Neutral endopeptidase expressed by decidualized stromal cells suppresses Akt phosphorylation and deoxyribonucleic acid synthesis induced by endothelin-1 in human endometrium
Neutral endopeptidase expressed by decidualized stromal cells suppresses Akt phosphorylation and deoxyribonucleic acid synthesis induced by endothelin-1 in human endometrium
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DOI：
10.1210/en.2006-0172
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发表时间：
2006-11-01
期刊：
影响因子：
4.8
通讯作者：
Kikkawa, Fumitaka
中科院分区：
文献类型：
--
作者：
Iwase, Akira;Ando, Hisao;Kikkawa, Fumitaka
内皮素-1 （ET-1）在人子宫内膜中被认为具有潜在的旁分泌作用，因为其受体也存在于该组织中。此外，ET-1的表达随月经周期的变化而变化，因此ET-1可能参与了人子宫内膜的周期性变化，如增殖、去个体化等。然而，无论是ET-1在子宫内膜中的失活，还是ET-1对子宫内膜细胞的旁分泌作用都尚未确定。我们研究了原代培养的人子宫内膜细胞中ET-1的产生和中性内肽酶（NEP）的存在，NEP可以切割和灭活ET-1。我们发现原代培养的子宫内膜上皮细胞，而不是基质细胞，是ET-1的主要来源。Western blot和RT-PCR结果显示NEP主要由子宫内膜基质细胞表达。我们还证明ET-1通过ETA受体和磷脂酰肌醇-3激酶信号通路刺激了子宫内膜基质细胞中Akt的磷酸化和DNA的合成。ET-1的作用受基质细胞表达的NEP调控。我们还发现含有来自子宫内膜上皮细胞培养的ET-1的条件培养基通过ETA受体刺激Akt的磷酸化。综上所述，ET-1对子宫内膜基质细胞具有Akt磷酸化和细胞增殖的旁分泌作用，该作用通过ETA受体和磷脂酰肌醇-3激酶信号通路发生，并受细胞表面NEP调控。
Endothelin-1 (ET-1) in human endometrium has been proposed to have a potential paracrine role, for its receptors are also present within this tissue. In addition, the expression of ET-1 varies during the menstrual cycle, and therefore, ET-1 may be involved in the cyclic change of the human endometrium, such as proliferation and decidualization. However, neither the inactivation of ET-1 in the endometrium nor the paracrine effect of ET-1 on endometrial cells has been determined. We investigated the production of ET-1 and the presence of neutral endopeptidase (NEP), which cleaves and inactivates ET-1, in primary cultured human endometrial cells. We found primary cultured endometrial epithelial cells, not stromal cells, to be the major source of ET-1. Western blot analysis and RT-PCR demonstrated that NEP was predominantly expressed by endometrial stromal cells. We also demonstrated that ET-1 stimulated the phosphorylation of Akt and DNA synthesis in endometrial stromal cells via the ETA receptor and phospahtidylinositol-3 kinase signaling pathways. The effect of ET-1 was regulated by NEP expressed by stromal cells. We also found that conditioned medium containing ET-1 from endometrial epithelial cell culture stimulated phosphorylation of Akt via the ETA receptor. In conclusion, ET-1 has a paracrine effect of Akt phosphorylation and cell proliferation on endometrial stromal cells, which occurs via the ETA receptor and phospahtidylinositol-3 kinase signaling pathways, and is regulated by cell-surface NEP.