Endocrine Abstracts

The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)₂D) is abundant in decidua but its role in placental development is unclear. We hypothesized that decidual 1,25(OH)₂D promotes placentation in early-pregnancy via actions on trophoblastic cell invasion. Using trophoblastic JEG3, BeWo and HTR8 cells we showed that 1,25(OH)₂D has no effect on trophoblastic cell proliferation and migration in plasticware culture. However, in Matrigel transwell cultures, 1,25(OH)₂D potently promoted trophoblastic cell invasion. Vitamin D system analysis showed complete absence of the nuclear vitamin D receptor (VDR) in plasticware culture of JEG3, BeWo and HTR8 cells, whilst TPC cells showed strong nuclear VDR and potent 1,25(OH)₂D-mediated induction of VDR target genes such as CYP24A1. Conversely, on Matrigel, trophoblastic cells showed abundant expression of VDR, with stronger nuclear localization in the presence of 1,25(OH)₂D, whilst TPC showed no VDR. Notably, all cells showed intracellular expression of the serum vitamin D binding protein (DBP) in Matrigel but not plastic culture. Intracellular expression of DBP appeared to be due to uptake of exogenous DBP, with serum-free cultures showing no intracellular DBP. Trophoblastic and TPC cells showed non-genomic response to 1,25(OH)₂D through induction and nuclear localization of phosphoERK1/2 (pERK1/2), and inhibition of ERK1/2 blocked DBP uptake and trophoblast Matrigel invasion. Likewise, low serum/low DBP culture dramatically suppressed trophoblastic matrix invasion. These data suggest VDR and DBP cooperate to promote decidual invasion by trophoblastic cells, with 1,25(OH)₂D enhancing cellular uptake of serum DBP by pERK-mediated signaling. We, therefore, propose that healthy placentation requires the actions of both 1,25(OH)₂D and its serum carrier protein, with maternal levels of DBP and its uptake by trophoblastic cells being a new important consideration in the overall impact of vitamin D on pregnancy success.