PREECLAMPSIA: MECHANISMS AND POST-PREGNANCY IMPLICATIONS

在过去的五年中，我们的特点和确定的机制异常滋养细胞侵袭先兆子痫，并支持参与氧化应激的链接异常植入全身综合征。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。异常着床和胎盘灌注减少不足以解释该综合征。显然，类似的变化也存在于妊娠并发宫内生长受限（IUGR）和三分之一的早产（PTB）。子项目9详细研究了先兆子痫、IUGR和PTB中的着床，提出分子机制的差异可以解释为什么只有先兆子痫导致母体综合征。项目III提出，胎盘灌注减少会产生胎儿/胎盘信号（他们建议测试的信号之一是瘦素），这些信号会改变母体代谢，增加向胎儿输送营养。这种有益的代谢变化在某些妇女中不能耐受，导致先兆子痫。IUGR是该信号钝化的结果。子项目10还涉及异常着床，探索导致他们发现缺氧诱导型转录因子HIF-1 α和HIF-2 α在先兆子痫胎盘中由于降解减缓而增加的细胞机制，并探索HIF 1a和HIF 2a的下游产物，包括瘦素（子项目11）。他们测试的是这种减少的降解存在于母体和其他胎儿组织中。子项目12和13评估先兆子痫的血管功能变化。子项目12和13提出，在妊娠早期未能增加母体动脉顺应性使妇女易受更高的剪切应力、内皮活化和氧化应激增加。项目V测量了妊娠前、妊娠期间和妊娠后高危人群（既往先兆子痫）的总体动脉顺应性，探讨了NO的作用和血管紧张素反应级联反应（包括抗体）组分对NADPH氧化酶的激活。子项目122、12和13既往证实了先兆子痫女性此时内皮舒张功能降低。

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.