Preeclampsia, IUGR and Hypertension: Targets for Treatment

先兆子痫、IUGR 和高血压：治疗目标

• 批准号: 8518448
• 负责人: Joey P. Granger
• 金额: $ 21.35万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8518448
• 关键词: Affect; Age; Angiogenesis Inhibitors; Angiogenic Factor; Arteries; Attenuated; Birth; Blood Pressure; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cessation of life; Chronic; Clinical Research; Conscious; Data; Disease; Endothelin; Endothelin-1; Event; Fetal Growth Retardation; Functional disorder; Glomerular Filtration Rate; Hypertension; Impairment; Inflammatory; Investigation; Ischemia; Kidney; Learning; Low Birth Weight Infant; Modeling; Morbidity - disease rate; Mothers; Myometrial; Nitric Oxide; Outcome; Perfusion; Perinatal; Peripheral Resistance; Pharmaceutical Preparations; Placenta; Placental Growth Factor; Placental Insufficiency; Plasma; Positioning Attribute; Pre-Eclampsia; Pregnancy; Production; Publishing; Rattus; Reactive Oxygen Species; Relaxation; Renal Plasma Flow; Renal function; Reporting; Risk Factors; Series; TNF gene; Testing; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factors; Woman; base; cytokine; fetal; improved; inhibitor/antagonist; instrument; new therapeutic target; novel therapeutic intervention; offspring; peripheral blood; phosphodiesterase V; pregnant; pressure; prevent; response; sildenafil; vascular endothelial dysfunction

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.

描述（由适用提供）：估计预修会影响美国在妊娠期间与PE发育相关的美国高血压的5-7％，而分娩后的PE发育与PE发生有关，将其隐含为疾病中的中心罪魁祸首。假定在PE中的启动涉及降低的放置灌注，从而通过涉及替代抗血管生成因子（例如SFLT-1）的机制，从而导致母体血管内皮功能障碍，例如SFLT-1（例如，拮抗内源性血管内层生长因子（VEGFF）和位置生长因子（PLGF）（PLGF）（PLGF）;炎性细胞因子，例如肿瘤坏死因子（TNF€）；和活性氧（ROS）。尽管它是孕产妇死亡的主要原因，也是导致孕产妇和围产期发病率的主要贡献者，但没有有效的药物治疗可以预防先兆子痫，并且当前的管理疗法具有重大局限性。基于最新的研究和本应用中介绍的初步数据，我们建议，磷酸二酯酶5抑制剂可能会为治疗前美术和低出生体重后体的心血管后果提供一种新型的治疗方法。基于我们令人兴奋的初步数据，我们建议测试中心假设，即PDE5抑制剂通过抑制SFLT-L产生来减轻怀孕大鼠的血压和肾脏反应。此外，我们提出PDE5抑制剂通过抑制TNF和活性氧（ROS）的斑点产生（ROS），并衰减TNFtnf¿和SFLT-1诱导的Endothelin（ET-1）的产生增加，从而改善了肾功能，并降低了总周围耐药性和血压。此外，我们建议PDE5抑制剂会减轻斑点缺血大鼠的低出生体重后代的高血压。为了检验这一假设，将在有意识的，长期降低子宫灌注压力（RUPP）的长期降低PE产生的意识，长期仪器的大鼠模型中检查动脉压，肾功能和内皮因子。此外，我们的IUGR的位置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。具体目的是： 1）测试以下假说：磷酸二酯酶5抑制剂减轻了对孕妇的血压，肾脏和SFLT-1对舒张性缺血的反应。降低斑点缺血大鼠的低出生体重后代的血压。