PREECLAMPSIA: MECHANISMS AND POST-PREGNANCY IMPLICATIONS

在过去的五年中，我们描述并确定了异常滋养细胞侵袭子痫前期的机制，并支持氧化应激参与异常植入与全身综合征的联系。该计划将研究扩展到详细的机械检查，并测试其对母亲和婴儿的长期意义。异常植入和胎盘灌注减少不足以解释该综合征。显然，类似的变化存在于妊娠合并宫内生长受限（IUGR）和三分之一的早产（PTB）。子项目9详细研究了子痫前期、IUGR和PTB的植入，提出分子机制的差异可以解释为什么只有子痫前期导致母体综合征。项目III提出，胎盘灌注减少会产生胎儿/胎盘信号（他们提议测试的信号之一是瘦素），从而改变母体代谢，增加向胎儿输送营养。这种有益的代谢变化在一些妇女和子痫前期结果中是不能容忍的。IUGR是这个信号变钝的结果。亚项目10也关注异常着床，探究细胞机制，他们发现缺氧诱导的转录因子HIF-1 α和HIF-2 α在子痫前期胎盘中由于降解减慢而增加，并探索HIF1a和HIF2a的下游产物，包括瘦素（亚项目11）。他们测试这种退化是否存在于母体和其他胎儿组织中。子项目12和13评估子痫前期血管功能的改变。子项目12和13提出，在妊娠早期未能提高母体动脉顺应性，会使女性更容易承受压力、内皮细胞激活和氧化应激增加。项目V测量妊娠前后高危人群（既往子痫前期）的整体动脉顺应性，通过血管紧张素反应级联成分（包括抗体）探索NO的作用和NADPH氧化酶的激活。子项目122、12和13先前证实有先兆子痫的妇女此时内皮松弛减少。

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.