ENDOMETRIAL STROMAL CELL VASOACTIVE PEPTIDE SYSTEM

子宫内膜基质细胞血管活性肽系统

• 批准号: 2206721
• 负责人: M LINETTE CASEY
• 金额: $ 24.75万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2206721
• 关键词: SDS polyacrylamide gel electrophoresis; cell growth regulation; endometrium; endothelin; enkephalins; enzyme activity; female; hormone regulation /control mechanism; human subject; human tissue; immunocytochemistry; menstrual cycle; parathyroid hormones; progesterone; progesterone receptors; progestins; tissue /cell culture; transforming growth factors; vasoactive intestinal peptide; vasoconstrictors; vasodilators; western blottings

In studies of human endometrium and separated endometrial stromal cells, considerable evidence has been assembled for the existence of an endometrial stromal cell vasoactive peptide system. The primary components of this system are (i) parathyroid hormone-related protein (PTH-rP, a vasorelaxant), (ii) endothelin-1 (ET-1, a vasocontractant), (iii) enkephalinase (a plasma membrane ectoenzyme that degrades ET-1), and (iv) transforming growth factors-beta (TGF-beta1, -2, and -3). Each of these components is synthesized in the endometrial stromal cells (which are contiguous with the spiral arteries/arterioles) in a manner that is regulated by sex steroid hormones (endocrine control) and modulated by locally-produced factors (autocrine/paracrine control). PTH- rP and ET-1 are known to be effective in modulating vascular tone/blood flow when acting via the adventitial surface of vessels. PTH-rP synthesis in stromal cells is stimulated by estradiol-17beta (E2). ET-1 synthesis is not affected by E2, but is inhibited by progestin. Moreover, the specific activity (SA) of enkephalinase is increased by progestin. Thus, progestin acts in a dualistic manner to maintain low levels of the vasoconstrictor, ET-1. TGF-beta1 is produced in endometrial stromal cells commencing during the luteal phase of the cycle; and, TGF-beta1 acts in concert with progesterone to promote decidualization. But in addition, TGF-beta acts in a highly selective, gene-specific manner to overcome selected actions of progesterone, viz., TGF-beta1 acts to overcome the progestin attenuation of ET-1 and PTH-rP synthesis; and, TGF-beta1 acts to overcome the progestin-induced increase in enkephalinase SA. Therefore, TGFs-beta plus progesterone promotes decidualization; but, TGFs-beta also complement progesterone withdrawal to prepare the endometrium for menstruation. We hypothesize that synthetic progestins act to modify the synthesis/degradation of stromal cell vasoactive peptides such that endometrial growth/development is adversely affected, giving rise to disturbed angiogenesis, atypical vascular endothelial cell function/integrity, aberrant endometrial development, and, thereby, erratic endometrial bleeding. The effects of synthetic progestins can be promulgated by the development of cellular estrogen unresponsiveness promoted by the actions of these steroids, via the progesterone receptor per se (or other steroid receptors), and by inducing alterations in the rate of stromal cell synthesis/activation of TGFs-beta. Therefore, the objectives of the research proposed are to define: (i) the regulation of expression of PTH-rP, ET-1, and enkephalinase in human endometrial stromal cells, (ii) the role and mechanism(s) of action of TGF-beta to complement or to oppose selected actions of progesterone, and (iii) the role of synthetic progestins in the synthesis/activation of TGFs-beta in endometrium. In selected studies, the action of progesterone will be compared and contrasted with those of synthetic progestins. To accomplish these objectives, we propose 3 specific aims: (i) to define the biomolecular processes by which the tissue levels and actions of PTH-rP and ET-1 in human endometrium are regulated; (ii) to identify the mechanism by which TGFs-beta act as highly-selective gene-specific antiprogestins in human endometrium; and (iii) to evaluate the potential for the regulation of latent TGF-beta synthesis and activation in human endometrium.

在对人子宫内膜和分离的子宫内膜间质细胞的研究中， 已经收集了相当多的证据证明存在一个 子宫内膜间质细胞血管活性多肽系统。初级阶段 该系统的组成包括：(I)甲状旁腺激素相关蛋白 (2)内皮素-1(ET-1，血管收缩药)， (3)脑啡肽酶(一种降解ET-1的质膜外酶)， 和(Iv)转化生长因子-β(转化生长因子-β1、-2和-3)。每个人 这些成分中的一种是在子宫内膜基质细胞中合成的 (与螺旋动脉/小动脉相邻)以一种方式 这是受性类固醇激素(内分泌控制)和 受本地产生的因素调节(自分泌/旁分泌控制)。PTH- 已知RP和ET-1在调节血管张力/血液方面有效 流经血管的外膜表面时的流动。甲状旁腺素-反式合成法 在基质细胞中是由雌二醇-17β(E2)刺激的。ET-1合成 不受雌激素的影响，但受孕酮的抑制。此外， 脑啡肽酶比活力(SA)在孕激素的作用下升高。因此， 孕激素以一种二元性的方式作用，以维持低水平的 血管收缩因子ET-1。子宫内膜间质细胞产生转化生长因子-β1 在周期的黄体期开始；转化生长因子-β1在 与黄体酮协调以促进蜕膜化。但除此之外， 转化生长因子-β以一种高度选择性、基因特异性的方式作用于克服 黄体酮的部分作用，即转化生长因子-β1，作用于克服 孕激素对ET-1和PTH-RP合成的抑制作用及转化生长因子-β1的作用 以克服孕激素诱导的脑啡肽酶SA的升高。 因此，转化生长因子-β+黄体酮促进蜕膜化；但是， 转化生长因子-β也补充了黄体酮的戒断，以准备 月经周期的子宫内膜。我们假设合成的孕激素 调节基质细胞血管活性的合成/降解 使子宫内膜生长/发育受到不利影响的多肽， 导致血管生成障碍的非典型血管内皮细胞 功能/完整性，子宫内膜发育异常，因此， 不稳定的子宫内膜出血。合成孕激素的作用可以是 由细胞雌激素无反应性的发展而颁布 在这些类固醇的作用下，通过孕激素受体促进 本身(或其他类固醇受体)，并通过诱导 基质细胞合成/激活转化生长因子-β的速率。因此， 拟议研究的目标是界定：(1)监管 PTH-RP、ET-1和脑啡肽酶在人子宫内膜中的表达 基质细胞，(II)转化生长因子-β作用于细胞外基质的作用和机制(S) 补充或反对黄体酮的选定作用，以及(Iii) 合成孕激素在转化生长因子-β合成/激活中的作用 子宫内膜。在选定的研究中，黄体酮的作用将是 与合成孕激素进行了比较和对比。要完成 在这些目标中，我们提出了三个具体目标：(I)界定 甲状旁腺激素-RP组织水平和作用的生物分子过程 和ET-1在人子宫内膜中的表达；(Ii)鉴定 转化生长因子-β作为高选择性基因特异性表达的机制 人类子宫内膜中的抗孕激素；和(Iii)评估其潜力 对人体内潜伏的转化生长因子-β合成和激活的调节 子宫内膜。