The human placenta expresses a wide spectrum of hormones, cytokines, and growth factors involved in blastocyte implantation, placentation, and development of a new individual while maintaining fetal-maternal immune tolerance during pregnancy. Therefore, the study of molecules involved in placental regulation is pivotal to understanding their functionality and interaction in the human placenta.

Calcitriol (1,25-dihydroxyvitamin D3) is a secosteroid synthesized through the action of the vitamin D-activating enzyme CYP27B1 (Diaz et al. 2000) and its local actions are mediated by the vitamin D receptor (VDR) (Avila et al. 2004). In addition to its calcemic effects, calcitriol modulates the synthesis of antimicrobial peptides, glycoproteins, and steroids hormones. Moreover, calcitriol inhibits TNF-α-induced inflammatory cytokines in human trophoblasts as well as down-regulates TNF-α and IL-6 expression in cultured placental cells from preeclamptic women, among others (Barrera et al., 2007, Barrera et al., 2008, Diaz et al., 2009, Noyola-Martinez et al., 2013). However, there is limited information about the effects of this secosteroid on the regulation of growth factors such as transforming growth factors β (TGF-βs) in cultured trophoblast cells.

In relation to TGF-β, there are three main isoforms (TGF-β1, TGF-β2, and TGF-β3), and each of them is encoded by a separate gene. These growth factors regulate several cellular functions in physiological and pathological conditions. In placental cells, previous studies have demonstrated the presence of these three isoforms, their receptors (TGF-βR1 and TGF-βR2) and the TGF-β signaling components (SMADs proteins) (Schilling and Yeh, 2000, Jones et al., 2006). In particular, it has been shown that TGF-β1 is involved in uterine spiral artery remodeling and contributes to fetal-maternal tolerance (Yang et al. 2021). Other studies have suggested that TGF-βs might be involved in the regulation of trophoblast differentiation and invasion (Cheng et al., 2013, Huang et al., 2017, Cheng et al., 2018, Yi et al., 2018, Chuva De Sousa Lopes et al., 2020, Fang et al., 2022, Zhou et al., 2023). On the other hand, in vitro studies have shown that TGF-β1 inhibits the secretion of human chorionic gonadotropin (hCG) as well as disrupts steroidogenesis in human trophoblast cells (Morrish et al., 1991, Luo et al., 2002, Zhou et al., 2009). Since low calcitriol and high TGF-β levels in peripheral blood have been associated with pathologic pregnancies such as preeclampsia (Djurovic et al., 1997, Shaarawy et al., 2001, Bodnar et al., 2007, Peracoli et al., 2008, Barrera et al., 2015, Olmos-Ortiz et al., 2015a, Fang et al., 2022, Koppisetty et al., 2023, Wang et al., 2023), the aim of the present study was to investigate the effects of calcitriol on the expression of the different TGF-β isoforms and their receptors in cultured trophoblast cells.