PREECLAMPSIA: MECHANISMS AND POST-PREGNANCY IMPLICATIONS

先兆子痫：机制和妊娠后影响

• 批准号: 7051876
• 负责人: James M Roberts
• 金额: $ 13.74万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7051876
• 关键词: clinical research; female; human subject; patient oriented research; preeclampsia; women' s health

In the past five years we characterized and identified mechanisms of abnormal trophoblast invasion in preeclampsia and supported the involvement of oxidative stress in the linkage of abnormal implantation to the systemic syndrome. This program extends the studies to detailed mechanistic examination and tests their long range significance to mother and baby. Abnormal implantation and reduced placental perfusion are insufficient to explain the syndrome. Apparently similar changes are present with pregnancies complicated by intrauterine growth restriction (IUGR) and one third of preterm pregnancy (PTB). Subproject 9 examines implantation in preeclampsia, IUGR and PTB in detail, proposing that differences in molecular mechanisms could explain why only preeclampsia results in the maternal syndrome. Project III proposes that reduced placental perfusion produces fetal/placental signals (one of which they propose to test is leptin) that alter maternal metabolism to increase nutrient delivery to the fetus. This beneficial metabolic change cannot be tolerated in some women and preeclampsia results. IUGR is the result of a blunting of this signal. Subproject 10 also concerns abnormal implantation, probing cellular mechanism responsible for their finding that the hypoxia inducible transcription factors HIF-1 alpha and HIF-2 alpha are increased in preeclampsia placentas due to slowed degradation and explores downstream products of HIF1a and HIF2a including leptin (Subproject 11) as one such product. They test is this reduced degradation is present in maternal and other fetal tissues. Subprojects 12 and 13 assess vascular functional changes in preeclampsia. Subprojects 12 and 13 propose a failure to increase maternal arterial compliance early in pregnancy predisposes the woman to higher sheer stresses, endothelial activation and increased oxidative stress. Project V measures global arterial compliance in high risk (prior preeclampsia) before during and after pregnancy, exploring the role of NO and activation of NADPH oxidase by components of the angiotensin response cascade including antibodies. Subprojects 122, 12, and 13 posit previously demonstrated reduced endothelial relaxation at this time in women with prior preeclampsia.

在过去的五年中，我们描述和确定了子痫前期滋养细胞异常侵袭的机制，并支持氧化应激参与着床异常与系统性综合征的联系。该计划将研究扩展到详细的机械性检查，并测试其对母婴的长期意义。植入异常和胎盘灌注量减少不足以解释该综合征。显然，妊娠合并宫内生长受限(IUGR)和三分之一的早产(PTB)也存在类似的变化。子项目9详细检查了子痫前期、IUGR和PTB的植入，提出分子机制的差异可以解释为什么只有先兆子痫才会导致母体综合征。项目三提出，减少胎盘灌注量会产生胎儿/胎盘信号(他们建议测试的信号之一是瘦素)，从而改变母亲的新陈代谢，增加对胎儿的营养输送。这种有益的代谢变化在一些女性中是不能容忍的，并导致先兆子痫。IUGR是这一信号减弱的结果。子项目10还涉及异常着床，探索导致他们发现缺氧诱导转录因子HIF-1α和HIF-2α在子痫前期胎盘中由于降解缓慢而增加的细胞机制，并探索HIF1a和HIF2A的下游产物，包括瘦素(子项目11)。他们测试的结果是，母体和其他胎儿组织中存在这种降解减少的现象。子项目12和13评估先兆子痫患者的血管功能变化。子项目12和13提出，在怀孕早期未能提高母亲的动脉顺应性，使妇女容易受到更高的纯粹压力，内皮激活和氧化应激增加。项目V测量怀孕前、怀孕期间和怀孕后高危人群(先兆子痫)的全球动脉顺应性，探索NO的作用和包括抗体在内的血管紧张素反应级联反应的组成部分对NADPH氧化酶的激活。子项目122、12和13先前的研究表明，在有先兆子痫史的妇女中，此时的内皮松弛减少。