Oxygen and placental development during the first trimester: Implications for the pathophysiology of pre-eclampsia

During early pregnancy, placentation occurs in a relatively hypoxic environ ment which is essential for appropriate embryonic development. Intervillous blood flow increases at around 10-12 weeks of gestation and results in exp osure of the trophoblast to increased oxygen tension (PO2). Prior to this t ime, low oxygen appears to prevent trophoblast differentiation towards an i nvasive phenotype. In other mammalian systems, oxygen tension effects are m ediated by hypoxia inducible factor-1 (HIF-1). We found that the ontogeny o f HIF-1 alpha subunit expression during the first trimester of gestation pa rallels that of transforming growth factor-beta(3) (TGF beta(3)), an inhibi tor of early trophoblast differentiation. Expression of both molecules is h igh in early pregnancy and falls at around 10 weeks of gestation when place ntal PO2 levels are believed to increase. Antisense-induced inhibition of H IF-1 alpha inhibited the expression of TGF beta(3), and stimulated extravil lous trophoblast (EVT) outgrowth and invasion. Of clinical significance we found that TGF beta(3) expression was increased in pre-eclamptic placentae when compared to age-matched controls. Significantly, inhibition of TGF bet a(3) by antisense oligonucleotides or antibodies restored the invasive capa bility to the trophoblast cells in pre-eclamptic explants. We speculate tha t if oxygen tension fails to increase, or trophoblasts do not detect this i ncrease, HIF-1 alpha and TGF beta(3) expression remain high, resulting in s hallow trophoblast invasion and predisposing the pregnancy to pre-eclampsia . Effective fetal-maternal interactions during early placentation are critica l for a successful pregnancy. Optimal placental perfusion requires the cont rolled invasion of trophoblast cells deep into the decidua to the spiral ar teries. Trophoblast stem cells, also referred to as cytotrophoblast cells, reside in chorionic villi of two types, floating and anchoring villi. Float ing villi, which represent the vast majority of chorionic villi, are bathed in maternal blood and primarily perform gas and nutrient exchange for the developing embryo. During early placentation, cytotrophoblast cells in the floating villi proliferate and differentiate by fusing to form the multinuc leate syncytiotrophoblast layer. Cytotrophoblast cells in anchoring villi e ither fuse to form the syncytiotrophoblast layer, or break through the sync ytium at selected sites and form multilayered columns of non-polarized extr avillous trophoblast cells, which physically connect the embryo to the uter ine wall (Figure 1). The extravillous trophoblast cells invade into the ute rine wall as far as the first third of the myometrium and its associated sp iral arteries, where they disrupt the endothelium and the smooth muscle lay er and replace the vascular wall. This results in the conversion of the nar row calibre arteries into distended uteroplacental arteries, thereby increa sing blood flow to the placenta and allowing an adequate supply of oxygen a nd nutrients to the growing fetus. The invasive activity of the extravillou s trophoblast cells is at a maximum during the first trimester of gestation , peaking at around 10-12 weeks and declining thereafter. Insufficient inva sion contributes to the development of pre-eclampsia, which often results i n fetal intrauterine growth restriction, maternal hypertension and proteinu ria. In contrast, unrestricted invasion is associated with premalignant con ditions, such as invasive mole, and with malignant choriocarcinoma. Invading trophoblast cells undergo striking and rapid changes in cellular f unctions that are temporally and spatially regulated along the invasive pat hway (Figure 1) (Cross, Werb and Fisher, 1994. The formation of the anchori ng villi is accompanied by changes in synthesis and degradation of extracel lular matrix proteins and their receptors, and changes in the spatial distr ibution of extracellular matrix proteins, as well as changes in the express ion of adhesion molecules (Damsky, Fitzgerald and Fisher, 1992; Bischof et al., 1993). For example, during invasion the expression of laminin is lost and the expression of fibronectin is acquired. Extravillous trophoblast cel ls lose the expression of E-cadherins, downregulate the expression of alpha (6)beta(4) integrin (a laminin receptor) and acquire the expression of alph a(5)beta(1) integrin (a fibronectin receptor). Subsequently extravillous tr ophoblast cells differentiate to acquire an invasive phenotype, which is in dicated by the expression of markers such as gelatinase B/MMP9 and alpha(1) integrin (a collagen/laminin receptor) as well as markers typical of a vas cular adhesion phenotype. Thus, specific changes in extracellular matrix pr oteins and their receptors are associated with the acquisition of an invasi ve phenotype by the extravillous trophoblast cells. (C) 2000 IFPA and Harco urt Publishers Ltd.