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

点击翻译按钮获取中文摘要

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.