Depressed uterine artery contractility plays a key role in the striking increase of uterine blood flow during pregnancy which ensures normal fetal development. Yet the mechanisms underlying the vascular adjustments to pregnancy are not understood. Further, the normal adaptation of uterine artery contractility to pregnancy can be interfered with hypoxia resulting in an increased vascular resistance and a reduction in uterine blood flow. The general aim of the proposed studies is to explore the mechanisms by which uterine artery contractile mechanisms adapt to pregnancy, and how this adaptation is altered by hypoxia. We hypothesize that decreased uterine artery contractility during pregnancy is due to the adjustments of both endothelial and vascular smooth muscle functions, whereas hypoxia interferes with one or more of these normal adaptations, and results in an increase of the vascular resistance. The research plan is designed to test several specific hypotheses using isolated sheep uterine arteries. We will test the hypothesis that pregnancy increases uterine artery endothelial nitric oxide synthesis/release, and acute hypoxia inhibits this increased endothelial function. We will then test the hypothesis that pregnancy decreases uterine artery smooth muscle alpha1-adrenergic and serotonin2 receptor densities and agonist binding affinities, and acute hypoxia increases agonist binding affinities. We will also test the hypothesis that pregnancy attenuates inositol 1,4,5-trisphosphate (IP3) synthesis and depresses intracellular Ca2+ release in uterine artery smooth muscle, and acute hypoxia enhances IP3 synthesis and elevates intracellular free Ca2+ concentration. Further, we will test the hypothesis that the importance and mechanisms of the vascular adjustments to pregnancy and their alterations by acute hypoxia vary as a function of artery generation. The results of these studies will reveal the mechanisms underlying increased uterine blood flow during pregnancy. Not only is this of basic physiological importance, elucidation of these mechanisms will also lead to greater insights into pathophysioIogy of clinical problems associated with the dysregulation of uterine blood flow. Indeed, the outcomes of proposed studies will provide original new information related to the mechanisms by which acute hypoxia contracts the uterine artery in pregnant animals. In so doing, they will provide a basis for and facilitate future studies related to the effects of long-term hypoxia on uterine artery contractility, which is of great interest in human pregnancy exposed to chronic hypoxia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HL054094-02
Application #
2378839
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1996-03-01
Project End
2000-02-29
Budget Start
1997-03-01
Budget End
1998-02-28
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Loma Linda University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Loma Linda
State
CA
Country
United States
Zip Code
92350
Zhu, Ronghui; Xiao, DaLiao; Zhang, Lubo (2013) Potassium channels and uterine vascular adaptation to pregnancy and chronic hypoxia. Curr Vasc Pharmacol 11:737-47
Bird, Ian M; Zhang, Lubo; Magness, Ronald R (2003) Possible mechanisms underlying pregnancy-induced changes in uterine artery endothelial function. Am J Physiol Regul Integr Comp Physiol 284:R245-58
Xiao, Daliao; Huang, Xiaohui; Bae, Soochan et al. (2002) Cortisol-mediated potentiation of uterine artery contractility: effect of pregnancy. Am J Physiol Heart Circ Physiol 283:H238-46
Xiao, Daliao; Zhang, Lubo (2002) ERK MAP kinases regulate smooth muscle contraction in ovine uterine artery: effect of pregnancy. Am J Physiol Heart Circ Physiol 282:H292-300
He, J; Xiao, Y; Zhang, L (2001) Cocaine-mediated apoptosis in bovine coronary artery endothelial cells: role of nitric oxide. J Pharmacol Exp Ther 298:180-7
Xiao, Y; Xiao, D; He, J et al. (2001) Maternal cocaine administration during pregnancy induces apoptosis in fetal rat heart. J Cardiovasc Pharmacol 37:639-48
Xiao, D; Bird, I M; Magness, R R et al. (2001) Upregulation of eNOS in pregnant ovine uterine arteries by chronic hypoxia. Am J Physiol Heart Circ Physiol 280:H812-20
Xiao, D; Pearce, W J; Zhang, L (2001) Pregnancy enhances endothelium-dependent relaxation of ovine uterine artery: role of NO and intracellular Ca(2+). Am J Physiol Heart Circ Physiol 281:H183-90
Xiao, D; Ducsay, C A; Zhang, L (2000) Chronic hypoxia and developmental regulation of cytochrome c expression in rats. J Soc Gynecol Investig 7:279-83
He, J; Xiao, Y; Zhang, L (2000) Cocaine induces apoptosis in human coronary artery endothelial cells. J Cardiovasc Pharmacol 35:572-80

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