H2S and Endometrial Angiogenesis

H2S 与子宫内膜血管生成

• 批准号: 10217220
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217220
• 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; Sheep; 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 一个关键的角色。子宫内膜中的血管生成，就像发生在任何其他器官中一样，是由增强的 血管生成因子的局部产生。硫化氢 (H2S) 是一种气态信号分子， 参与许多生理和病理生理过程的调节。内源性 H2S 主要由胱硫醚-β-合酶 (CBS) 和胱硫醚-γ-裂解酶从 L-半胱氨酸产生 （CSE）。 H2S 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) 体外和体内血管生成。 CBS和CSE已在许多器官中发现，但它们的表达是 组织/细胞特异性；在某些组织中，这两种酶都需要产生 H2S，而其中一种酶就足够了 其他的。最近的研究表明，H2S 在子宫内膜功能调节中发挥着重要作用。 月经周期和怀孕；然而，迄今为止已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 血管生成。 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 女性增殖期和妊娠期间的 EMEC 血管生成。这个假设将是 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) 依赖的 CBS 转录和体外介导的；目标 3 将 确定 ESC 衍生的 H2S 是否介导 EMEC 血管生成的雌激素刺激。实现这些 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。