Fibroblast growth factors and endometrial decidualization: models, mechanisms, and related pathologies.

The onset of pregnancy is marked by the formation of a zygote, while the culmination of gestation is manifested by the delivery of a fetus. Meanwhile, a successful pregnancy entails a meticulously coordinated sequence of events from embryo implantation to sustained decidualization of the uterus to placental development and childbirth. The decidual reaction, a pivotal process occurring within the endometrium during pregnancy, is finely regulated by sex steroids and cytokines. Notably, fibroblast growth factors (FGFs), particularly FGF2, play a critical role in this physiological cascade. Dysregulated FGF expression may trigger inadequate decidualization, precipitating a spectrum of adverse pregnancy outcomes, including preeclampsia, recurrent implantation failure, and miscarriage. Furthermore, the human decidua, distinct from most mammalian species and similar to great apes, undergoes regular cycles of formation and shedding, independent of the presence of the embryo in the endometrium. This process is also tightly controlled by various FGFs. In this review, we comprehensively compare diverse research decidualization models, delineate the trend of endometrial FGFs during the menstrual cycle, and provide a synopsis of endometrial diseases triggered by FGF dysregulation. 摘要 受精卵的形成代表妊娠的开始,胎儿的分娩则代表妊娠的结束。成功怀孕需要一系列精心策划的阶段:胚胎植入、子宫持续蜕膜化、胎盘形成和分娩。蜕膜化是妊娠期间子宫内膜发生的重要事件,需要性激素和细胞因子精确调节。其中,成纤维细胞生长因子(FGFs),尤其是FGF2,在这一生理过程中发挥着至关重要的作用。FGF的表达失调可导致蜕膜化不足,进而引发包括先兆子痫、反复着床失败和流产等多种不良妊娠结局。此外,与大多数哺乳动物物种不同,人类子宫内膜的蜕膜化具有规律性的形成和脱落周期,与胚胎是否存在无关。在这篇综述中,我们全面比较各种研究蜕膜化的模型,同时总结子宫内膜FGFs在月经周期中的变化趋势以及由FGF失调引发的子宫内膜疾病。 Similar content being viewed by others

Afrin S, el Sabah M, Manzoor A, et al., 2023. Adipocyte coculture induces a pro-inflammatory, fibrotic, angiogenic, and proliferative microenvironment in uterine leiomyoma cells. Biochim Biophys Acta (BBA)-Mol Basis Dis, 1869(1): 166564. https://doi.org/10.1016/j.bbadis.2022.166564 Afshar Y, Miele L, Fazleabas AT, 2012. Notch1 is regulated by chorionic gonadotropin and progesterone in endometrial stromal cells and modulates decidualization in primates. Endocrinology, 153(6):2884–2896. https://doi.org/10.1210/en.2011-2122 Baerwald AR, Adams GP, Pierson RA, 2012. Ovarian antral folliculogenesis during the human menstrual cycle: a review. Hum Reprod Update, 18(1):73–91. https://doi.org/10.1093/humupd/dmr039 Bhurke AS, Bagchi IC, Bagchi MK, 2016. Progesterone-regulated endometrial factors controlling implantation. Am J Reprod Immunol, 75(3):237–245. https://doi.org/10.1111/aji.12473 Bodner-Adler B, Mayerhofer K, Czerwenka K, et al., 2016. The role of fibroblast growth factor 2 in patients with uterine smooth muscle tumors: an immunohistochemical study. Eur J Obstet Gynecol Reprod Biol, 207:62–67. https://doi.org/10.1016/j.ejogrb.2016.10.028 Borahay MA, Al-Hendy A, Kilic GS, et al., 2015. Signaling pathways in leiomyoma: understanding pathobiology and implications for therapy. Mol Med, 21(1):242–256. https://doi.org/10.2119/molmed.2014.00053 Buell-Acosta JD, Garces MF, Parada-Baños AJ, et al., 2022. Maternal fibroblast growth factor 21 levels decrease during early pregnancy in normotensive pregnant women but are higher in preeclamptic women—a longitudinal study. Cells, 11(14):2251. https://doi.org/10.3390/cells11142251 Chavan AR, Griffith OW, Wagner GP, 2017. The inflammation paradox in the evolution of mammalian pregnancy: turning a foe into a friend. Curr Opin Genet Dev, 47:24–32. https://doi.org/10.1016/j.gde.2017.08.004 Cheng JH, Liang J, Li YZ, et al., 2022. Shp2 in uterine stromal cells critically regulates on time embryo implantation and stromal decidualization by multiple pathways during early pregnancy. PLoS Genet, 18(1):e1010018. https://doi.org/10.1371/journal.pgen.1010018 Cheng JH, Sha ZZ, Li JY, et al., 2023. Progress on the role of estrogen and progesterone signaling in mouse embryo implantation and decidualization. Reprod Sci, 30(6):1746–1757. https://doi.org/10.1007/s43032-023-01169-0 Cho JH, Yoon MS, Koo JB, et al., 2011. The progesterone receptor as a transcription factor regulates phospholipase D1 expression through independent activation of protein kinase A and Ras during 8-Br-cAMP-induced decidualization in human endometrial stromal cells. Biochem J, 436(1): 181–191. https://doi.org/10.1042/bj20101614 Chung D, Gao F, Jegga AG, et al., 2015. Estrogen mediated epithelial proliferation in the uterus is directed by stromal Fgf10 and Bmp8a. Mol Cell Endocrinol, 400:48–60. https://doi.org/10.1016/j.mce.2014.11.002 Conrad KP, Rabaglino MB, Post Uiterweer ED, 2017. Emerging role for dysregulated decidualization in the genesis of preeclampsia. Placenta, 60:119–129. https://doi.org/10.1016/j.placenta.2017.06.005 Dambaeva S, Bilal M, Schneiderman S, et al., 2021. Decidualization score identifies an endometrial dysregulation in samples from women with recurrent pregnancy losses and unexplained infertility. F S Rep, 2(1):95–103. https://doi.org/10.1016/j.xfre.2020.12.004 de Clercq K, Hennes A, Vriens J, 2017. Isolation of mouse endometrial epithelial and stromal cells for in vitro decidualization. J Vis Exp, (121):55168. https://doi.org/10.3791/55168 Dey SK, Lim H, Das SK, et al., 2004. Molecular cues to implantation. Endocr Rev, 25(3):341–373. https://doi.org/10.1210/er.2003-0020 Ding JH, Tan XJ, Song KK, et al., 2018. Bushen Huoxue recipe alleviates implantation loss in mice by enhancing estrogen-progesterone signals and promoting decidual angiogenesis through FGF2 during early pregnancy. Front Pharmacol, 9:437. https://doi.org/10.3389/fphar.2018.00437 Ding JL, Yin TL, Yan NN, et al., 2019. FasL on decidual macrophages mediates trophoblast apoptosis: a potential cause of recurrent miscarriage. Int J Mol Med, 43(6):2376–2386. https://doi.org/10.3892/ijmm.2019.4146 Ding NZ, Qi QR, Gu XW, et al., 2018. De novo synthesis of sphingolipids is essential for decidualization in mice. Theriogenology, 106:227–236. https://doi.org/10.1016/j.theriogenology.2017.09.036 Duncan WC, 2021. The inadequate corpus luteum. Reprod Fertil, 2(1):C1–C7. https://doi.org/10.1530/RAF-20-0044 Emera D, Romero R, Wagner G, 2012. The evolution of menstruation: a new model for genetic assimilation: explaining molecular origins of maternal responses to fetal invasiveness. BioEssays, 34(1):26–35. https://doi.org/10.1002/bies.201100099 Estella C, Herrer I, Moreno-Moya JM, et al., 2012. miRNA signature and Dicer requirement during human endometrial stromal decidualization in vitro. PLoS ONE, 7(7):e41080. https://doi.org/10.1371/journal.pone.0041080 Evans J, Salamonsen LA, Winship A, et al., 2016. Fertile ground: human endometrial programming and lessons in health and disease. Nat Rev Endocrinol, 12(11):654–667. https://doi.org/10.1038/nrendo.2016.116 Fabi F, Grenier K, Parent S, et al., 2017. Regulation of the PI3K/Akt pathway during decidualization of endometrial stromal cells. PLoS ONE, 12(5):e0177387. https://doi.org/10.1371/journal.pone.0177387 Fang ZS, Tian Y, Sui C, et al., 2022. Single-cell transcriptomics of proliferative phase endometrium: systems analysis of cell-cell communication network using CellChat. Front Cell Dev Biol, 10:919731. https://doi.org/10.3389/fcell.2022.919731 Ferriani RA, Charnock-Jones DS, Prentice A, et al., 1993. Immunohistochemical localization of acidic and basic fibroblast growth factors in normal human endometrium and endometriosis and the detection of their mRNA by polymerase chain reaction. Hum Reprod, 8(1):11–16. https://doi.org/10.1093/oxfordjournals.humrep.a137856 Figueroa V, Rodríguez MS, Lanari C, et al., 2019. Nuclear action of FGF members in endocrine-related tissues and cancer: interplay with steroid receptor pathways. Steroids, 152:108492. https://doi.org/10.1016/j.steroids.2019.108492 Flannery CA, Fleming AG, Choe GH, et al., 2016. Endometrial cancer-associated FGF18 expression is reduced by bazedoxifene in human endometrial stromal cells in vitro and in murine endometrium. Endocrinology, 157(10):3699–3708. https://doi.org/10.1210/en.2016-1233 Fu T, Zheng HT, Zhang HY, et al., 2019. Oncostatin M expression in the mouse uterus during early pregnancy promotes embryo implantation and decidualization. FEBS Lett, 593(15):2040–2050. https://doi.org/10.1002/1873-3468.13468 Fujimoto J, Hori M, Ichigo S, et al., 1996a. Ability of ovarian steroids to regulate the expression of the fibroblast growth factor family in fibroblasts derived from uterine endometrium. J Biomed Sci, 3(4):280–285. https://doi.org/10.1007/bf02253708 Fujimoto J, Hori M, Ichigo S, et al., 1996b. Expression of basic fibroblast growth factor and its mRNA in uterine endometrium during the menstrual cycle. Gynecol Endocrinol, 10(3):193–197. https://doi.org/10.3109/09513599609027988 Garrido-Gomez T, Quiñonero A, Dominguez F, et al., 2020. Preeclampsia: a defect in decidualization is associated with deficiency of Annexin A2. Am J Obstet Gynecol, 222(4): 376.e1–376.e17. https://doi.org/10.1016/j.ajog.2019.11.1250 Garrido-Gómez T, Castillo-Marco N, Cordero T, et al., 2022. Decidualization resistance in the origin of preeclampsia. Am J Obstet Gynecol, 226(2S):S886–S894. https://doi.org/10.1016/j.ajog.2020.09.039 Gellersen B, Reimann K, Samalecos A, et al., 2010. Invasiveness of human endometrial stromal cells is promoted by decidualization and by trophoblast-derived signals. Hum Reprod, 25(4):862–873. https://doi.org/10.1093/humrep/dep468 Gibson DA, Simitsidellis I, Cousins FL, et al., 2016. Intracrine androgens enhance decidualization and modulate expression of human endometrial receptivity genes. Sci Rep, 6: 19970. https://doi.org/10.1038/srep19970 Gong H, Wu WQ, Xu JJ, et al., 2019. Flutamide ameliorates uterine decidualization and angiogenesis in the mouse hyperandrogenemia model during mid-pregnancy. PLoS ONE, 14(5):e0217095. https://doi.org/10.1371/journal.pone.0217095 Guo B, Tian XC, Li DD, et al., 2014. Expression, regulation and function of Egr1 during implantation and decidualization in mice. Cell Cycle, 13(16):2626–2640. https://doi.org/10.4161/15384101.2014.943581 Hague S, Manek S, Oehler MK, et al., 2002. Tamoxifen induction of angiogenic factor expression in endometrium. Br J Cancer, 86(5):761–767. https://doi.org/10.1038/sj.bjc.6600157 Halari CD, Nandi P, Jeyarajah MJ, et al., 2020. Decorin production by the human decidua: role in decidual cell maturation. Mol Hum Reprod, 26(10):784–796. https://doi.org/10.1093/molehr/gaaa058 Hassan E, Kojima R, Ozawa F, et al., 2022. Abnormal ciliogenesis in decidual stromal cells in recurrent miscarriage. J Reprod Immunol, 150:103486. https://doi.org/10.1016/j.jri.2022.103486 Helmke BM, Markowski DN, Müller MH, et al., 2011. HMGA proteins regulate the expression of FGF2 in uterine fibroids. Mol Hum Reprod, 17(2): 135–142. https://doi.org/10.1093/molehr/gaq083 Jagodzińska A, Chudecka-Głaz A, Michalczyk K, et al., 2023. The diagnostic role of FGF 21 in endometrial cancer and other pathologies of the uterine corpus. Diagnostics, 13(3):399. https://doi.org/10.3390/diagnostics13030399 Jiang YL, Liao YX, He H, et al., 2015. FoxM1 directs STAT3 expression essential for human endometrial stromal decidualization. Sci Rep, 5:13735. https://doi.org/10.1038/srep13735 Jin ZY, Liu CK, Hong YQ, et al., 2022. BHPF exposure impairs mouse and human decidualization. Environ Pollut, 304: 119222. https://doi.org/10.1016/j.envpol.2022.119222 Jones RL, Salamonsen LA, Findlay JK, 2002. Activin A promotes human endometrial stromal cell decidualization in vitro. J Clin Endocrinol Metab, 87(8):4001–4004. https://doi.org/10.1210/jcem.87.8.8880 Jukic AM, Baird DD, Weinberg CR, et al., 2013. Length of human pregnancy and contributors to its natural variation. Hum Reprod, 28(10):2848–2855. https://doi.org/10.1093/humrep/det297 Kajihara T, Brosens JJ, Ishihara O, 2013. The role of FOXO1 in the decidual transformation of the endometrium and early pregnancy. Med Mol Morphol, 46(2):61–68. https://doi.org/10.1007/s00795-013-0018-z Kato N, Iwase A, Ishida C, et al., 2019. Upregulation of fibroblast growth factors caused by heart and neural crest derivatives expressed 2 suppression in endometriotic cells: a possible therapeutic target in endometriosis. Reprod Sci, 26(7):979–987. https://doi.org/10.1177/1933719118802053 Kimura F, Takakura K, Takebayashi K, et al., 2001. Messenger ribonucleic acid for the mouse decidual prolactin is present and induced during in vitro decidualization of endometrial stromal cells. Gynecol Endocrinol, 15(6):426–432. https://doi.org/10.1080/gye.15.6.426.432 Kusama K, Yamauchi N, Yoshida K, et al., 2021. Senolytic treatment modulates decidualization in human endometrial stromal cells. Biochem Biophys Res Commun, 571:174–180. https://doi.org/10.1016/j.bbrc.2021.07.075 Larraín D, Prado J, 2024. New insights into molecular pathogenesis of uterine fibroids: from the lab to a clinician-friendly review. In: Hamid GA (Ed.), Soft Tissue Sarcoma and Leiomyoma—Diagnosis, Management, and New Perspectives. IntechOpen, London, UK, p.91–122. https://doi.org/10.5772/intechopen.1002969 Lash GE, Ernerudh J, 2015. Decidual cytokines and pregnancy complications: focus on spontaneous miscarriage. J Reprod Immunol, 108:83–89. https://doi.org/10.1016/j.jri.2015.02.003 Li B, Yan YP, Liang C, et al., 2022. Primary cilia restrain PI3K-AKT signaling to orchestrate human decidualization. Int J Mol Sci, 23(24):15573. https://doi.org/10.3390/ijms232415573 Li DD, Gao YJ, Tian XC, et al., 2014. Differential expression and regulation of Tdo2 during mouse decidualization. J Endocrinol, 220(1):73–83. https://doi.org/10.1530/joe-13-0429 Li MJ, Zhang H, Zhao XB, et al., 2014. SPRY4-mediated ERK1/2 signaling inhibition abolishes 17β-estradiol-induced cell growth in endometrial adenocarcinoma cell. Gynecol Endocrinol, 30(8):600–604. https://doi.org/10.3109/09513590.2014.912264 Li QX, Kannan A, Demayo FJ, et al., 2011. The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2. Science, 331(6019):912–916. https://doi.org/10.1126/science.1197454 Li XK, Wang C, Xiao J, et al., 2016. Fibroblast growth factors, old kids on the new block. Semin Cell Dev Biol, 53:155–167. https://doi.org/10.1016/j.semcdb.2015.12.014 Li XY, Shen C, Liu XQ, et al., 2017. Exposure to benzo[a]pyrene impairs decidualization and decidual angiogenesis in mice during early pregnancy. Environ Pollut, 222:523–531. https://doi.org/10.1016/j.envpol.2016.11.029 Li Y, Kang ZL, Qiao N, et al., 2017. Effects of excess copper ions on decidualization of human endometrial stromal cells. Biol Trace Elem Res, 177(1):10–15. https://doi.org/10.1007/s12011-016-0840-y Li YN, Qiang WN, Griffin BB, et al., 2020. HMGA2-mediated tumorigenesis through angiogenesis in leiomyoma. Fertil Steril, 114(5):1085–1096. https://doi.org/10.1016/j.fertnstert.2020.05.036 Lim W, Bae H, Bazer FW, et al., 2017. Stimulatory effects of fibroblast growth factor 2 on proliferation and migration of uterine luminal epithelial cells during early pregnancy. Biol Reprod, 96(1):185–198. https://doi.org/10.1095/biolreprod.116.142331 Liu H, Huang XB, Mor G, et al., 2020. Epigenetic modifications working in the decidualization and endometrial receptivity. Cell Mol Life Sci, 77(11):2091–2101. https://doi.org/10.1007/s00018-019-03395-9 Liu MY, Deng WB, Tang L, et al., 2022. Menin directs regionalized decidual transformation through epigenetically setting PTX3 to balance FGF and BMP signaling. Nat Commun, 13:1006. https://doi.org/10.1038/s41467-022-28657-2 Lv SJ, Wang N, Ma J, et al., 2019. Impaired decidualization caused by downregulation of circadian clock gene BMAL1 contributes to human recurrent miscarriage. Biol Reprod, 101(1):138–147. https://doi.org/10.1093/biolre/ioz063 Mak IYH, Brosens JJ, Christian M, et al., 2002. Regulated expression of signal transducer and activator of transcription, Stat5, and its enhancement of PRL expression in human endometrial stromal cells in vitro. J Clin Endocrinol Metab, 87(6):2581–2588. https://doi.org/10.1210/jcem.87.6.8576 Martinez-Fierro ML, Garza-Veloz I, Castañeda-Lopez ME, et al., 2022. Evaluation of the effect of the fibroblast growth factor type 2 (FGF-2) administration on placental gene expression in a murine model of preeclampsia induced by L-NAME. Int J Mol Sci, 23(17):10129. https://doi.org/10.3390/ijms231710129 Massimiani M, Lacconi V, la Civita F, et al., 2020. Molecular signaling regulating endometrium-blastocyst crosstalk. Int J Mol Sci, 21(1):23. https://doi.org/10.3390/ijms21010023 McConaha ME, Eckstrum K, An J, et al., 2011. Microarray assessment of the influence of the conceptus on gene expression in the mouse uterus during decidualization. Reproduction, 141(4):511–527. https://doi.org/10.1530/rep-10-0358 Meng N, Yang Q, He YP, et al., 2019. Decreased NDRG1 expression is associated with pregnancy loss in mice and attenuates the in vitro decidualization of endometrial stromal cells. Mol Reprod Dev, 86(9):1210–1223. https://doi.org/10.1002/mrd.23238 Meng XH, Chen CQ, Qian JF, et al., 2023. Energy metabolism and maternal-fetal tolerance working in decidualization. Front Immunol, 14:1203719. https://doi.org/10.3389/fimmu.2023.1203719 Mestre-Citrinovitz AC, Kleff V, Vallejo G, et al., 2015. A suppressive antagonism evidences progesterone and estrogen receptor pathway interaction with concomitant regulation of Hand2, Bmp2 and ERK during early decidualization. PLoS ONE, 10(4):e0124756. https://doi.org/10.1371/journal.pone.0124756 Möller B, Rasmussen C, Lindblom B, et al., 2001. Expression of the angiogenic growth factors VEGF, FGF-2, EGF and their receptors in normal human endometrium during the menstrual cycle. Mol Hum Reprod, 7(1):65–72. https://doi.org/10.1093/molehr/7.1.65 Mori S, Hatori N, Kawaguchi N, et al., 2017. The integrinbinding defective FGF2 mutants potently suppress FGF2 signalling and angiogenesis. Biosci Rep, 37(2):BSR20170173. https://doi.org/10.1042/bsr20170173 Murata H, Tsuzuki T, Kido T, et al., 2019. Progestin-induced heart and neural crest derivatives-expressed transcript 2 inhibits angiopoietin 2 via fibroblast growth factor 9 in human endometrial stromal cells. Reprod Biol, 19(1): 14–21. https://doi.org/10.1016/j.repbio.2019.02.005 Murata H, Tanaka S, Okada H, 2022. The regulators of human endometrial stromal cell decidualization. Biomolecules, 12(9):1275. https://doi.org/10.3390/biom12091275 Murray CM, Orr CJ, 2020. Hormonal regulation of the menstrual cycle and ovulation. In: Kovacs CS, Deal CL (Eds.), Maternal-Fetal and Neonatal Endocrinology. Academic Press, London, p.159–167. https://doi.org/10.1016/B978-0-12-814823-5.00012-X Muter J, Brosens JJ, 2018. Decidua. Academic Press, Oxford, UK, p.424–430. Nagashima T, Maruyama T, Uchida H, et al., 2008. Activation of SRC kinase and phosphorylation of signal transducer and activator of transcription-5 are required for decidual transformation of human endometrial stromal cells. Endocrinology, 149(3):1227–1234. https://doi.org/10.1210/en.2007-1217 Nakamura M, Takakura M, Fujii R, et al., 2013. The PRB-dependent FOXO1/IGFBP-1 axis is essential for progestin to inhibit endometrial epithelial growth. Cancer Lett, 336(1):68–75. https://doi.org/10.1016/j.canlet.2013.04.010 Nnamani MC, Ganguly S, Erkenbrack EM, et al., 2016. A derived allosteric switch underlies the evolution of conditional cooperativity between HOXA11 and FOXO1. Cell Rep, 15(10):2097–2108. https://doi.org/10.1016/j.celrep.2016.04.088 Okada H, Tsuzuki T, Murata H, 2018. Decidualization of the human endometrium. Reprod Med Biol, 17(3):220–227. https://doi.org/10.1002/rmb2.12088 Orazov MR, Radzinskiy VE, Kostin IN, et al., 2021. Endometrial asynchrony in pathogenesis of implantation impairment in women with infertility associated with endometriosis. Gynecol Endocrinol, 37(S1):1–3. https://doi.org/10.1080/09513590.2021.2006437 Paiva P, Hannan NJ, Hincks C, et al., 2011. Human chorionic gonadotrophin regulates FGF2 and other cytokines produced by human endometrial epithelial cells, providing a mechanism for enhancing endometrial receptivity. Hum Reprod, 26(5):1153–1162. https://doi.org/10.1093/humrep/der027 Pan-Castillo B, Gazze SA, Thomas S, et al., 2018. Morpho-physical dynamics of human endometrial cells during decidualization. Nanomedicine, 14(7):2235–2245. https://doi.org/10.1016/j.nano.2018.07.004 Paria BC, Ma WG, Tan J, et al., 2001. Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors. Proc Natl Acad Sci USA, 98(3):1047–1052. https://doi.org/10.1073/pnas.98.3.1047 Paul EN, Burns GW, Carpenter TJ, et al., 2021. Transcriptome analyses of myometrium from fibroid patients reveals phenotypic differences compared to non-diseased myometrium. Int J Mol Sci, 22(7):3618. https://doi.org/10.3390/ijms22073618 Peterse D, de Clercq K, Goossens C, et al., 2018. Optimization of endometrial decidualization in the menstruating mouse model for preclinical endometriosis research. Reprod Sci, 25(11):1577–1588. https://doi.org/10.1177/1933719118756744 Popovici RM, Kao LC, Giudice LC, 2000. Discovery of new inducible genes in in vitro decidualized human endometrial stromal cells using microarray technology. Endocrinology, 141(9):3510–3515. https://doi.org/10.1210/endo.141.9.7789 Qi QR, Zhao XY, Zuo RJ, et al., 2015. Involvement of atypical transcription factor E2F8 in the polyploidization during mouse and human decidualization. Cell Cycle, 14(12): 1842–1858. https://doi.org/10.1080/15384101.2015.1033593 Ran LM, Song HB, 2011. The promotion effect of cAMP on decidualization process in vitro of stromal cells in eutopic endometrium of patients with endometriosis. Matern Child Health Care China, 26(7):1092–1094 (in Chinese). Rauk PN, Surti U, Roberts JM, et al., 1995. Mitogenic effect of basic fibroblast growth factor and estradiol on cultured human myometrial and leiomyoma cells. Am J Obstet Gynecol, 173(2):571–577. https://doi.org/10.1016/0002-9378(95)90284-8 Redman CW, Sargent IL, Staff AC, 2014. IFPA Senior Award Lecture: making sense of pre-eclampsia—two placental causes of preeclampsia? Placenta, 35(Suppl):S20–S25. https://doi.org/10.1016/j.placenta.2013.12.008 Rider V, Carlone DL, Foster RT, 1997. Oestrogen and progesterone control basic fibroblast growth factor mRNA in the rat uterus. J Endocrinol, 154(1):75–84. https://doi.org/10.1677/joe.0.1540075 Rytkönen KT, Erkenbrack EM, Poutanen M, et al., 2019. Decidualization of human endometrial stromal fibroblasts is a multiphasic process involving distinct transcriptional programs. Reprod Sci, 26(3):323–336. https://doi.org/10.1177/1933719118802056 Sahin Ersoy G, Zhou YP, Inan H, et al., 2017. Cigarette smoking affects uterine receptivity markers. Reprod Sci, 24(7): 989–995. https://doi.org/10.1177/1933719117697129 Sahu MB, Deepak V, Gonzales SK, et al., 2019. Decidual cells from women with preeclampsia exhibit inadequate decidualization and reduced sFlt1 suppression. Pregnancy Hypertens, 15:64–71. https://doi.org/10.1016/j.preghy.2018.11.003 Sak ME, Gul T, Evsen MS, et al., 2013. Fibroblast growth factor-1 expression in the endometrium of patients with repeated implantation failure after in vitro fertilization. Eur Rev Med Pharmacol Sci, 17(3):398–402. Salamonsen LA, Jones RL, 2003. Endometrial remodeling. In: Henry HL, Norman AW (Eds.), Encyclopedia of Hormones. Academic Press, Amsterdam, p.504–512. https://doi.org/10.1016/B0-12-341103-3/00080-2 Samathanam CA, Adesanya OO, Zhou J, et al., 1998. Fibroblast growth factors 1 and 2 in the primate uterus. Biol Reprod, 59(3):491–496. https://doi.org/10.1095/biolreprod59.3.491 Sangha RK, Li XF, Shams M, et al., 1997. Fibroblast growth factor receptor-1 is a critical component for endometrial remodeling: localization and expression of basic fibro-blast growth factor and FGF-R1 in human endometrium during the menstrual cycle and decreased FGF-R1 expression in menorrhagia. Lab Invest, 77(4):389–402. Sevostyanova O, Lisovskaya T, Chistyakova G, et al., 2020. Proinflammatory mediators and reproductive failure in women with uterine fibroids. Gynecol Endocrinol, 36(S1): 33–35. https://doi.org/10.1080/09513590.2020.1816726 Shuya LL, Menkhorst EM, Yap J, et al., 2011. Leukemia inhibitory factor enhances endometrial stromal cell decidualization in humans and mice. PLoS ONE, 6(9):e25288. https://doi.org/10.1371/journal.pone.0025288 Song Z, Li B, Li MY, et al., 2022. Caveolin-1 regulation and function in mouse uterus during early pregnancy and under human in vitro decidualization. Int J Mol Sci, 23(7): 3699. https://doi.org/10.3390/ijms23073699 Soufla G, Sifakis S, Spandidos DA, 2008. FGF2 transcript levels are positively correlated with EGF and IGF-1 in the malignant endometrium. Cancer Lett, 259(2):146–155. https://doi.org/10.1016/j.canlet.2007.10.002 Stepan H, Kley K, Hindricks J, et al., 2013. Serum levels of the adipokine fibroblast growth factor-21 are increased in preeclampsia. Cytokine, 62(2):322–326. https://doi.org/10.1016/j.cyto.2013.02.019 Strassmann BI, 1996. The evolution of endometrial cycles and menstruation. Quart Rev Biol, 71(2):181–220. https://doi.org/10.1086/419369 Šućurović S, Nikolić T, Brosens JJ, et al., 2017. Spatial and temporal analyses of FGF9 expression during early pregnancy. Cell Physiol Biochem, 42(6):2318–2329. https://doi.org/10.1159/000480004 Sutton EF, Morrison CD, Stephens JM, et al., 2018. Fibroblast growth factor 21, adiposity, and macronutrient balance in a healthy, pregnant population with overweight and obesity. Endocr Res, 43(4):275–283. https://doi.org/10.1080/07435800.2018.1473421 Tanaka K, Minoura H, Isobe T, et al., 2003. Ghrelin is involved in the decidualization of human endometrial stromal cells. J Clin Endocrinol Metab, 88(5):2335–2340. https://doi.org/10.1210/jc.2002-021024 Tang ZJ, Guan HY, Wang L, et al., 2021. Research progress on human endometrium decidualization in vitro cell models. Reprod Dev Med, 5(2):119–127. https://doi.org/10.4103/2096-2924.320882 Tang ZJ, Wang L, Huang ZS, et al., 2022. CD55 is upregulated by cAMP/PKA/AKT and modulates human decidualization via Src and ERK pathway and decidualization-related genes. Mol Reprod Dev, 89(5–6):256–268. https://doi.org/10.1002/mrd.23569 Taniguchi F, Harada T, Sakamoto Y, et al., 2003. Activation of mitogen-activated protein kinase pathway by keratinocyte growth factor or fibroblast growth factor-10 promotes cell proliferation in human endometrial carcinoma cells. J Clin Endocrinol Metab, 88(2):773–780. https://doi.org/10.1210/jc.2002-021062 Teng CB, Diao HL, Ma XH, et al., 2004. Differential expression and activation of Stat3 during mouse embryo implantation and decidualization. Mol Reprod Dev, 69(1): 1–10. https://doi.org/10.1002/mrd.20149 Tong J, Lv SJ, Yang JQ, et al., 2022. Decidualization and related pregnancy complications. Matern-Fetal Med, 4(1):24–35. https://doi.org/10.1097/FM9.0000000000000135 Tsai JH, Schulte M, O’Neill K, et al., 2013. Glucosamine inhibits decidualization of human endometrial stromal cells and decreases litter sizes in mice. Biol Reprod, 89(1): 16, 1–10. https://doi.org/10.1095/biolreprod.113.108571 Vasquez YM, Mazur EC, Li XL, et al., 2015. FOXO1 is required for binding of PR on IRF4, novel transcriptional regulator of endometrial stromal decidualization. Mol Endocrinol, 29(3):421–433. https://doi.org/10.1210/me.2014-1292 Wang C, Zhao M, Zhang WQ, et al., 2020. Comparative analysis of mouse decidualization models at the molecular level. Genes, 11(8):935. https://doi.org/10.3390/genes11080935 Wang HD, Zhang M, Ge L, 2022. Cholesterol: enhancing FGF2 translocation in unconventional secretion. J Cell Biol, 221(11): e202210007. https://doi.org/10.1083/jcb.202210007 Wu D, Kimura F, Zheng LY, et al., 2017. Chronic endometritis modifies decidualization in human endometrial stromal cells. Reprod Biol Endocrinol, 15(1):16. https://doi.org/10.1186/s12958-017-0233-x Wu SP, Li R, DeMayo FJ, 2018. Progesterone receptor regulation of uterine adaptation for pregnancy. Trends Endocrinol Metab, 29(7):481–491. https://doi.org/10.1016/j.tem.2018.04.001 Wu XX, Blanck A, Olovsson M, et al., 2001. Expression of basic fibroblast growth factor (bFGF), FGF receptor 1 and FGF receptor 2 in uterine leiomyomas and myometrium during the menstrual cycle, after menopause and GnRHa treatment. Acta Obstet Gynecol Scand, 80(6):497–504. https://doi.org/10.1034/j.1600-0412.2001.080006497.x Xu XX, Wang JZ, Guo XY, et al., 2023. GPR30-mediated non-classic estrogen pathway in mast cells participates in endometriosis pain via the production of FGF2. Front Immunol, 14:1106771. https://doi.org/10.3389/fimmu.2023.1106771 Yagel S, Goldman-Wohl DS, 2019. Placental implantation and development. In: Yagel S, Silverman NH, Gembruch U (Eds.), Fetal Cardiology: Embryology, Genetics, Physiology, Echocardiographic Evaluation, Diagnosis, and Perinatal Management of Cardiac Diseases, 3rd Ed. CRC Press, Boca Raton, p.54–66. https://doi.org/10.1201/9780429461118 Yan XY, Rong MM, Zhou QH, et al., 2022. DCAF13 is essential for the pathogenesis of preeclampsia through its involvement in endometrial decidualization. Mol Cell Endocrinol, 556:111741. https://doi.org/10.1016/j.mce.2022.111741 Yang SC, Park M, Hong KH, et al., 2023. CFP1 governs uterine epigenetic landscapes to intervene in progesterone responses for uterine physiology and suppression of endometriosis. Nat Commun, 14:3220. https://doi.org/10.1038/s41467-023-39008-0 Yerlikaya G, Balendran S, Pröstling K, et al., 2016. Comprehensive study of angiogenic factors in women with endometriosis compared to women without endometriosis. Eur J Obstet Gynecol Reprod Biol, 204:88–98. https://doi.org/10.1016/j.ejogrb.2016.07.500 Yin XQ, Pavone ME, Lu ZX, et al., 2012. Increased activation of the PI3K/AKT pathway compromises decidualization of stromal cells from endometriosis. J Clin Endocrinol Metab, 97(1):E35–E43. https://doi.org/10.1210/jc.2011-1527 Yin Y, Haller ME, Chadchan SB, et al., 2021. Signaling through retinoic acid receptors is essential for mammalian uterine receptivity and decidualization. JCI Insight, 6(17):e150254. https://doi.org/10.1172/jci.insight.150254 Yoshie M, Kusama K, Tamura K, 2015. Molecular mechanisms of human endometrial decidualization activated by cyclic adenosine monophosphate signaling pathways. J Mamm Ova Res, 32(3):95–102. https://doi.org/10.1274/jmor.32.95 Yu HF, Duan CC, Yang ZQ, et al., 2020. Malic enzyme 1 is important for uterine decidualization in response to progesterone/cAMP/PKA/HB-EGF pathway. FASEB J, 34(3):3820–3837. https://doi.org/10.1096/fj.201902289R Yu SL, Lee SI, Park HW, et al., 2022. SIRT1 suppresses in vitro decidualization of human endometrial stromal cells through the downregulation of forkhead box O1 expression. Reprod Biol, 22(3):100672. https://doi.org/10.1016/j.repbio.2022.100672 Yu XY, Wang YP, Tan XW, et al., 2021. Upregulation of fibro-blast growth factor 2 contributes to endometriosis through SPRYs/DUSP6/ERK signaling pathway. Acta Histochem, 123(5):151749. https://doi.org/10.1016/j.acthis.2021.151749 Zhang XQ, Ibrahimi OA, Olsen SK, et al., 2006. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem, 281(23): 15694–15700. https://doi.org/10.1074/jbc.M601252200 Zhang Y, Zhang Z, Kang NN, et al., 2022. Generation of a mouse artificial decidualization model with ovariectomy for endometrial decidualization research. J Vis Exp, (185): e64278. https://doi.org/10.3791/64278 Zhao LJ, Yang HL, Xuan Y, et al., 2015. Increased expression of fibroblast growth factor receptor 1 in endometriosis and its correlation with endometriosis-related dysmenorrhea and recurrence. Eur J Obstet Gynecol Reprod Biol, 184:117–124. https://doi.org/10.1016/j.ejogrb.2014.11.013 Zhao M, Zhang WQ, Liu JL, 2017. A study on regional differences in decidualization of the mouse uterus. Reproduction, 153(5):645–653. https://doi.org/10.1530/REP-16-0486 Zhao WJ, Xu CF, Peng LJ, et al., 2023. cAMP/PKA signaling promotes AKT deactivation by reducing CIP2A expression, thereby facilitating decidualization. Mol Cell Endocrinol, 571:111946. https://doi.org/10.1016/j.mce.2023.111946 Zheng WL, Zhao SF, He H, et al., 2023. E2F2 is upregulated by the ERK pathway and regulates decidualization via MCM4. Gene, 871:147400. https://doi.org/10.1016/j.gene.2023.147400 Zhou PY, Ouyang LQ, Jiang T, et al., 2024. Progesterone and cAMP synergistically induce SHP2 expression via PGR and CREB1 during uterine stromal decidualization. FEBS J, 291(1):142–157. https://doi.org/10.1111/febs.16966 Zhou WJ, Hou XX, Wang XQ, et al., 2017. Fibroblast growth factor 7 regulates proliferation and decidualization of human endometrial stromal cells via ERK and JNK pathway in an autocrine manner. Reprod Sci, 24(12):1607–1619. https://doi.org/10.1177/1933719117697122 Zhu DL, Tuo XM, Rong Y, et al., 2020. Fibroblast growth factor receptor signaling as therapeutic targets in female reproductive system cancers. J Cancer, 11(24):7264–7275. https://doi.org/10.7150/jca.44727 Zhu J, Li ZY, Yin FL, et al., 2023. Fibroblast growth factor 1 ameliorates thin endometrium in rats through activation of the autophagic pathway. Front Pharmacol, 14: 1143096. https://doi.org/10.3389/fphar.2023.1143096 Acknowledgments This work was supported by the National Natural Science Foundation of China (Nos. 91949123 and 81871155). Author information Authors and Affiliations Contributions Zhijian SU and Xiaokun LI conceived and designed the manuscript. Xueni ZHANG, Yidi MO, Chunbin LU, and Zhijian SU contributed to the data acquisition and figure preparation. Xueni ZHANG and Zhijian SU drafted the manuscript. All authors have read and approved the final manuscript. Corresponding authors Ethics declarations Xueni ZHANG, Yidi MO, Chunbin LU, Zhijian SU, and Xiaokun LI declare that they have no conflicts of interest. This article does not contain any studies with human or animal subjects performed by any of the authors. Rights and permissions About this article Cite this article Zhang, X., Mo, Y., Lu, C. et al. Fibroblast growth factors and endometrial decidualization: models, mechanisms, and related pathologies. J. Zhejiang Univ. Sci. B 26, 573–588 (2025). https://doi.org/10.1631/jzus.B2300830 Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1631/jzus.B2300830