Hypertensive Mechanisms in Preeclampsia

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Project Abstract Preeclampsia remains a major health concern, affecting 5-10% of all pregnancies in the United States. It is a leading cause of maternal and perinatal morbidity and mortality. Currently, there is no effective therapy for the management of the preeclamptic patient, with the disease only remitting after birth. While the underlying mechanisms are not clear, it is believed that inadequate remodeling of the maternal vasculature leads to placental hypo-perfusion, resulting in chronic placental hypoxia/ischemia. In response the placenta releases pathogenic factors into the maternal blood stream, leading to widespread maternal endothelial dysfunction and hypertension. In recent years, a great deal of attention has been focused on the secretion of an anti- angiogenic protein, the fms-like tyrosine kinase-1 (sFlt-1). This protein is secreted into the maternal circulation by the ischemic placenta, where it directly antagonizes VEGF, and is responsible for a significant pathology associated with preeclampsia, including hypertension. While a great deal of research has focused on the pathogenic role of the protein, the molecular mechanisms which regulate its secretion remain obscure. One potential mechanism is suggested through the presence of a heparin binding site on the sFlt-1 protein and recent evidence from the literature that the switch between local retention and systemic release of sFlt-1 during normal pregnancy can be regulated by the expression of heparanase, which cleaves extracellular heparan, presumably releasing sFlt-1 into the extracellular space. This proposal seeks to test the hypothesis that the secretion of maternal sFlt-1, and thus the maternal hypertension, by the ischemic placenta is regulated by the expression of heparanase. Further, I will investigate the molecular mechanisms which regulate hypoxia- induced heparanase expression. Finally I propose that manipulation of either heparanase activity, or manipulation of the molecules regulating heparanase expression, can attenuate the hypertension produced by placental ischemia, suggesting new therapeutic approaches for the management of preeclampsia. In order to test these hypotheses, a number of in vitro and in vivo approaches will be used.