Preeclampsia, IUGR and Hypertension: Targets for Treatment

描述(由申请人提供)：在美国，先兆子痫估计影响所有妊娠的5%-7%。与PE相关的高血压在怀孕期间发生，并在分娩后缓解，这意味着胎盘是疾病的主要罪魁祸首。在PE中启动的EVEN被认为涉及胎盘灌注量减少，导致广泛的母体血管内皮功能障碍，其机制涉及胎盘释放抗血管生成因子，如sFlt-1，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)；以及活性氧(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贡献者，但目前还没有有效的药物治疗来预防先兆子痫，目前的管理疗法有很大的局限性。根据最近的研究和本申请的初步数据，我们认为，磷酸二酯酶-5抑制剂可能为治疗先兆子痫和低出生体重儿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，我们建议检验这一中心假设，即PDE5抑制剂通过抑制sFlt-L的产生来减轻妊娠大鼠对胎盘缺血的血压和肾脏反应。此外，我们认为PDE5抑制剂可通过抑制胎盘产生的肿瘤坏死因子和活性氧物种(ROS)，以及减轻由肿瘤坏死因子和可溶性Flt-1诱导的内皮素(ET-1)的产生，从而改善肾功能，降低外周阻力和血压。此外，我们认为PDE5抑制剂可以减轻胎盘缺血大鼠低出生体重子代的高血压。为了验证这一假说，将在长期降低子宫灌注压(RUPP)产生的有意识的、慢性仪器化的PE大鼠模型中检查动脉压、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测PDE5抑制剂对低出生体重儿心血管功能的影响。具体目标是： 1)检验磷酸二酯酶-5抑制剂减弱胎盘缺血引起的血压、肾脏和sFlt-1反应的假说；2)检验磷酸二酯酶-5抑制剂减弱胎盘缺血引起的活性氧和肿瘤坏死因子反应的假说；3)检验磷酸二酯酶-5抑制剂降低胎盘缺血低出生体重仔鼠血压的假说。

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.