Soluble flt-1 and the angiopoietins in the development and regulation of placental vasculature.

One of the key roles of the placenta is to mediate exchange of oxygen, nutrients and waste products between the maternal and fetal circulations. While some nutrients are actively taken up, oxygen is passively transported (i.e. it moves down a simple concentration gradient). To ensure an adequate supply as gestation progresses, the vascular structures in the human placenta remodel to facilitate this transfer. Under conditions in which oxygen is limited, at high altitude for example, these adaptations become more pronounced. In placentae obtained from high altitude the mean diameter of vessels is increased and the number of perivascular cells (pericytes) is reduced. Pericytes play an important role in modulating endothelial cell function and in their absence the endothelial cells are sensitive to growth factor withdrawal. The vascular remodelling that occurs in normal pregnancy is in part mediated by soluble factors (some produced by pericytes) and the level of these may in turn be regulated by local oxygen tension. We have shown that the mRNAs encoding both angiopoietins are present in the placenta and both are regulated by local PO2. Ang-2 mRNA transcription is increased under reduced oxygen and the stability of Ang-1 mRNA is reduced under similar conditions. Thus the ratio of mRNAs encoding these antagonistic factors changes (in favour of Ang-2), in the placenta in response to a reduction in PO2. The adaptations seen in the placenta and the mechanism by which they are achieved may be generally applicable.