H2S and Endometrial Angiogenesis

项目摘要 由现有血管形成的新血管称为血管生成，是子宫内膜形成的关键机制 雌激素在月经周期和正常妊娠期间的周转和再生 一个关键的角色。子宫内膜的血管生成，就像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， 参与多种生理和病理生理过程的调节。内生性 硫化氢主要由L半胱氨酸通过胱硫醚-β-合成酶和胱硫醚-γ-裂解酶产生 (CSE)。硫化氢是一种有效的促血管新生血管扩张剂，因为硫化氢供体促进内皮细胞(EC) 体外和体内的血管生成。CBS和CSE在许多器官中都被发现，但它们的表达是 组织/细胞特有的；两种酶都是在某些组织中产生硫化氢所必需的，而一种酶在 其他。最近的研究表明，硫化氢在子宫内膜功能调节中起着重要作用。 月经周期与妊娠的关系；然而，迄今为止，关于子宫内膜是否产生硫化氢的报道尚未见报道。 系统在月经周期和妊娠期间的调节以及硫化氢在子宫内膜中是否起作用 血管生成。这种R03的总体假设是，升高的雌激素刺激雌激素 受体(ERα/β)依赖的间质CBS-H_2S生成上调，进而刺激 增生期和妊娠期子宫内膜上皮细胞的血管生成。这一假设将是 用剖宫产子宫内膜活检组织和子宫内膜间质细胞进行检测 从这些组织衍生的胚胎干细胞(ESC)和子宫内膜微血管内皮细胞(EMEC)模型。 目的1确定子宫内膜硫化氢的产生是否与子宫内膜血管生成指数相关。 内源性雌激素在体外对女性的影响；目的2确定雌激素是否刺激胚胎干细胞硫化氢 产生是通过ER(ERα/ER)依赖的cbs转录和体外介导的，Aim 3将 确定ESC来源的硫化氢是否介导雌激素刺激血管内皮细胞血管生成。实现这些目标 重要的特异性靶点将建立ESC来源的硫化氢在子宫内膜中的新的旁分泌生理作用 血管内皮细胞血管生成。

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.