Preeclampsia is one of the leading causes of maternal and fetal morbidity and mortality. It is estimated to affect 6 percent to 10 percent of all pregnancies in the United States. Despite extensive research, the pathophysiology of preeclampsia is still poorly understood. It is well known that the renin- angiotensin-aldosterone system (RAAS) is stimulated in normal pregnancy. The physiological consequences of the stimulated RAAS in normal pregnancy are incompletely understood; and even less understood is the question of how this system may be altered and contribute to the hypertensive disorder of pregnancy. The cardiovascular consequences of normal pregnancy include an increase in cardiac output by 30-40 percent and plasma volume by 50 percent, which are associated with a decrease in total peripheral resistance (TPR). Thus, blood pressure is normal or reduced by the end of the first trimester and reaches its nadir by the second trimester. The reasons for the reduced TPR are not established, but a number of vasodilator substances have been studied. In preeclampsia, the cardiovascular consequences associated with hypertension include increased TPR, failure to develop the hypervolemia of pregnancy, reduced renal blood flow, and glomerular filtration rate. It has been suggested that preeclampsia may arise not only because of stimulation of vasoactive substances, but because of a defect in the contribution of the vasodilator systems. New data from our laboratory in normal human subjects have indicated that a novel vasodilator of the RAAS, angiotensin-(1-7) [Ang-(1-7)], is increased in pregnancy and reduced in preeclampsia subjects. It is our hypothesis that normal pregnancy is a balance of the RAAS comprising both vasoconstrictor [Ang II] and vasodilator [Ang-(1- 7)] pathways. Preeclampsia shifts the balance of the RAAS by maintaining an elevated vasoconstrictor component in the face of a reduced vasodilator pathway. The hypothesis will be tested by the following Specific Aims: 1) Determine the time course of circulating and urinary profiles of the vasoconstrictor (Ang II) and the vasodilator [Ang-(1-7)] components during normal pregnancy and preeclampsia. Other indices of the RAAS, including plasma total renin, active renin, and prorenin, Ang I, platelet AT1 receptor binding and/or mRNA, serum ACE activity and monocyte ACE mRNA, in normal and preeclampsia pregnant subjects will be measured. 2) Determine the physiological role of the Ang-(1-7) by measuring the blood pressure and systemic (cardiac output and total peripheral resistance) and regional (muscle and skin) hemodynamic changes to the vasodilator Ang-(1-7) and its antagonist D-Ala Ang-(1-7) in normal and preeclampsia subjects. In summary, the ultimate goal of this study is to understand the contribution of both vasodilator and vasoconstrictor components of the RAAS to blood pressure regulation in normal and preeclampsia pregnancy.
| Yamaleyeva, Liliya M; Merrill, David C; Ebert, Thomas J et al. (2014) Hemodynamic responses to angiotensin-(1-7) in women in their third trimester of pregnancy. Hypertens Pregnancy 33:375-88 |
| Anton, Lauren; Merrill, David C; Neves, Liomar A A et al. (2009) The uterine placental bed Renin-Angiotensin system in normal and preeclamptic pregnancy. Endocrinology 150:4316-25 |
| Anton, Lauren; Merrill, David C; Neves, Liomar A A et al. (2008) Activation of local chorionic villi angiotensin II levels but not angiotensin (1-7) in preeclampsia. Hypertension 51:1066-72 |
