Effect of obesity on antiangiogenic and inflammatory mechanisms mediating hypertension during pregnancy

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 DESCRIPTION (provided by applicant): The incidence of preeclampsia (PE), a complex disorder of new-onset hypertension during pregnancy, 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) to elicit 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. Therefore, the central hypothesis for my K99 is that obesity and leptin amplify placental ischemia-induced production of sFlt-1 via a HIF-1α-dependent mechanism, which mediates an exaggerated blood pressure response via ET-1 with specific aims testing 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. The rationale for my R00 phase is that placental ischemia elicits a pro-inflammatory response with activation of maternal CD4+ T lymphocyte cells, which release TNFα and promotes B cells to secrete AT1-AA. Each of these factors causes hypertension when infused into normal pregnant rats via ET-1. As human data have hinted that these inflammatory factors are exaggerated in obese PE pregnancies, the central hypothesis of my R00 is that obesity and leptin can exaggerate the development of placental ischemia-induced hypertension via immune mechanisms with specific aims testing the hypotheses that: 3) obesity and chronic leptin excess enhance placental ischemia-induced increases in CD4+ T helper resulting in exaggerated hypertension and renal ET-1 responses mediated by TNFα, and 4) obesity and chronic leptin excess enhance placental ischemia-induced increases in B cells resulting in exaggerated hypertension and renal ET-1 responses mediated by AT1-AA. I have strong preliminary data to support my hypotheses using a unique obese pregnant rat model (melanocortin-4 receptor-deficient rats), which I will plan to combine with techniques that I have learned to induce placental ischemia in the rat and those that I plan to learn such as adoptive transfer of immune cells and flow cytometry to test my hypotheses in this proposal. 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.