Preeclampsia is a two stage disease, reduced perfusion (Stage 1) often secondary to abnormal implantation and Stage 2, the maternal syndrome. Stage 1 does not always result in Stage 2. Intrauterine growth restricted (IUGR) pregnancies and one third of preterm births also have abnormal vascular remodeling and implantation but without Stage 2. We propose that reduced placental perfusion generates fetal/placental signals influencing maternal metabolism and physiology to increase fetal nutrient delivery. This appropriate fetal/placental response can result in normal fetal growth despite reduced placental perfusion. We hypothesize some women cannot tolerate this signal and oxidative stress ensues leading to the maternal syndrome. Conversely, tome pregnancies have inadequate fetal signal or maternal response and reduced perfusion leads to IUGR. We propose that one such fetal signal is leptin, produced by human adipose and placental tissue. Leptin acts centrally to reduce appetite and activate sympathetic response increasing lipolysis. It also acts directly upon adipose tissue to modify insulin sensitivity and lead to preferential oxidation rather than storage of fats. These effects would all benefit the fetus and are compatible with the metabolic changes of pregnancy that re augmented in preeclampsia. We propose to examine placental bed histology, metabolic changes, markers of oxidative stress and endothelial activation, and measure maternal and cord blood leptin concentrations in women with preeclampsia, IUGR or normal pregnancies. We will also test tissue sensitivity to leptin and quantify expression of leptin target molecules in fat and placenta. We propose that leptin can beneficially affect placental function. We will correlate changes in relevant leptin target molecules in placenta with leptin and test in vitro up-regulation of these molecules by leptin. Leptin has cytokine like activities to increase inflammatory responses and induce oxidative stress in endothelial cells. We will test whether such effects of leptin could contribute to preeclampsia We will also measure the same case control study to determine if changes antedate clinically evident disease, supporting causality. Finally, we propose that the maternal sensitivity or propensity to over or under produce leptin antedates pregnancy and hence will be present 6 to 12 months postpartum.
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