Thre precise regulation of uterine blood flow during pregnancy is important not only for the survival and growth of the fetus but also for the cardiovascular well-being for the mother. Our preliminary in vitro studied indicted that contractile sensitivity of the uterine artery to norepinephrine, the sympathetic neurotransmitter which plays a key role in moment-to-moment regulation of vascular tone, was decreased in near-term pregnant sheep who had been exposed to long-term high altitude hypoxia. Yet the cellular/molecular mechanisms underlying the vascular adjustments to chronic hypoxia are not understood. Further, the impact of this alteration in vascular contractility on uterine blood flow is unknown. The proposed studies focus on these mechanisms and address the general hypothesis that moderate chronic hypoxia augments pregnancy-induced vascular adjustments of the uterine artery by enhancing endothelial function, and depressing smooth muscle pharmacomechanical coupling. Four of its main corollaries will be addressed by 4 Specific Aims which will test whether moderate chronic hypoxia a) up-regulates endothelial isoform of nitric oxide synthase (ecNOS) activity and gene expression in the uterine artery, b) attenuates pharmacomechanical coupling of alpha1- adrenergic receptors in the uterine artery, c) affects the production of nitric oxide and uterine vascular resistance in vivo in ways similar to in vitro, and test whether d) cGMP plays a key role in chronically hypoxic- induced attenuation of pharmacomechanical coupling in the uterine artery. To acheive these aims, we will measure in vitro uterine artery endothelial nitric oxide release, expression of nitric oxide synthase (ecNOS), smooth muscle alpha/1-adrenergic receptors, inositol 1,4,5-triphosphate (Ip/3) synthesis, IP/3 receptor affinity and density, intracellular free calcium concentration, and calcium sensitivity of contractile myofilaments, and will measure in vivo uterine nitrite/nitrate secretion, uterine blood flow, and vascular resistance in near-term (140 d) pregnant sheep maintained near sea level (approximately 300 m) and at a high altitude ( 3,820 m) from 30 days gestation. The results of the proposed studies will provide important original insights into biochemical. cellular, and physiologic adaptive mechanisms involved in adjusting uteroplacental circulation in response to moderate chronic hypoxia, and will help improve our understanding of maternal cardiovascular disorders and fetal developmental abnormalities associated with the maladaptation of uterine circulation to chronic hypoxia and permit us to address them in a more meaningful way.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057787-02
Application #
6043948
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1998-08-14
Project End
2002-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Loma Linda University
Department
Biology
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
Xiong, Fuxia; Zhang, Lubo (2013) Role of the hypothalamic-pituitary-adrenal axis in developmental programming of health and disease. Front Neuroendocrinol 34:27-46
Patterson, A J; Zhang, L (2010) Hypoxia and fetal heart development. Curr Mol Med 10:653-66
Zhang, Hongying; Zhang, Lubo (2008) Role of protein kinase C isozymes in the regulation of alpha1-adrenergic receptor-mediated contractions in ovine uterine arteries. Biol Reprod 78:35-42
Chang, Katherine; Lubo Zhang (2008) Review article: steroid hormones and uterine vascular adaptation to pregnancy. Reprod Sci 15:336-48
Xue, Qin; Ducsay, Charles A; Longo, Lawrence D et al. (2008) Effect of long-term high-altitude hypoxia on fetal pulmonary vascular contractility. J Appl Physiol 104:1786-92
Zhang, Hongying; Zhang, Lubo (2007) Regulation of alpha1-adrenoceptor-mediated contractions of the uterine artery by protein kinase C: role of the thick- and thin-filament regulatory pathways. J Pharmacol Exp Ther 322:1253-60
Zhang, Haitao; Darwanto, Agus; Linkhart, Thomas A et al. (2007) Maternal cocaine administration causes an epigenetic modification of protein kinase Cepsilon gene expression in fetal rat heart. Mol Pharmacol 71:1319-28
Xiao, DaLiao; Huang, Xiaohui; Lawrence, Jennifer et al. (2007) Fetal and neonatal nicotine exposure differentially regulates vascular contractility in adult male and female offspring. J Pharmacol Exp Ther 320:654-61
Xiao, Daliao; Huang, Xiaohui; Yang, Shumei et al. (2007) Direct effects of nicotine on contractility of the uterine artery in pregnancy. J Pharmacol Exp Ther 322:180-5

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