Preeclampsia, IUGR and Hypertension: Targets for Treatment

描述（由申请人提供）：在美国，先兆子痫估计影响5-7%的妊娠。与PE相关的高血压在妊娠期间发生，分娩后缓解，暗示胎盘是该病的主要罪魁祸首。据推测，即使是PE的起始也涉及胎盘灌注减少，通过胎盘释放抗血管生成因子（如sFlt-1）的机制导致广泛的母体血管内皮功能障碍，sFlt-1可拮抗内源性血管内皮生长因子（VEGF）和胎盘生长因子（PlGF）；炎症因子如肿瘤坏死因子（TNF¿）；活性氧（ROS）。尽管它是孕产妇死亡的主要原因，也是孕产妇和围产期发病率的主要原因，但没有有效的药物治疗来预防先兆子痫，目前的治疗方法也有很大的局限性。根据最近的研究和本应用程序提供的初步数据，我们提出磷酸二酯酶-5抑制剂可能为治疗子痫前期和低出生体重后代的心血管后果提供一种新的治疗方法。基于我们令人兴奋的初步数据，我们提出验证PDE5抑制剂通过抑制sflt - 1的产生来减轻妊娠大鼠胎盘缺血的血压和肾脏反应的中心假设。此外，我们提出PDE5抑制剂通过抑制胎盘TNF和活性氧（ROS）的产生以及减弱TNF和sflt -1诱导的内皮素（ET-1）产生的增加来改善肾功能，降低总外周阻力和血压。此外，我们提出PDE5抑制剂可以减轻胎盘缺血大鼠低出生体重后代的高血压。为了验证这一假设，我们将在子宫灌注压（RUPP）长期降低而产生的PE大鼠模型中检测动脉压、肾功能和内皮因子。此外，我们的IUGR胎盘功能不全模型将用于检查PDE5抑制剂对低出生体重后代心血管功能的影响。具体目标是：

DESCRIPTION (provided by applicant): Preeclampsia is estimated to affect 5-7% of all pregnancies in the U.S. Hypertension associated with PE develops during pregnancy and remits after parturition implicating the placenta as a central culprit in the disease. The initiating even in PE is postulated to involve reduced placental perfusion that leads to widespread maternal vascular endothelial dysfunction by mechanisms involving the placental release of antiangiogenic factors such as sFlt-1, which antagonizes endogenous vascular endothelial growth factor (VEGF) and placental growth factor (PlGF); inflammatory cytokines such as tumor necrosis factor (TNF ¿); and reactive oxygen species (ROS). Despite its position as a leading cause of maternal death and major contributor to maternal and perinatal morbidity, there is no effective drug treatment to prevent preeclampsia, and current management therapies have significant limitations. Based on recent studies and on preliminary data presented in this application, we propose that, phosphodiesterase-5 inhibitors may provide a novel therapeutic approach for the treatment of preeclampsia and the cardiovascular consequences in the low birthweight offspring. Based on our exciting preliminary data, we propose to test the central hypothesis that PDE5 inhibitors attenuate the blood pressure and renal responses to placental ischemia in pregnant rats by inhibition of sFlt-l production. In addition, we propose that PDE5 inhibitors improve renal function and decrease total peripheral resistance and blood pressure by inhibiting the placental production of TNF and reactive oxygen species (ROS) and attenuating TNF¿ and sFlt-1-induced increases in production of endothelin (ET-1). Moreover, we propose that PDE5 inhibitors will attenuate the hypertension in low birth weight offspring of placental ischemic rats. To test this hypothesis, arterial pressure, renal function, and endothelial factors will be examined in a conscious, chronically instrumented rat model of PE produced by long-term reductions in uterine perfusion pressure (RUPP). In addition, our placental insufficiency model of IUGR will be used to examine the effects of PDE5 inhibitors on cardiovascular function in the low birthweight offspring. Specific aims are: 1) To test the hypothesis that phosphodiesterase-5 inhibitors attenuate the blood pressure, renal, and sFlt-1 responses to placental ischemia in pregnant rats 2) To test the hypothesis that phosphodiesterase-5 inhibitors attenuate the reactive oxygen species and TNF responses to placental ischemia 3) To test the hypothesis that phosphodiesterase-5 inhibitors decreases blood pressure in low birth weight offspring of placental ischemic rats.