Mechanisms of Pregnancy Induced Hypertension

描述（由申请人提供）：本研究的目的是明确介导妊娠高血压的机制。本研究的中心假设是，子宫胎盘灌注压的降低通过降低肾压尿钠而引起高血压。由于胎盘和/或白细胞来源的细胞因子引起内皮细胞活化，导致内皮素的形成增强，导致压力钠尿症的减少。这些异常减少了肾血浆流量和肾小球滤过，从而降低了肾钠排泄功能。为了验证这一假设，我们将在一个由子宫灌注压（RUPP）长期降低引起的慢性PIH大鼠模型中检测动脉压、肾脏、激素和内皮功能。此外，利用内皮细胞培养的体外研究将用于确定炎症细胞因子、性类固醇和内皮素产生之间的相互作用。具体目标是：1)验证子宫胎盘灌注压慢性降低过程中心血管和肾脏功能异常是由于母体血浆炎症细胞因子如TNF α和IL-6水平升高的假设；2)验证雌激素和/或孕激素增强内皮细胞激活和对TNF α和IL-6的高血压反应的假设。

DESCRIPTION (provided by applicant): The objective of this research is to define the mechanisms mediating pregnancy induced hypertension. The central hypothesis to be tested in this proposal is that a reduction in uteroplacental perfusion pressure causes hypertension by reducing renal-pressure natriuresis. The reduction in pressure natriuresis occurs as a result of placental and/or leukocyte-derived cytokines causing endothelial cell activation that leads to enhanced formation of endothelin. These abnormalities reduced renal plasma flow and glomerular filtration thereby decreasing renal sodium excretory function. To test this hypothesis, arterial pressure, renal, hormonal, and endothelial function will be examined in a conscious, chronically-instrumented rat model of chronic PIH produced by long-term reductions in uterine perfusion pressure (RUPP). In addition, in vitro studies utilizing endothelial cell culture will be used to determine the interaction between inflammatory cytokines, sex steroids and endothelin production. Specific aims to be addressed are: 1) To test the hypothesis that abnormalities in cardiovascular and renal function during chronic reductions in uteroplacental perfusion pressure are due to elevations in maternal plasma levels of inflammatory cytokines such as TNF alpha and IL-6; 2) To test the hypothesis that estrogens and/or progesterone enhance the endothelial activation and hypertensive response to TNF alpha and IL-6 .