H2S and Endometrial Angiogenesis

H2S 与子宫内膜血管生成

• 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
• 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

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.

项目摘要 现有血管生成的现有血管形成的新血管形成是子宫内膜的关键机制 月经周期和正常怀孕期间雌激素发挥的营业额和再生 关键作用。像在任何其他器官中一样，子宫内膜中的血管生成是由增强的 血管生成因子的局部生产。硫化氢（H2S）是一种气态信号分子 参与对许多生理和病理生理过程的调节。内源性 H2S主要由Cystathionine-β合作蛋白（CBS）和胱胱氨而在硫代氨基氨基酶产生的L-半胱氨酸产生 （CSE）。 H2S是一种有效的促血管生成血管扩张剂，因为H2S供体促进内皮细胞（EC） 体外和体内血管生成。 CBS和CSE在许多器官中都发现了 组织/细胞特异性；两者都需要在某些时间内产生H2，而一种酶就足够了 其他的。最近的研究已经在控制子宫内膜功能方面发挥了H2S的作用 月经周期和怀孕；但是，迄今已报告了子宫内膜H2S生成 在月经周期和妊娠期间调节系统，以及H2S是否在子宫内膜中起作用 血管生成。该RO3的总体假设是升高的雌激素刺激雌激素 基质CBS-H2S产生的接收器（ERα/β）依赖性更新，进而刺激 在增殖阶段和女性怀孕期间的EMEC血管生成。这个假设将是 通过使用剖宫产子宫切除术和原发性子宫内膜细胞的子宫内膜活检测试 （ESC）和子宫内膜微血管内皮细胞（EMEC）细胞模型来自这些组织。 AIM 1将确定子宫内膜H2S的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）依赖的CBS转录和体外介导的。 AIM 3将 确定ESC衍生的H2S是否介导了EMEC血管生成的雌激素刺激。完成这些 重要的具体目标将建立ESC衍生的H2在子宫内膜中的新旁分泌物理作用 EMEC血管生成。