Early in normal gestation, there is a decrease in maternal vascular resistance accompanied by a 20% of 100% expansion of maternal blood volume. At the same time, the uterine arteries undergo profound remodeling and dilation -- termed """"""""physiologic change"""""""" -- to provide adequate blood flow to the developing conceptus. Failed volume expansion and failed or abnormal physiologic change are associated with a variety of common pregnancy complications, including preeclampsia, intrauterine growth retardation (IUGR), and preterm labor. Molecular variants of the angiotensinogen gene, which increase angiotensinogen expression in certain local systems, predispose women to develop preeclampsia and related pregnancy complications. This competing renewal proposes to test the hypothesis that disease-associated angiotensinogen alleles promote abnormal spiral artery remodeling and inhibit maternal plasma volume expansion. Three interrelated approaches are proposed: 1) an affected sister-pair linkage analysis of polymorphisms in angiotensinogen and other relevant genes, 2) gene expression and quantitative histology studies of spiral artery remodeling using an existing large collection of human pregnancy tissues, and 3) transgenic mouse and human studies to evaluate the newly-described paracrine tubular renin angiotensinogen system's role in maternal blood volume expansion. The investigators state that this work may lead to predictive and diagnostic tests that indicate a woman's increased risk for complications early in pregnancy, allowing improved monitoring, earlier diagnosis, and new opportunities for treatment. They further state that the ultimate goal of this research is the development of improved preventive measures and effective treatments for these common pregnancy disorders. Through an understanding of particular genetic subsets of preeclampsia, they note that they may find that once promising therapies, such as low-dose aspirin, do have a role in some patients. Finally, they note that new biologic pathways may be discovered that suggest novel therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055812-07
Application #
6389552
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Barouch, Winifred
Project Start
1995-08-20
Project End
2003-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
7
Fiscal Year
2001
Total Cost
$595,750
Indirect Cost
Name
University of Utah
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Zhang, X Q; Craven, C; Nelson, L et al. (2007) Placental abruption is more frequent in women with the angiotensinogen Thr235 mutation. Placenta 28:616-9
Lantelme, Pierre; Rohrwasser, Andreas; Gociman, Barbu et al. (2002) Effects of dietary sodium and genetic background on angiotensinogen and Renin in mouse. Hypertension 39:1007-14