H2S and Endometrial Angiogenesis

项目摘要 血管生成是子宫内膜异位症的一个关键机制， 在月经周期和正常怀孕期间，雌激素发挥作用， 一个关键的角色。子宫内膜中的血管生成，就像它发生在任何其他器官中一样，是由增强的 局部产生血管生成因子。硫化氢（H2S）是一种气体信号分子， 参与许多生理和病理生理过程的调节。内源 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）。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） 在体外和体内的血管生成。CBS和CSE在许多器官中都有表达，但它们的表达是不稳定的。 组织/细胞特异性;在某些组织中需要两种酶来产生H2S，而在某些组织中一种酶就足够了。 他人最近的研究表明，H2S在子宫内膜异位症中调节子宫内膜功能的作用。 月经周期和妊娠;然而，迄今为止，已经报道了子宫内膜是否产生H2S， 在月经周期和妊娠期间，H2S是否在子宫内膜中起作用， 血管生成RO 3的总体假设是雌激素水平升高刺激雌激素水平 受体（ERα/β）依赖性上调基质CBS-H2S产生，这反过来刺激 女性在增殖期和妊娠期的EMEC血管生成。这一假设将是 通过使用来自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)和源自这些组织的子宫内膜微血管内皮细胞（EMEC）细胞模型。 目的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离体影响;目的2确定雌激素是否刺激ESC H2S 通过ERα/ER β依赖的CBS转录和体外介导产生; Aim 3将 确定ESC衍生的H2S是否介导EMEC血管生成的雌激素刺激。完成这些 一个重要的具体目标将建立一个新的旁分泌生理作用的ESC衍生的H2S在子宫内膜 EMEC血管生成。

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.