H2S and Endometrial Angiogenesis

H2S 与子宫内膜血管生成

基本信息

批准号：
10039472
负责人：
DONGBAO CHEN
金额：
$ 7.85万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10039472
关键词：
Angiogenesis Promoter Angiogenic Factor Applications Grants Area Arteries Biology Biopsy Birth Cell Culture Techniques Cell model Cells Cesarean section Coculture Techniques Cystathionine Cysteine Data Decidual Cell Reactions Discipline of obstetrics Disease Embryo Endometrial Endometrial Stromal Cell Endometrium Endothelial Cells Enzymes Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens Female Fertility Future Genetic Transcription Goals Gonadal Steroid Hormones Grant Gynecologic Human Hydrogen Sulfide Hysterectomy Impairment In Vitro Infertility Investigation Knock-out Link Lyase Malignant Neoplasms Mammalian Oviducts Maternal-fetal medicine Mediating Menstrual cycle Modeling Mus Natural regeneration Organ Outcome Periodicity Phase Physiological Placentation Play Postmenopause Pre-Eclampsia Pregnancy Pregnancy Maintenance Process Production Progesterone Regulation Replacement Therapy Reporting Reproduction Research Role Sampling Signaling Molecule Smooth Muscle Steroidal Estrogen System Testing Time Tissues Up-Regulation Uterus Vascular Endothelial Growth Factors Vasodilation Vasodilator Agents Woman angiogenesis endometriosis in vivo indexing migration new therapeutic target novel paracrine pregnant proliferative phase Menstrual cycle promoter protein expression trophoblast

项目摘要

Project Summary New vessel formation from existing vessels termed angiogenesis is a key mechanism for endometrial turnover and regeneration during the menstrual cycle and normal pregnancy during which estrogens play a critical role. Angiogenesis in endometrium, like it occurs in any other organs, is initiated by enhanced local production of angiogenic factors. Hydrogen sulfide (H2S) is a gaseous signaling molecule that participates into the regulation of numerous physiological and pathophysiological processes. Endogenous H2S is mainly produced from L-cysteine by cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE). H2S is a potent proangiogenic vasodilator because H2S donors promote endothelial cell (EC) angiogenesis in vitro and in vivo. CBS and CSE have been found in many organs but their expression is tissue/cell-specific; both are needed to generate H2S in some tissues while one enzyme is sufficient in others. Recent studies have implicated a role of H2S in regulating endometrial function during the menstrual cycle and pregnancy; however, hitherto it has reported whether endometrial H2S generating system is regulated during the menstrual cycle and pregnancy and whether H2S plays a role in endometrial angiogenesis. The overall hypothesis of this RO3 is that elevated estrogens stimulate estrogen receptor (ERα/β) dependent upregulation of stromal CBS-H2S production, which in turn stimulates EMEC angiogenesis during the proliferative phase and pregnancy in women. This hypothesis will be tested by using endometrial biopsies from Cesarean hysterectomies and primary endometrial stromal cells (ESC) and endometrial microvascular endothelial cells (EMEC) cell models derived from these tissues. Aim 1 will determine if endometrial H2S production correlates to endometrial angiogenesis index under the influence of endogenous estrogens in women ex vivo; Aim 2 To determine if estrogens stimulate ESC H2S production is mediated via ER (ERα/ER) dependent CBS transcription and in vitro; and Aim 3 will determine if ESC-derived H2S mediates estrogen stimulation of EMEC angiogenesis. Accomplishing these important specific aims will establish a new paracrine physiological role of ESC-derived H2S in endometrial EMEC angiogenesis.

项目概要从现有血管形成新血管（称为血管生成）是子宫内膜异位症的关键机制月经周期和正常怀孕期间雌激素发挥作用的周转和再生子宫内膜中的血管生成与任何其他器官中的血管生成一样，是通过增强来启动的。局部产生血管生成因子硫化氢 (H2S) 是一种气体信号分子，参与多种生理和病理生理过程的调节。 H2S主要由L-半胱氨酸通过胱硫醚-β-合酶（CBS）和胱硫醚-γ-裂解酶产生 (CSE) 是一种有效的促血管生成血管舒张剂，因为 H2S 供体可促进内皮细胞 (EC) 的生长。体外和体内的血管生成已在许多器官中发现，但它们的表达是有限的。组织/细胞特异性；在某些组织中，两者都需要产生 H2S，而其中一种酶就足够了最近的研究表明 H2S 在子宫内膜功能调节中发挥着作用。月经周期和妊娠；然而，迄今为止有报道子宫内膜是否产生H2S 系统在月经周期和怀孕期间受到调节以及H2S是否在子宫内膜中发挥作用 RO3 的总体假设是雌激素升高会刺激雌激素。受体 (ERα/β) 依赖性上调基质 CBS-H2S 的产生，进而刺激 EMEC 血管生成在女性的增殖期和妊娠期间。通过使用剖腹产子宫切除术的子宫内膜活检和原代子宫内膜基质细胞进行测试 (ESC) 和子宫内膜微血管内皮细胞 (EMEC) 细胞模型源自这些组织。目标 1 将确定子宫内膜 H2S 产生是否与子宫内膜血管生成指数相关内源性雌激素对女性离体的影响；目标 2 确定雌激素是否刺激 ESC H2S 生产是通过 ER (ERα/ER) 依赖性 CBS 转录介导的，并且 Aim 3 将在体外进行；确定 ESC 衍生的 H2S 是否介导 EMEC 血管生成的雌激素刺激。重要的具体目标将建立 ESC 衍生的 H2S 在子宫内膜中新的旁分泌生理作用 EMEC 血管生成。