PREDISPOSITION TO DEVELOP PREECLAMPSIA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 先兆子痫影响3-5%的妊娠，并对孕产妇和新生儿的发病率和死亡率有很大影响。我们已经产生了一个关于先兆子痫发生的新假说，该假说假定有两个主要特征独立地促进了子痫前期的发展。一个特征是妊娠前的表型，包括血浆容量减少，交感神经张力升高，子宫血流量减少和血小板激活增强。血管紧张素原(TT235)的特定遗传多态与先兆子痫的风险增加有关，提示了这一特征。在我们的初步数据中，这种多态与先兆子痫的关键病理生理特征有关，在怀孕前进行检查的妇女中，先兆子痫以前被认为是妊娠独有的。第二个特征是妊娠的生理性体积扩张。我们的理论认为，先兆子痫的明显临床表现在妊娠晚期变得明显，原因是1)由于对低血管内容量的长期适应(异常孕前表型)而无法耐受的女性的正常体积扩张，或2)妊娠前表型正常的女性(即双胞胎、葡萄胎妊娠)的过度体积扩张。在这项拨款中，我们建议检查三个主要的特定目标，采用详细的全身生理测量，这将支持这种先兆子痫发展的病理生理学观点：1)我们将确认在高加索人和亚洲人中与先兆子痫有关的血管紧张素原基因与非妊娠人群中血浆容量的减少有关，并且这种血浆容量收缩与交感神经张力升高、子宫血流减少和怀孕前血小板激活增加有关，2)当我们跟踪这些妇女进入怀孕时，我们将证明；A)孕前血浆容量低与妊娠早期(12周)交感神经张力升高和子宫血流减少相关，尽管血浆容量扩张相似，但仍易发生胎盘异常；以及b)孕前血浆容量与妊娠晚期平均动脉压(校正后的血浆容量扩张)和血小板激活程度间接相关，3)最后，我们将证明怀孕后产后血浆容量和动脉顺应性均增加，从而降低未来怀孕时先兆子痫和以后生活中高血压的风险。这将是一项对照的前瞻性纵向研究，考察先兆子痫发生的综合病理生理机制。这项研究建议对一种新的假设进行评估，该假设将表面上相互矛盾的数据综合成一个统一的理论。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Preeclampsia affects 3-5% of pregnancies and contributes significantly to maternal and neonatal morbidity and mortality. We have generated a novel hypothesis regarding the development of pre-eclampsia that postulates that two primary features contribute independently to its development. One feature is a pre-pregnancy phenotype that includes reduced plasma volume, elevated sympathetic tone, reduced uterine blood flow and enhanced platelet activation. This feature has been suggested by the association of a specific genetic polymorphism of angiotensinogen (TT 235) with an increased risk for pre-eclampsia. This polymorphism has been linked in our preliminary data to key pathophysiologic features of pre-eclampsia, previously thought to be exclusive to pregnancy, in women who are examined prior to pregnancy. The second feature is the physiologic volume expansion of pregnancy. We have theorized that the overt clinical manifestations of pre-eclampsia become apparent in late pregnancy as a result of either 1) a normal volume expansion in women unable to tolerate it due to a chronic adaptation to low intravascular volume (abnormal prepregnancy phenotype) or 2) an excessive volume expansion in women with a normal prepregnancy phenotype (i.e. twins, molar pregnancies). In this grant we propose to examine 3 primary specific aims, employing detailed whole body physiologic measurements in women, that will support this pathophysiologic view of the development of preeclampsia; 1) We will confirm that the angiotensinogen genotype that has been linked to preeclampsia in Caucasians and Asians is associated with reduced plasma volume in a nulligravid population and that this plasma volume constriction is associated with elevated sympathetic tone, reduced uterine blood flow and heightened platelet activation prior to pregnancy, 2) As we follow these women into pregnancy we will demonstrate; a) that low prepregnancy plasma volume is associated with elevated sympathetic tone and reduced uterine blood flow in early pregnancy (12 weeks) predisposing to abnormal placentation despite similar plasma volume expansion, and b) that prepregnancy plasma volume is indirectly related to both the change in mean arterial pressure (corrected for plasma volume expansion) and degree of platelet activation in the third trimester, 3) Finally, we will demonstrate that pregnancy results in an increase in both post-puerperal plasma volume and arterial compliance lowering the risk for both preeclampsia in future pregnancies and hypertension in later life. This will be a controlled prospective longitudinal study examining an integrated pathophysiologic mechanism underlying the development of preeclampsia. This study proposes to evaluate a novel hypothesis that synthesizes apparently contradictory data into a single coherent theory.