Our group first showed that angiotensin-(1-7) [Ang-(1-7)] increases in the plasma and urine of normal pregnant women. In preeclamptic pregnant subjects we demonstrated a decrease of plasma Ang-(1-7) greater than that of Ang II. These initial findings provide a basis for an important physiological role for Ang-(1-7) in the course of pregnancy and in pregnancy-induced hypertension (PIH) where there may be a diminished influence of Ang-(1-7) to oppose the local tissue actions of Ang II. New data from our laboratory showed that Ang-(1-7) enhanced mesentery artery dilation in pregnancy and this was accompanied by increased kidney and urine levels of Ang-(1-7) in normal pregnant rats. Preliminary studies showed that urinary excretion of Ang-(1-7) was reduced in an animal model that resembles PIH. In addition, our recent discovery that angiotensin converting enzyme 2 (ACE2), a carboxypeptidase that exhibits high efficacy for Ang II metabolism to Ang-(1-7), is present in the kidney and uterus of pregnant rats, is localized to similar regions in kidney and uterus as Ang-(1-7), and is up-regulated in pregnancy suggests the hypothesis that increased expression of ACE2 leads to an enhanced formation of Ang-(1-7) during pregnancy. The hypothesis to be assessed in these studies is twofold: 1) that pregnancy is a model of overexpression of Ang-(1-7) resulting from increased expression of ACE2; 2) that the resulting hemodynamic profile (i.e the decreased peripheral resistance seen in normal pregnancy) is dependent upon up-regulation of ACE2 leading to enhanced formation of Ang-(1-7), whereas PIH (characterized by increased total peripheral resistance and uteroplacental ischemia) is due to unbridled pressor/ischemic actions of Ang-II as a consequence of a marked reduction of the formation and vasodepressor effects of Ang-(1-7).
The Specific Aims are: 1) to assess the evolutionary expression of Ang-(1-7) and ACE2 at early, mid and late gestation in normal and the reduced uterine perfusion pressure (RUPP) pregnant rats; 2) to determine the contribution of the ACE2 pathway to Ang-(1-7) formation at early, mid and late gestation in normal pregnant and RUPP pregnant rats; 3) to assess the systemic and regional hemodynamic role of Ang-(1-7) and ACE2 in normal and RUPP pregnant rats; and 4) to characterize the null ACE2-/- pregnant mouse by detertm'ning the impact of the loss of the gene on blood pressure regulation. The proposed research will establish a novel and significant new dimension to the contribution of the RAS in the physiology and pathology of pregnancy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL051952-11
Application #
6853117
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
11
Fiscal Year
2004
Total Cost
$171,493
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Type
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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