Research using the primary cell culture of trophoblasts to clarify how is the differentiation of trophoblasts regulated

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Sufficient cytotrophoblasts (CTs) differentiation and subsequent remodeling of maternal uterine vasculature is critical to establish uteroplacental circulation. The production of vascular endothelial growth factor (VEGF) family molecules is confirmed in placental cells including CTs. However, it is not elucidated how the differentiation of CTs along with the alteration of their function, especially VEGF system in CTs, is controlled by local environment in placenta such as oxygen tension and maternal immune cells, and how it is involved in the development of placental circulation. To address this, we explored the effect of oxygen tension and maternal immune cells on the expression of VEGF and its antagonist, soluble fms-like tyrosine kinase-1 (sFlt-1) using a primary CT culture system. Reduced oxygen resulted in a pronounced increase in sFlt-1 production in CTs, whereas this was not the case in other placental cells. VEGF production was also stimulated by reduced oxygen in CTs but much … More less than sFlt-1 production. These results implicate that CTs possess a unique property to enhance sFlt-1 production under reduced oxygen, which could consequently antagonize angiogenic activity of VEGF. As for maternal immune cells, CTs pretreated with decidual lymphokine-activated killer (LAK) cells released more sFlt-1 compared with those pretreated with non-activated lymphocytes. The production of VEGF from CTs was not altered by pretreatment with either activated or non-activated decidual lymphocytes(DMCs). In preeclamptic placenta, LAK cells induced from DMCs by co-existing IL-2 may react to the CTs and enhance the release of sFlt-1 from CTs without any change of VEGF secretion. This might result in the reduction of actual angiogenic potential of the VEGF system in decidua and the placental vascular system might be compromised, which may lead to the hypoxia in placenta and hypoxia in placenta might further antagonize the placental vasculature by secreting more sFlt-1 and develop preeclampsia. Less