Hydrogen sulfide (H2S) has been recently accepted as the third member of the gasotransmitter family that includes nitric oxide (NO) and carbon monoxide (CO). Due to homologous biological functions to NO, we posit that H2S has a critical role in estrogen-induced uterine vasodilatation. Endogenous H2S is mainly produced by metabolizing L-cysteine via two key enzymes: cystathionine ?-lyase (CSE) and cystathionine ?- synthase (CBS). We have obtained compelling data showing that estrogens stimulate CBS but not CSE expression, in ovine uterine artery (UA) endothelium and smooth muscle in vitro and in vivo as well as human UAs. Inhibition of uterine artery endothelial and smooth muscle cell H2S production by a CBS inhibitor attenuated estrogen-stimulated endothelial NO synthase (eNOS) activation in UA endothelial cells in vitro and the vasodilatory effects of estrogen on KCl-preconstricted UAs in rats. Thus, in this competitive renewal application we propose to test a novel hypothesis that endogenous H2S production by enhanced CBS expression in UA endothelium and smooth muscle functions as a novel vasodilator for mediating estrogen actions on uterine endothelium via interactions with endothelial eNOS-NO. This conjecture will be tested by four specific aims with comprehensive biochemical, cellular, molecular, physiological, and pharmacological approaches using in vitro cell culture models of UA endothelial and smooth muscle cells and ex vivo studies of various artery samples collected from sheep estrogen replacement therapy models and human UAs associated with different estrogens status from hysterectomy.
Aim 1 will determine if estrogens stimulate H2S production via upregulating endothelial and smooth muscle CBS expression in UA but not systemic arteries from animal models ex vivo.
Aim 2 will determine the mechanisms by which estrogens utilize to stimulate CBS expression and H2S production in UAEC vs. UASM cells in vitro.
Aim 3 will determine if UASM and endothelium-derived H2S functions as a mediator for estrogen activation of the eNOS-NO pathway in endothelial cells.
Aim 4 will determine if endogenous H2S mediates vascular reactivity to estrogens in human UAs from hysterectomies of post- and pre-menopausal (both secretory and proliferative phases) as well as late pregnant women. The proposed studies are novel because they are entirely different from the existing literature and they will determine for the first time whether a new vasodilator H2S mediates estrogen-induced uterine vasodilatation and the underlying mechanisms. Thus, data obtained will significantly improve our cellular and molecular understanding of estrogen and uterine blood flow biology; this, in turn, will drive the development of new strategies for combating preeclampsia, intrauterine uterine restriction, and other pregnancy failures. New data obtained will also shed lights on the understanding of the cardiovascular protective effects of estrogens.

Public Health Relevance

This competitive renewal RO1 HL70562 application aims to determine if a 'new' vasodilator hydrogen sulfide functions as key mediator of estrogen-induced uterine vasodilatation that has a major physiological significance during the menstrual cycle and pregnancy. New data obtained will greatly enhance the cellular and molecular understanding of estrogen and uterine blood flow biology; this, in turn, will drive the development of new strategies for combating preeclampsia, intrauterine uterine restriction, and other pregnancy failures. New data obtained will also shed lights on the understanding of the cardiovascular protective effects of estrogens.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070562-12
Application #
9463448
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Gao, Yunling
Project Start
2001-09-25
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
12
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
Lechuga, Thomas J; Bilg, Amanpreet K; Patel, Bansari A et al. (2018) Estradiol-17? stimulates H2 S biosynthesis by ER-dependent CBS and CSE transcription in uterine artery smooth muscle cells in vitro. J Cell Physiol :
Lei, Jinzhi; Nie, Qing; Chen, Dong-Bao (2018) A single-cell epigenetic model for paternal psychological stress-induced transgenerational reprogramming in offspring. Biol Reprod 98:846-855
Chen, Dong-Bao; Feng, Lin; Hodges, Jennifer K et al. (2017) Human trophoblast-derived hydrogen sulfide stimulates placental artery endothelial cell angiogenesis. Biol Reprod 97:478-489
Zhang, Hong-Hai; Chen, Jennifer C; Sheibani, Lili et al. (2017) Pregnancy Augments VEGF-Stimulated In Vitro Angiogenesis and Vasodilator (NO and H2S) Production in Human Uterine Artery Endothelial Cells. J Clin Endocrinol Metab 102:2382-2393
Sheibani, Lili; Lechuga, Thomas J; Zhang, Honghai et al. (2017) Augmented H2S production via cystathionine-beta-synthase upregulation plays a role in pregnancy-associated uterine vasodilation. Biol Reprod 96:664-672
Zhang, Hong-Hai; Lechuga, Thomas J; Chen, Yuezhou et al. (2016) Quantitative Proteomics Analysis of VEGF-Responsive Endothelial Protein S-Nitrosylation Using Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and LC-MS/MS. Biol Reprod 94:114
Zhang, Hong-hai; Lechuga, Thomas J; Tith, Tevy et al. (2015) S-nitrosylation of cofilin-1 mediates estradiol-17?-stimulated endothelial cytoskeleton remodeling. Mol Endocrinol 29:434-44
Lechuga, Thomas J; Zhang, Hong-hai; Sheibani, Lili et al. (2015) Estrogen Replacement Therapy in Ovariectomized Nonpregnant Ewes Stimulates Uterine Artery Hydrogen Sulfide Biosynthesis by Selectively Up-Regulating Cystathionine ?-Synthase Expression. Endocrinology 156:2288-98
Zhang, Hong-Hai; Wang, Wen; Feng, Lin et al. (2015) S-nitrosylation of Cofilin-1 Serves as a Novel Pathway for VEGF-Stimulated Endothelial Cell Migration. J Cell Physiol 230:406-17
Jiang, Yi-Zhou; Li, Yan; Wang, Kai et al. (2014) Distinct roles of HIF1A in endothelial adaptations to physiological and ambient oxygen. Mol Cell Endocrinol 391:60-7

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