Sources and mechanisms of sFlt expression in preeclampsia. Preeclampsia is a hypertensive and multi-system disorder of pregnancy. In recent studies higher circulating concentrations of the soluble VEGF receptor, sFlt, have been implicated in the pathogenesis of preeclampsia. Circulating levels of sFlt-1 fall dramatically after delivery suggesting a major role for the placenta in sFlt production, and we and others have confirmed the production of sFlt by the placenta and isolated cytotrophoblasts. However, we also have evidence to suggest that there may be additional sources for excess sFlt production, particularly the maternal leukocytes. Levels of sFlt mRNA in preeclamptic placental biopsies are dramatically reduced (up to 80%) when a simple rinsing step is introduced to remove blood at the time of biopsy collection and villous explants from preeclamptic placentas show only a modest increase in sFlt mRNA levels under these conditions compared to controls. These data suggest a significant proportion of sFlt mRNA is present in maternal blood. Based on this simple but interesting and valuable observation, we analyzed the peripheral blood mononuclear cells (PBMCs) for their ability to produce sFlt. We have found that PBMCs from preeclamptic women express excess sFlt, and this sFlt overexpression tends to extend in some women who had prior preeclampsia, remote from pregnancy even after 18-24 months. We hypothesize that Flt-1/sFlt gene (dys) regulation in PBMCs of pregnant women could be a potential mechanism that contributes to pathogenesis of preeclampsia. Therefore, we propose to study whether 1) PBMCs are a significant source of sFlt production in preeclampsia, 2) if placental factors regulate sFlt expression in PBMCs and 3) investigate the molecular mechanism(s) specific for sFlt up regulation during preeclampsia. The study holds promise to provide new information toward our understanding of preeclampsia. Additionally, since sFlt is involved in angiogenesis, a better understanding of sFlt regulation may be beneficial for vascular and cancer biology. The soluble form of VEGF receptor, sFlt is found in the circulation of normal healthy human and is a molecule of intense study in cardiovascular and cancer research. Recently it attained notoriety in preeclampsia, a pregnancy related hypertensive disorder because of its elevated levels preeclamptic women and its ability to duplicate the symptoms of the disease in experimental animals. It is widely believed that the excess sFlt is produced in placenta. But our data shows that maternal blood cells, leukocytes may be the source of excess sFlt. If it can be proven, this holds promise to human health in general and especially in pregnancy, because this proposal is aimed at defining the factors and mechanisms that activate the leukocytes that behave normally otherwise. ? ? ?
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| Rajakumar, A; Powers, R W; Hubel, C A et al. (2009) Novel soluble Flt-1 isoforms in plasma and cultured placental explants from normotensive pregnant and preeclamptic women. Placenta 30:25-34 |
| Jeyabalan, A; McGonigal, S; Gilmour, C et al. (2008) Circulating and placental endoglin concentrations in pregnancies complicated by intrauterine growth restriction and preeclampsia. Placenta 29:555-63 |
