Preeclampsia, IUGR and Hypertension: Targets for Treatment

描述（由申请人提供）：据估计，先兆子痫影响美国所有妊娠的5-7%。与PE相关的高血压在妊娠期间发展，并在分娩后缓解，暗示胎盘是该疾病的主要罪魁祸首。甚至在PE中的起始也被假定涉及胎盘灌注减少，其通过涉及胎盘释放抗血管生成因子（如sFlt-1，其拮抗内源性血管内皮生长因子（VEGF）和胎盘生长因子（PlGF））、炎性细胞因子（如肿瘤坏死因子（TNF））和活性氧（ROS）的机制导致广泛的母体血管内皮功能障碍。尽管其作为孕产妇死亡的主要原因和孕产妇和围产期发病率的主要贡献者的地位，没有有效的药物治疗，以防止先兆子痫，目前的管理疗法有显着的局限性。基于最近的研究和本申请中提供的初步数据，我们提出，磷酸二酯酶-5抑制剂可能为治疗先兆子痫和低出生体重后代的心血管后果提供新的治疗方法。基于我们令人兴奋的初步数据，我们建议测试中心假设，即PDE 5抑制剂通过抑制sFlt-1的产生来减弱妊娠大鼠对胎盘缺血的血压和肾脏反应。此外，我们提出PDE 5抑制剂通过抑制胎盘产生TNF和活性氧（ROS）以及减弱TNF和sFlt-1诱导的内皮素（ET-1）产生增加来改善肾功能并降低总外周阻力和血压。此外，我们提出PDE 5抑制剂将减轻胎盘缺血大鼠低出生体重后代的高血压。为了检验这一假设，将在通过长期降低子宫灌注压（RUPP）产生的清醒、慢性仪器化大鼠PE模型中检查动脉压、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PDE 5抑制剂对低出生体重后代心血管功能的影响。具体目标是： 1)检验磷酸二酯酶-5抑制剂减弱妊娠大鼠对胎盘缺血的血压、肾脏和sFlt-1反应的假设2）检验磷酸二酯酶-5抑制剂减弱活性氧和TNF对胎盘缺血的反应的假设3）检验磷酸二酯酶-5抑制剂降低胎盘缺血大鼠低出生体重后代血压的假设。

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.