(1)新規生理活性物質・物理的刺激による子宮内膜の時間的・空間的機能調節(シンポジウム2「子宮内膜の機能調節とその病態」,第62回日本産科婦人科学会・学術講演会)

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The endometrium is unique in its capacity to break and remodel constantly throughout reproductive life. In order to maintain its integrity, the endometrium requires spatiotemporal regulation throughout the menstrual cycle. In addition to ovarian steroid, i.e. estrogen and progesterone, local bioactive molecules and physiological stimuli are also known to contribute to control the endometrial function. We have been exploring a variety of factors that regulate endometrial function for a decade, and in this review, we will introduce a part of them by dividing them into four groups. 1) Activation of protease-activated receptor 2 (PAR2) during the menstrual phase 2) Cyclic stretch/contraction which peaks in the menstrual phase 3) Angiogenin and angiogenesis 4) Control of inflammation via p38 Mitogen-activated protein kinase (p38MAPK) and Protein kinase A (PKA) pathway during implantation. 1) Activity of proteases such as elastase and triptase produced by leukocyte in the endometrium is elevated during menstrual phase. PAR2 is a receptor which is activated by these protease. We hypothesized that the activation of PAR2 may affect on the process of endometrial remodeling. Activation of PAR2 in cultured endometrial stromal cells resulted in the increased production of Interleukin 8 (IL8), Stem cell factor (SCF) and DNA synthesis, and activation of PAR2 in endometrial epithelial cells increased the production of IL8 and activation of Matrixmetalloproteinase 7 (MMP7). This suggested that the activation of PAR2 during the menstrual phase induces a variety of local bioactive molecules and contributes to the remodeling of endometrium. 2) Uterine myometrium exhibits a spontaneous cyclic stretch/contraction even in non-pregnant women, and its magnitude and frequency peak at the menstrual phase. We hypothesized that the myometrial contraction may affect on endometrial stroma adjacent to the myometrium and contribute to the endometrial remodeling. Cyclic stretch induced the production of IL8, Groα in cultured endometrial stromal cells and promoted neutrophil migration. Production of activin and activation of MMP1 were also induced by cyclic stretch. These findings indicated that the physiological stimulus (myometrium contraction) affects on the endometrium and it is transmitted into bioactive molecules that contribute to the endometrial remodeling. 3) Angiogenin is a potent angiogenic factor which can proliferate vascular endothelial cells and induce their tube formation. We found that angiogenin is expressed in both endometrial epithelial and stromal cells and the expression is increased during the decidualization. In vitro deciualization for endometrial stromal cells also induced the expression of angiogenin. In addition to the hormonal stimuli, hypoxic condition also induced the production of antiogenin in both endometrial epithelial and stromal cells. These findings suggest that not only ovarian steroid but also oxygen tension controls angiogenin expression and this angiogenic factor regulates the endometrial angiogenesis in a spatiotemporal manner. 4) Implantation is characterized as an 'inflammation-like event' which entails local expression of inflammatory molecules such as IL1β. This inflammation, however, should be finely regulated and excess inflammation rather results in implantation failure. We hypothesized that decidualizaion may control the inflammation spatiotemporally. Treatment of endometrial stromal cells with IL1β provoked an activation of p38MAPK, which results in the expression of inflammatory molecules such as IL8, TNFα, MCP1 and COX2. Decidualization of stromal cells induced PKA activation and this activation inhibited the IL1β-induced p38MAPK activation. Collectively, we found that during and after implantation, the endometrial decidualization has a regulatory effect of inflammation by inducing PKA activation and that control p38MAPK activation.
2010-11-01

(1)新規生理活性物質・物理的刺激による子宮内膜の時間的・空間的機能調節(シンポジウム2「子宮内膜の機能調節とその病態」,第62回日本産科婦人科学会・学術講演会)

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