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Preeclampsia (PE) is a complex disorder of new-onset hypertension during pregnancy. Its incidence is on the rise calling for studies examining how the increasing prevalence of risk factors like obesity exaggerates the mechanisms that promote this hypertension. Although human studies have consistently shown a positive association between obesity and PE, there are no mechanistic studies to speak of. Insight into such mechanisms comes from classical studies showing that placental ischemia in pregnant rats results in the release of antiangiogenic factors such as soluble fms-like 1 tyrosine kinase (sFlt-1) from the placenta, mediated by the transcription factor HIF-1α, into the maternal circulation where it antagonizes placental growth factor (PlGF) and vascular endothelial growth factor (VEGF). This collectively elicits increased renal endothelin-1 (ET-1) then hypertension. Human data highlight a possible connection between sFlt-1 and the obesity-related metabolic factor leptin to greater hypertension in obese PE women. Leptin is known to mediate obesity-induced hypertension in non-pregnant cases, but role of this factor in regulation of the blood pressure to placental ischemia is unknown. In this project, I plan to test the hypotheses that: 1) obesity and leptin enhance hypoxia and/or placental ischemia-induced increases placental production of sFlt-1 in a HIF-1α-dependent mechanism, and 2) obesity and leptin exacerbate the blood pressure and renal hemodynamics to placental ischemia or chronic sFlt-1 excess via ET-1 signaling. In order to accomplish this, I will utilize a unique obese pregnant rat model (melanocortin-4 receptor-deficient rats), which will be combined with a surgical model of placental ischemia-induced hypertension in the pregnant rat. Also, I will determine if the hypertensive response to placental ischemia is exaggerated in the presence of chronic leptin excess using leptin infusion experiments. Thus, my goal is to identify the pathways whereby obesity amplifies the risk for PE by examining the mechanisms linking placental ischemia to hypertension. The hope is that these studies aid in the development of therapeutic strategies to circumvent the development PE.
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