Hypertensive Mechanisms in Preeclampsia

先兆子痫的高血压机制

• 批准号: 8835143
• 负责人: Eric Matthew George
• 金额: $ 24.86万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-08 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8835143
• 关键词: Affect; Angiogenic Proteins; Antioxidants; Attention; Attenuated; Bilirubin; Binding Sites; Biological Availability; Birth; Blood; Blood Circulation; Blood Pressure; Brain Hypoxia-Ischemia; Cathepsin L; Cell surface; Cessation of life; Characteristics; Chronic; Cleaved cell; Data; Disease; Disease Management; Etiology; Exhibits; Extracellular Matrix; Extracellular Space; Goals; Health; Heparin; Heparin Binding; Human; Hyperbilirubinemia; Hypertension; Hypoxia; In Vitro; Individual; Investigation; Ischemia; Kidney; Literature; Mentors; Modeling; Molecular; Morbidity - disease rate; Mothers; Mus; Newborn Infant; Oxidative Stress; Pathology; Pathway interactions; Patients; Perfusion; Perinatal; Phase; Placenta; Pre-Eclampsia; Pregnancy; Proteins; Proteinuria; Purinergic P1 Receptors; Rattus; Receptor Signaling; Regulation; Research; Rodent; Role; Stream; Study models; Symptoms; Techniques; Testing; Therapeutic; Tissues; United States; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Vasodilator Agents; Woman; abstracting; base; effective therapy; endothelial dysfunction; extracellular; heme oxygenase-1; heparanase; in vivo; maternal hypertension; mortality; novel therapeutic intervention; overexpression; pregnancy disorder; pregnant; pressure; receptor; release factor; research study; response

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.

项目摘要