumar S: Circulating biomarkers associated with placental dysfunction and their utility for predicting fetal growth restriction. Clin Sci (Lond). 137:579–595. 2023.PubMed/NCBI View Article : Google Scholar
19	Dietrich B, Haider S, Meinhardt G, Pollheimer J and Knöfler M: WNT and NOTCH signaling in human trophoblast development and differentiation. Cell Mol Life Sci. 79(292)2022.PubMed/NCBI View Article : Google Scholar
20	Scifres CM and Nelson DM: Intrauterine growth restriction, human placental development and trophoblast cell death. J Physiol. 587:3453–3458. 2009.PubMed/NCBI View Article : Google Scholar
21	Gale NW, Dominguez MG, Noguera I, Pan L, Hughes V, Valenzuela DM, Murphy AJ, Adams NC, Lin HC, Holash J, et al: Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc Natl Acad Sci USA. 101:15949–15954. 2004.PubMed/NCBI View Article : Google Scholar
22	Thurston G and Gale NW: Vascular endothelial growth factor and other signaling pathways in developmental and pathologic angiogenesis. Int J Hematol. 80:7–20. 2004.PubMed/NCBI View Article : Google Scholar
23	Herr F, Schreiner I, Baal N, Pfarrer C and Zygmunt M: Expression patterns of Notch receptors and their ligands Jagged and Delta in human placenta. Placenta. 32:554–563. 2011.PubMed/NCBI View Article : Google Scholar
24	Kirici P, Çağıran FT, Kali Z, Tanriverdi ES, Mavral N and Ecin SM: Determination of maternal serum pro-inflammatory cytokine changes in intrauterine growth restriction. Eur Rev Med Pharmacol Sci. 27:1996–2001. 2023.PubMed/NCBI View Article : Google Scholar
25	Al-Azemi M, Raghupathy R and Azizieh F: Pro-inflammatory and anti-inflammatory cytokine profiles in fetal growth restriction. Clin Exp Obstet Gynecol. 44:98–103. 2017.PubMed/NCBI
26	Kluivers ACM, Biesbroek A, Visser W, Saleh L, Russcher H, Danser AHJ and Neuman RI: Angiogenic imbalance in pre-eclampsia and fetal growth restriction: enhanced soluble fms-like tyrosine kinase-1 binding or diminished production of placental growth factor? Ultrasound Obstet Gynecol. 61:466–473. 2023.PubMed/NCBI View Article : Google Scholar
27	Gadde R, Cd D and Sheela SR: Placental protein 13: An important biological protein in preeclampsia. J Circ Biomark. 7(1849454418786159)2018.PubMed/NCBI View Article : Google Scholar
28	Yu N, Cui H, Chen X and Chang Y: First trimester maternal serum analytes and second trimester uterine artery Doppler in the prediction of preeclampsia and fetal growth restriction. Taiwan J Obstet Gynecol. 56:358–361. 2017.PubMed/NCBI View Article : Google Scholar
29	Rana S, Burke SD and Karumanchi SA: Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders. Am J Obstet Gynecol. 226 (2S):S1019–S1034. 2022.PubMed/NCBI View Article : Google Scholar
30	Garcia-Manau P, Mendoza M, Bonacina E, Garrido-Gimenez C, Fernandez-Oliva A, Zanini J, Catalan M, Tur H, Serrano B and Carreras E: Soluble fms-like tyrosine kinase to placental growth factor ratio in different stages of early-onset fetal growth restriction and small for gestational age. Acta Obstet Gynecol Scand. 100:119–128. 2021.PubMed/NCBI View Article : Google Scholar
31	Zhang Z, Liu H, Shi Y, Xu N, Wang Y, Li A and Song W: Increased circulating Th22 cells correlated with Th17 cells in patients with severe preeclampsia. Hypertens Pregnancy. 36:100–107. 2017.PubMed/NCBI View Article : Google Scholar
32	Liu ZZ, Sun GQ, Hu XH, Kwak-Kim J and Liao AH: The transdifferentiation of regulatory T and Th17 cells in autoimmune/inflammatory diseases and its potential implications in pregnancy complications. Am J Reprod Immunol. 78:2017.PubMed/NCBI View Article : Google Scholar
33	Niedźwiecki M, Budziło O, Zieliński M, Adamkiewicz-Drożyńska E, Maciejka-Kembłowska L, Szczepański T and Trzonkowski P: CD4⁺CD25^highCD127^low/-FoxP₃⁺ regulatory T cell subpopulations in the bone marrow and peripheral blood of children with ALL: Brief report. J Immunol Res. 2018(1292404)2018.PubMed/NCBI View Article : Google Scholar
34	Matsuda M, Terada T, Kitatani K, Kawata R and Nabe T: Analyses of Foxp3⁺ Treg cells and Tr1 cells in subcutaneous immunotherapy-treated allergic individuals in humans and mice. Nihon Yakurigaku Zasshi. 154:17–22. 2019.PubMed/NCBI View Article : Google Scholar : (In Japanese).
35	Laresgoiti-Servitje E: A leading role for the immune system in the pathophysiology of preeclampsia. J Leukoc Biol. 94:247–257. 2013.PubMed/NCBI View Article : Google Scholar
36	Wang LL, Li ZH, Wang H, Kwak-Kim J and Liao AH: Cutting edge: The regulatory mechanisms of macrophage polarization and function during pregnancy. J Reprod Immunol. 151(103627)2022.PubMed/NCBI View Article : Google Scholar
37	Yao Y, Xu XH and Jin L: Macrophage polarization in physiological and pathological pregnancy. Front Immunol. 10(792)2019.PubMed/NCBI View Article : Google Scholar
38	Bezemer RE, Faas MM, van Goor H, Gordijn SJ and Prins JR: Decidual macrophages and Hofbauer cells in fetal growth restriction. Front Immunol. 15(1379537)2024.PubMed/NCBI View Article : Google Scholar
39	Berezhna VA, Mamontova TV and Gromova AM: Cd68+ M1 macrophages is associated with placental insufficiency under fetal growth restriction. Wiad Lek. 74:213–219. 2021.PubMed/NCBI