Background Fetal growth restriction (FGR) is associated with glucocorticoid (GC) excess in human pregnancies and animal models. In mice and rats, GC treatment reduces placental angiogenesis and dysregulates the expression of angiogenic factors. It is not known whether GCs reduce angiogenesis in the human placenta.
Hypothesis Glucocorticoid excess in the human placenta inhibits angiogenesis by dysregulating angiogenic factors.
Methods Human umbilical vein endothelial cells (HUVECs) and human placental artery endothelial cells (HPAECs) were treated with hydrocortisone (HC), prednisolone (PRED) and dexamethasone (DEX) for 24–48 hours. Tube-like structure (TLS) formation on matrigel, cell migration, proliferation and apoptosis were assessed. Chorionic plate arteries (CPAs) from normal placentas (n = 10) were cultured for 48 hours with HC or DEX. mRNA expression of six angiogenic factors were quantified using real-time Q-PCR with normalisation to TBP.
Results Pilot studies in HUVECs (n = 3, p < 0.05) and subsequent experiments in HPAECs (n = 7, p < 0.05–0.01) treated with 10–1,000 nM HC, PRED and DEX showed reduced TLS formation and cell migration compared to vehicle control cells. GCs had no effect on cell proliferation, apoptosis or viability. HC and DEX treatment reduced the expression of fibroblast growth factor-2 (FGF-2) (p < 0.001), interleukin-8 (p < 0.001), VEGF-A (p < 0.01), VEGF-C (p < 0.01), matrix metalloproteinase-16 (p < 0.01), matrix metalloproteinase-1 (p < 0.05) and CCL-2 (p < 0.05).
Discussion GCs reduced tube formation and cell migration, key facets of angiogenesis, in HUVEC and HPAEC models. These findings indicate that GCs inhibit human placental angiogenesis, which could contribute to the pathogenesis of FGR. The downregulation of specific angiogenic factors by GCs identifies putative mechanistic pathways involved.
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