We propose to test the following hypothesis: 1) The pregnancy related increase in uterine blood flow mediated by release of nitric oxide (NO) is flow dependent; 2) The mechanism by which this flow-dependent alteration of the vascular tone occurs is partly mediated by release of bradykinin (Bk) by endothelial cells, which in turn releases NO; 3) The mechanism of the flow dependent alteration of the vascular tone during pregnancy is also partly dependent on the release of NO by activation of the potassium channel; 4) The increase in serum concentrations of estradiol and progesterone during pregnancy is also responsible for the flow related release of NO by the uterine vascular bed.
Five specific aims are proposed to achieve our objective.
Specific Aim 1 We will assess whether the decrease in tone of th uterine vascular bed during pregnancy is mediated by flow-dependent release of NO.
This specific aim will test hypothesis 1.
Specific Aim 2 We will assess the modulating role of endothelium derived bradykinin in the flow dependent release of NO from the perfused uterine vascular bed in vitro.
This specific aim will test hypothesis 2.
Specific Aim 3 We will assess the role of K+channel activation on the flow related release of NO from the perfused uterine vascular bed.
This specific aim will test hypothesis 3.
Specific Aim 4 We will assess the role of estradiol and progesterone in modulating tone in the uterine microvasculature and also the cellular and molecular mechanisms involved.
This specific aim will test hypothesis 4.
Specific Aim 5 We will assess the mechanism of increase in uterine blood flow during pregnancy utilizing an in vivo model.
This specific aim will test some key parts of hypothesis 1-4 in vivo. An understanding of the basic mechanism involved in modulating uterine blood flow (UBF) during pregnancy will have important basic and clinical implications. The results of these studies will indicate the local regulatory mechanism by which No is released and how sex steroids can modify this effect. The results of these studies would lay the foundation for our understanding of how these mechanisms may be altered in certain disease states associated with pregnancy such as hypertension, diabetes, and intrauterine growth retardation conditions where the fetus may be adversely affected.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL046843-05
Application #
2392676
Study Section
Special Emphasis Panel (ZRG4-ECS (01))
Project Start
1991-08-01
Project End
2001-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
5
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Shah, S; Nathan, L; Singh, R et al. (2001) E2 and not P4 increases NO release from NANC nerves of the gastrointestinal tract: implications in pregnancy. Am J Physiol Regul Integr Comp Physiol 280:R1546-54
Nathan, L; Shi, W; Dinh, H et al. (2001) Testosterone inhibits early atherogenesis by conversion to estradiol: critical role of aromatase. Proc Natl Acad Sci U S A 98:3589-93
Singh, R; Pervin, S; Karimi, A et al. (2000) Arginase activity in human breast cancer cell lines: N(omega)-hydroxy-L-arginine selectively inhibits cell proliferation and induces apoptosis in MDA-MB-468 cells. Cancer Res 60:3305-12
Singh, R; Pervin, S; Shryne, J et al. (2000) Castration increases and androgens decrease nitric oxide synthase activity in the brain: physiologic implications. Proc Natl Acad Sci U S A 97:3672-7
Shah, S; Hobbs, A; Singh, R et al. (2000) Gastrointestinal motility during pregnancy: role of nitrergic component of NANC nerves. Am J Physiol Regul Integr Comp Physiol 279:R1478-85
Nathan, L; Pervin, S; Singh, R et al. (1999) Estradiol inhibits leukocyte adhesion and transendothelial migration in rabbits in vivo : possible mechanisms for gender differences in atherosclerosis. Circ Res 85:377-85
Grewal, M; Cuevas, J; Chaudhuri, G et al. (1999) Effects of calcitonin gene-related peptide on vascular resistance in rats: role of sex steroids. Am J Physiol 276:H2063-8
Hyun, J; Chaudhuri, G; Fukuto, J M (1999) The reductive metabolism of nitric oxide in hepatocytes: possible interaction with thiols. Drug Metab Dispos 27:1005-9
Pervin, S; Singh, R; Rosenfeld, M E et al. (1998) Estradiol suppresses MCP-1 expression In vivo : implications for atherosclerosis. Arterioscler Thromb Vasc Biol 18:1575-82
Nathan, L; Chaudhuri, G (1997) Estrogens and atherosclerosis. Annu Rev Pharmacol Toxicol 37:477-515

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