Hypertensive Mechanisms in Preeclampsia

描述（由申请人提供）：先兆子痫仍然是一个主要的健康问题，影响5-10%的所有怀孕在美国。它是产妇和围产期发病率和死亡率的主要原因。目前，对于先兆子痫患者的管理没有有效的治疗方法，该疾病仅在出生后缓解。虽然潜在的机制尚不清楚，但据信母体血管系统的不充分重塑导致胎盘灌注不足，从而导致慢性胎盘缺氧/缺血。作为回应，胎盘释放致病因子进入母体血流，导致广泛的母体内皮功能障碍和高血压。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）的分泌上。这种蛋白质由缺血性胎盘分泌到母体循环中， 直接拮抗VEGF，并导致与先兆子痫相关的重要病理学，包括高血压。虽然大量的研究集中在蛋白质的致病作用，但调节其分泌的分子机制仍然不清楚。一个潜在的机制是通过sFlt-1蛋白上的肝素结合位点的存在和来自文献的最近证据表明，在正常妊娠期间sFlt-1的局部保留和全身释放之间的切换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乙酰肝素，推测释放sFlt-1到细胞外空间。该提议试图检验缺血性胎盘对母体sFlt-1的分泌以及由此引起的母体高血压受乙酰肝素酶表达调节的假设。此外，我将研究调节低氧诱导的乙酰肝素酶表达的分子机制。最后，我建议，操纵乙酰肝素酶的活性，或操纵乙酰肝素酶的表达调节分子，可以减轻胎盘缺血产生的高血压，这表明新的治疗方法来管理先兆子痫。为了检验这些假设，将使用许多体外和体内方法。

DESCRIPTION (provided by applicant): 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.