Hypertensive Mechanisms in Preeclampsia

描述(由申请人提供)：子痫前期仍然是一个主要的健康问题，影响到美国所有怀孕的5%-10%。它是孕产妇和围产儿发病率和死亡率的主要原因。目前，还没有有效的治疗方法来处理先兆子痫患者，这种疾病只有在出生后才会缓解。虽然其潜在的机制尚不清楚，但人们认为母体血管重构不充分会导致胎盘低灌注量，从而导致胎盘慢性缺氧/缺血。作为回应，胎盘将致病因子释放到母体血液中，导致广泛的母体内皮功能障碍和高血压。近年来，一种抗血管生成蛋白--FMS样酪氨酸激酶-1(sFlt-1)的分泌受到了极大的关注。这种蛋白质由缺血的胎盘分泌到母体循环中，在那里它 直接拮抗血管内皮生长因子，并负责与子痫前期相关的重要病理，包括高血压。虽然大量的研究集中在蛋白质的致病作用上，但调节其分泌的分子机制仍然不清楚。一种可能的机制是通过sFlt-1蛋白上肝素结合位点的存在和最近的文献证据表明，正常妊娠期间sFlt-1的局部滞留和全身释放之间的切换可以由肝素酶的表达来调节，肝素酶可以裂解细胞外肝素，推测释放sFlt-1到细胞外空间。这一建议试图验证这样一种假设，即缺血胎盘对母体sFlt-1的分泌，从而对母体高血压的影响是由肝素酶的表达调节的。进一步，我将研究低氧诱导乙酰肝素酶表达的分子机制。最后，我提出，控制肝素酶活性或调节肝素酶表达的分子，都可以减轻胎盘缺血引起的高血压，为先兆子痫的治疗提供了新的治疗方法。为了验证这些假说，将使用一些体外和体内的方法。

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.