Role of Ang-(1-7) in normal and hypertensive pregnancy

描述(由申请人提供)：据估计，在美国，妊高征会影响7%到10%的怀孕。尽管妊高征是孕产妇死亡的主要原因之一，也是孕产妇和围产儿发病率的主要贡献者，但其发病机制尚不清楚。众所周知，RAAS在正常妊娠时受到刺激。正常妊娠中受刺激的RAAS的生理后果尚不完全清楚。我们小组的初步研究结果表明，RAAS的新七肽Ang-(1-7)在妊娠期间增加，在妊高征和先兆子痫中减少。由于Ang-(1-7)已被证明具有血管扩张剂的作用，因此可能与Ang II的作用相反，我们的发现为Aug-(1-7)在妊娠过程中可能发挥重要的生理作用提供了基础。我们的假设是，血管紧张素Ⅱ和血管紧张素Ⅱ-(1-7)分别作用于RAAS的血管收缩和血管扩张成分的适当平衡构成了无并发症妊娠期间心血管调节的一个重要特征。特别是，正常妊娠的特征可能是Aug-(1-7)的血管扩张作用平衡了Ang-II的血管收缩作用。相反，妊高征和先兆子痫可能是由于Ang-(1-7)的降压作用显著减少而导致Ang-II的过度升压作用所致。这一假设将通过以下具体目标进行检验。具体目标1将确定血管紧张素Ⅱ和血管紧张素-(1-7)分别作为血管紧张剂和血管扩张剂的主要成分在大鼠妊娠过程中循环和尿液水平变化的时间进程。在正常妊娠大鼠身上获得的结果将与子宫胎盘灌注压(RUPP)慢性降低所致的妊高征大鼠模型进行比较。我们还将监测正常妊娠大鼠和RUPP大鼠的活性肾素浓度、Ang I、血管紧张素转换酶(ACE)、血管紧张素原(Aogen)和醛固酮水平。具体目的2将证明，在正常妊娠大鼠中，通过长期输注Ang-(1-7)特异性拮抗剂([D-Ala7]-Ang-(1-7))来长期阻断Ang-(1-7)，可以使血压调节的平衡向高血压倾斜。此外，我们还将确定长期服用Ang-(1-7)是否能逆转RUPP动物的高血压。我们还建议评估正常妊娠和由RUPP引起的高血压患者肠系膜和子宫阻力小动脉对ANG多肽的反应。这些研究的主要目的是了解RAAS的血管扩张剂成分对正常妊娠血压调节的贡献。

DESCRIPTION (provided by applicant): PIH is estimated to affect 7% to 10% of all pregnancies in the United States. Despite being one of the leading causes of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of PIH are unclear. It is well known that the RAAS is stimulated in normal pregnancy. The physiological consequences of the stimulated RAAS in normal pregnancy are incompletely understood. Initial findings from our group demonstrate that the novel heptapeptide of the RAAS, Ang-(1-7) is increased in pregnancy and reduced in PIH and preeclampsia. Since Ang-(1- 7) has been shown to act as a vasodilator and thus may counter regulate the actions of Ang II, our findings provide a basis for a possibly important physiological role of Aug-( 1- 7) in the course of pregnancy. It is our hypothesis that an appropriate balance of the vasoconstrictor and vasodilator components of the RAAS exerted by Ang II and Ang-(1- 7), respectively, constitute a crucial feature of cardiovascular regulation during an uncomplicated pregnancy. In particular, normal pregnancy may be characterized by vasodilatory actions of Aug-(1-7) that balance the vasoconstrictor effects of Ang II. In contrast, PIH and preeclampsia may result from an unbridled pressor action of Ang II as a consequence of marked reduction of vasodepressor effects of Ang-(1- 7). The hypothesis will be tested by the following Specific Aims. Specific Aim 1 will determine the time course of changes in the circulating and urinary levels of Ang II and Ang-(1- 7) as the principal vasoconstrictor and vasodilator components, respectively, of the RAAS throughout the course pregnancy of pregnancy in rats. Findings obtained in normal pregnant rats will be compared to a rat model of PIH produced by chronic reduction in utero placental perfusion pressure (RUPP). We will also monitor levels of active renin concentration, Ang I, angiotensin converting enzyme (ACE), Angiotensinogen (Aogen), and aldosterone in normal pregnant rats and in rats subjected to RUPP. Specific Aim 2 will demonstrate that long-term blockade of Ang-(1- 7) by chronic infusion of the Ang-(1- 7) specific antagonist, ([D-Ala7]-Ang-(1-7) in otherwise normal pregnant rats tips the balance of blood pressure regulation toward hypertension. Also we will determine whether chronic administration of Ang-(1-7) reverses the hypertension of RUPP animals. We also propose to assess the response of mesenteric and uterine resistance arterioles to Ang peptides in normal pregnancy and hypertension caused by RUPP. The major goal of these studies is to understand the contribution of the vasodilator component of the RAAS to blood pressure regulation in normal pregnancy.