The long-term goal of the project is to understand the mechanisms underlying the regulation of uterine blood flow during pregnancy. Previous in vivo studies have suggested an important role of estrogen and progesterone in the regulation of uterine blood flow in pregnancy. In addition to the effects on endothelial nitric oxide synthesis/release, the direct effects and mechanisms of the steroid hormones on the adaptation of uterine artery contractility to pregnancy remain poorly understood. Recently, we have demonstrated that PKC and ERK1/2 interact and regulate pressure-induced myogenic tone of resistance-sized uterine arteries, which is significantly attenuated in pregnant animals. Pressure-dependent myogenic contraction is an important physiologic mechanism that regulates basal vascular tone, and is a major contributor to the modulation of blood flow. Our preliminary data showed that physiological relevant concentrations of estrogen and progesterone had direct genomic effects, and up-regulated ERK1/2 and suppressed PKC-mediated myogenic contractions in the uterine artery. The proposed studies will focus on the mechanisms, and test the main hypothesis that the steroid hormones differentially regulate the ERK1/2 and PKC signaling pathways, resulting in a decrease in actin polymerization and myogenic tone of the uterine artery during pregnancy. To test the hypothesis, 3 Specific Aims are formulated, which will determine whether 1) estrogen/progesterone up-regulate ERK1/2 gene expression and suppress PKC activity in the uterine artery, 2) ERK1/2 and PKC differentially regulate actin polymerization and myogenic vascular tone in the uterine artery during pregnancy, and 3) estrogen and progesterone inhibit actin polymerization and suppress vascular tone through the regulation of ERK/PKC pathways in the uterine artery during pregnancy. The studies will be performed in nonpregnant and pregnant ovine uterine arteries in an ex vivo tissue culture model system, and will determine the direct effects of the steroid hormones on gene expression pattern and activities of ERK1/2 and PKC isozymes, actin polymerization, and pressure-induced myogenic contraction in the uterine arteries. The results will provide exciting novel insights into the mechanisms of steroid hormones in the adaptation of uteroplacental circulation during pregnancy, which have obvious clinical implications because the mal-adaptation of uterine circulation to pregnancy is associated with fetal developmental abnormalities and maternal cardiovascular disorders.
Uterine blood flow increases significantly during human pregnancy, which ensures normal fetal development. In addition to growth and remodeling of uterine vasculature, there is a significant decrease in uterine vascular resistance resulting from increased relaxation and decreased contraction of the uterine artery. The mechanisms in adaptation of uterine artery contractility to pregnancy are complex, and are not fully understood. The proposed studies will investigate the molecular mechanisms of steroid hormones in the adaptation of uterine circulation during pregnancy, and will help provide a mechanistic basis for understanding clinical problems associated with mal-adaptation and abnormal pregnancy that lead to many fetal development abnormalities including intrauterine growth restriction, as well as maternal cardiovascular disorders including hypertension in pregnancy. In addition, these studies will provide very useful information in understanding fetal origins of cardiovascular disease, which is one of the most provocative recent findings in modern medicine.
|Hu, Xiang-Qun; Huang, Xiaohui; Xiao, Daliao et al. (2016) Direct effect of chronic hypoxia in suppressing large conductance Ca(2+)-activated K(+) channel activity in ovine uterine arteries via increasing oxidative stress. J Physiol 594:343-56|
|Chen, Man; Xiao, Daliao; Hu, Xiang-Qun et al. (2015) Hypoxia Represses ER-? Expression and Inhibits Estrogen-Induced Regulation of Ca2+-Activated K+ Channel Activity and Myogenic Tone in Ovine Uterine Arteries: Causal Role of DNA Methylation. Hypertension 66:44-51|
|Xiao, DaLiao; Dasgupta, Chiranjib; Li, Yong et al. (2014) Perinatal nicotine exposure increases angiotensin II receptor-mediated vascular contractility in adult offspring. PLoS One 9:e108161|
|Ma, Qingyi; Xiong, Fuxia; Zhang, Lubo (2014) Gestational hypoxia and epigenetic programming of brain development disorders. Drug Discov Today 19:1883-96|
|Zhu, Ronghui; Huang, Xiaohui; Hu, Xiang-Qun et al. (2014) Gestational hypoxia increases reactive oxygen species and inhibits steroid hormone-mediated upregulation of Ca(2+)-activated K(+) channel function in uterine arteries. Hypertension 64:415-22|
|Xiao, Daliao; Zhu, Ronghui; Zhang, Lubo (2014) Gestational hypoxia up-regulates protein kinase C and inhibits calcium-activated potassium channels in ovine uterine arteries. Int J Med Sci 11:886-92|
|Chen, Man; Dasgupta, Chiranjib; Xiong, Fuxia et al. (2014) Epigenetic upregulation of large-conductance Ca2+-activated K+ channel expression in uterine vascular adaptation to pregnancy. Hypertension 64:610-8|
|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|
|Chen, Man; Xiong, Fuxia; Zhang, Lubo (2013) Promoter methylation of Egr-1 site contributes to fetal hypoxia-mediated PKC? gene repression in the developing heart. Am J Physiol Regul Integr Comp Physiol 304:R683-9|
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