PROJECT II - ENDOTHELIAL FACTORS, THE KIDNEY AND HYPERTENSION PROJECT SUMMARY/ABSTRACT A central theme of this PPG has been the renal-body fluid feedback control system in which the kidneys play a dominant role in the long-term regulation of body fluid volumes and arterial pressure. A common defect that has been found in all forms of hypertension examined to date is a hypertensive shift in the pressure natriuresis relationship (1-3). The overall objective of Project 2 is to determine pathophysiological mechanisms whereby obesity alters endothelial factors, renal hemodynamcis, pressure natriuresis, and blood pressure regulation in a rat model of pregnancy-induced hypertension (PIH), produced by chronic reductions in uterine perfusion pressure or chronic sFlt-1 excess (3-6). While recent studies have demonstrated adverse effects of obesity on placental function, the effects of obesity and metabolic factors such as leptin on the pathways that link placental ischemia, endothelial dysfunction, and maternal blood pressure are unknown (7-9). Based on our preliminary data and the work of others, we propose to test the central hypothesis that obesity and metabolic factors such as leptin enhance the blood pressure responses to placental ischemia in pregnant rats by enhancing placental and adipose tissue production of sFlt-1. In addition, we propose that obesity and metabolic factors such as leptin exacerbate the blood pressure responses to placental ischemia or chronic sFLt-1 excess by exacerbating TNF? and AT1-AA induced endothelial cell production of ET-1. We also propose that high fat diet induced obesity reduces placental perfusion by attenuating cytotrophoblast proliferation/migration and spiral artery remodeling during pregnancy by suppressing the Notch-2/JAG1 pathway. To test this hypothesis, arterial pressure will be examined in conscious, chronically instrumented rat models of preeclampsia produced by long-term reductions in uterine perfusion pressure (RUPP model) or by chronic sFlt-1 excess. We will examine the effects of obesity utilizing a genetic model of obesity which has a Mc4r mutation (MC4R+/-). In addition to animal models, in vitro placental explant cultures will be used to examine the effect of obesity on hypoxia-induced sFlt-1 production, and endothelial cell culture models to examine the effects of obesity on TNF? and AT1-AA-induced ET-1 production by endothelial cells. Cultured cytotrophoblasts, micro-CT, and Doppler velocimetry will be utilized to assess how obesity affects cytotrophoblast proliferation/migration, spiral artery remodeling and uterine artery resistance index. Thus, a wide range of molecular, biochemical, pharmacological, physiological, and imaging techniques as well as in vitro and in vivo models derived from various Cores will be used to test our central hypothesis.

Public Health Relevance

PROJECT II - ENDOTHELIAL FACTORS, THE KIDNEY AND HYPERTENSION NARRATIVE Preeclampsia (PE) is estimated to affect 5-7% of all pregnancies and is a leading cause of maternal death and major contributor to maternal and perinatal morbidity. Strikingly, the incidence of PE has increased by 40% over the last several decades as a result of a significant increase in risk factors such as obesity. Obesity is a major epidemic in developed countries and the percentage of women who are obese or overweight has increased almost 60% in the last 30 years. Despite the fact that obesity is the leading attributable risk for PE, the pathophysiological mechanisms whereby obesity and related metabolic factors increase the risk for developing PE are unclear. The full elucidation of these mechanisms will hopefully lead to a more complete understanding of the etiology of preeclampsia and successful therapeutic intervention through the targeted disruption of novel pathways.

National Institute of Health (NIH)
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Heart, Lung, and Blood Program Project Review Committee (HLBP)
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University of Mississippi Medical Center
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