Hypertensive Mechanisms in Preeclampsia

工程摘要 先兆子痫仍然是一个主要的健康问题，影响美国所有怀孕的5-10%。这是一个 产妇和围产期发病率和死亡率的主要原因。目前，没有有效的治疗方法， 先兆子痫患者的管理，疾病仅在出生后缓解。虽然底层 机制尚不清楚，但据信母体脉管系统的不充分重塑导致 胎盘灌注不足，导致慢性胎盘缺氧/缺血。作为回应， 致病因子进入母体血流，导致广泛的母体内皮功能障碍， 高血压近年来，大量的注意力集中在抗- 血管生成蛋白，fms样酪氨酸激酶-1（sFlt-1）。这种蛋白质被分泌到母体循环中 通过缺血性胎盘，它直接拮抗VEGF，并负责一个重要的病理 与先兆子痫有关，包括高血压虽然大量的研究集中在 由于该蛋白质的致病作用，调节其分泌的分子机制仍然不清楚。一 通过sFlt-1蛋白上肝素结合位点的存在提出了潜在的机制， 来自文献的最新证据表明，sFlt-1的局部保留和全身释放之间的转换在 正常妊娠可以通过乙酰肝素酶的表达来调节，乙酰肝素酶切割细胞外的乙酰肝素， 推测释放sFlt-1进入细胞外空间。这项建议旨在检验以下假设： 缺血性胎盘分泌母体sFlt-1，从而导致母体高血压，是由 乙酰肝素酶的表达。此外，我将研究调节缺氧的分子机制- 诱导乙酰肝素酶表达。最后，我建议操纵乙酰肝素酶活性，或 操纵调节乙酰肝素酶表达的分子，可以减轻由乙酰肝素酶引起的高血压。 胎盘缺血，提出了新的治疗方法的管理先兆子痫。为了 为了检验这些假设，将使用许多体外和体内方法。

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.