Causes of Sex Differences in male and female offspring born from inflammation mediated hypertensive pregnancy - OVERALL SUMMARY Preeclampsia (PE) is characterized by hypertension, proteinuria, renal and endothelial damage, intrauterine growth restriction and cerebrovascular dysfunction during pregnancy. The overall theme of this SCORE application is to elucidate novel mechanisms linking placental ischemia and maternal systemic hemodynamic, cerebral and renal dysfunction and to identify therapeutic targets for the treatment of PE and associated IUGR/low birth weight-induced programming of hypertension in offspring. The premise of the SCORE derives from the fact that despite its position as a leading cause of maternal death and major contributor to maternal and perinatal morbidity, there is no effective drug treatment to prevent or delay the progression of PE. At present, the only effective treatment for PE is early delivery. The lack of progress in elucidating novel pathophysiological mechanisms linking placental ischemia and maternal cardiovascular dysfunction and in identifying new therapeutic targets for the treatment of PE is due in part to paucity of animal models that replicate human PE. We have demonstrated that placental ischemia is critical in causing maternal endothelial and cardiovascular dysfunction in PE. Our laboratories have developed and characterized 3 distinct models of models of PE (RUPP model and spontaneous model of superimposed PE and PE derived CD4+ T cell induced PE) that is associated with placental ischemia, maternal endothelial and cardiovascular dysfunction, IUGR and low birthweight (LBW) offspring that develop hypertension at an early age. These models have many of the features of PE in women and provide a superb investigative tool to elucidate novel pathophysiological mechanisms in PE, identify novel therapeutic targets and the cardiovascular and cerebrovascular consequences in the mother and in LBW offspring. The goals of this SCORE will be to examine relevant factors in association with hypertension and cerebrovascular dysfunction in a clinical population of PE and normotensive women and their children(Project 1) and utilize multifaceted translational approaches including cellular, molecular, physiological and pharmacological tools to examine the importance of these factors to cause PE and potential sex difference that cause longterm consequences in IUGR offspring from animal models of PE postpartum (Projects 2, 3, 4). The proposed program brings together investigators with expertise in the field of neurovascular, pharmacological and PE research. The synergy between this highly collaborative and productive team of investigators should ensure efficiency and effectiveness of the program and continued development of innovative ideas, approaches, and state of the art techniques.
