Progestins inhibit estradiol-induced vascular endothelial growth factor and stromal cell–derived factor 1 in human endometrial stromal cells

Okada, Hidetaka; Okamoto, Rei; Tsuzuki, Tomoko; Tsuji, Shoko; Yasuda, Katsuhiko; Kanzaki, Hideharu

doi:10.1016/j.fertnstert.2011.06.048

Cited by 35 publications

(23 citation statements)

References 37 publications

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“…Although our finding with miR-200c regulation of KLF9 is the first of such validation, others reported VEGFA, FLT1, ETS1, SUZ12, PDGF, TGF-b2, and conexin43, as well as Notch pathway components, such as Jagged1 (JAG1) and mastermind-like [24][25][26][27][28][29][30]41 Because of the lack of adequate endometrial biopsies and endometrial cancer tissues, we could not determine the coexpression of VEGFA, FLT1, IKKb, and KLF9 in the same tissues; however, several studies reported their expression in human endometrium with altered or aberrant expression in endometriosis and endometrial cancer. [48][49][50][51][52][53][54][55][56][57][58] The biological significance of VEGFA and their receptors (FLT1 and VEGFR1), in various activities, including angiogenesis, is well established, including in normal endometrium throughout the menstrual cycle, dysfunctional uterine bleeding, and endometrial repair and endometrial cancer. 53,54,57 Additionally, IKKb by serving as a cofactor for activation of NFkb pathway plays a key role in regulating the expression of many proinflammatory mediators, including interleukin 8.…”

Section: Mir-200c Targets the Expression Of Zebs Vegfa Flt1 Ikkb mentioning

confidence: 99%

Endometrial miR-200c is Altered During Transformation into Cancerous States and Targets the Expression of ZEBs, VEGFA, FLT1, IKKβ, KLF9, and FBLN5

et al. 2012

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A number of microRNAs (miRNAs), including miR-200 family, are aberrantly expressed in endometriosis and endometrial cancer. Here we assessed the expression and functional aspects of miR-200c in endometrial tissues (N ¼ 52) from normal endometrial biopsies (N ¼ 15), endometrial tissues including those exposed to hormonal therapies (N ¼ 20), and grade I-III endometrial cancer (N ¼ 17). miR-200c expression was elevated in normal endometrial biopsies from mid-and late-luteal phase, and in endometrial tumors as compared to endometrial tissues from peri-and postmenopausal period (P < .05) and its pattern of temporal expression displayed an inverse relationship with the expression of ZEBs. The expression of E-cadherin (CDH1) varied, but expressed at low levels, specifically in endometrial tissues and endometrial tumors. The endometrial expression of ZEBs and CDH1 in patients who were exposed to Depo-Provera and gonadotropin-releasing hormone agonist GnRHa displayed a trend toward lower expression as compared to proliferative phase; however, treatment of Ishikawa cells with 17b-estradiol, progesterone, and medroxy progesterone acetate had modest effects on the expression of miR-200c and ZEBs without affecting CDH1 expression. Gain of function of miR-200c in Ishikawa cells repressed ZEBs, as well as VEGFA, FLT1, IKKb, and KLF9 expression at transcriptional and translational levels through direct interaction with their respective 3 0 untranslated regions and increased the rate of their proliferation. These results indicated that endometrial miR200c expression undergoes dynamic changes during transition from normal into cancerous states; possibly influenced by hormonal milieu and by targeting the expression of specific genes with key regulatory functions in cellular transformation, inflammation, and angiogenesis may influence these events during normal and disease progression.

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Section: Mir-200c Targets the Expression Of Zebs Vegfa Flt1 Ikkb mentioning

confidence: 99%

Endometrial miR-200c is Altered During Transformation into Cancerous States and Targets the Expression of ZEBs, VEGFA, FLT1, IKKβ, KLF9, and FBLN5

et al. 2012

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“…In HUVECs, Pg and MPA decreased thromboxane A2 release and enhanced prostacyclin synthase gene and protein expression in a PgR-dependent manner (Oviedo et al 2011). MPA antagonizes the E 2 stimulation of VEGF expression in human endometrial stromal cells through a mechanism of action that involves the PgR (Okada et al 2011). Using RU486 as a PgR antagonist, we obtained evidence that PgR participates in the fast action of both steroids on NO synthesis regulation, with slight differences.…”

Section: Discussionmentioning

confidence: 87%

Differential regulation of endothelium behavior by progesterone and medroxyprogesterone acetate

Cutini¹,

Campelo²,

Massheimer³

2013

Journal of Endocrinology

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Medroxyprogesterone acetate (MPA) is a synthetic progestin commonly used in hormone replacement therapy (HRT). The aim of this research was to study and compare the effect of progesterone (Pg) and MPA on the regulation of cellular events associated with vascular homeostasis and disease. Platelet adhesion to endothelial cells (ECs), nitric oxide (NO) production, and cell migration were studied using murine ECs in vitro exposed to the progestins. After 7 min of treatment, MPA significantly inhibited NO synthesis with respect to control values; meanwhile, Pg markedly increased vasoactive production. In senile ECs, the stimulatory action of Pg decreases; meanwhile, MPA maintained its ability to inhibit NO synthesis. The presence of RU486 antagonized the action of each steroid. When ECs were preincubated with PD98059 (MAPK inhibitor) or chelerythrine (protein kinase C (PKC) inhibitor) before Pg or MPA treatment, the former totally suppressed the steroid action, but the PKC antagonist did not affect NO production. In the presence of a PI3K inhibitor (LY294002), a partial reduction in Pg effect and a reversal of MPA action were detected. Using indomethacin, the contribution of the cyclooxygenase (COX) pathway was also detected. On platelet adhesion assays, Pg inhibited and MPA stimulated platelet adhesion to ECs. Under inflammatory conditions, Pg prevented platelet adhesion induced by lipopolysaccharide (LPS); meanwhile, MPA potentiated the stimulatory action of LPS. Finally, although both steroids enhanced migration of ECs, MPA exhibited a greater effect. In conclusion, the data presented in this research provide evidence of a differential regulation of vascular function by Pg and MPA.

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“…Estrogen and progesterone not only regulate the expressions of CXCL12, CXCR4, and CXCR7, but also affect CXCL12-mediated cell survival and cell growth as well as normal angiogenesis [65,[79][80][81]. Estrogen-induced production of CXCL12 is mediated by estrogen receptor-α (ERα), but not by ERβ [81].…”

Section: Role Of Steroid Hormones and Regulatory Factors In Cxcl12-mementioning

confidence: 99%

“…Furthermore, CXCL12/CXCR4 signaling can increase ER transcriptional activity and activate ERα and ERβ, which further promotes the estrogen-mediated signaling pathways [82]. However, progesterone may inhibit CXCL12-mediated signaling via downregulating the expressions of CXCL12 and CXCR4 [79,83]. Belot et al [83] proved that progesterone inhibits the migration of mast cells toward CXCL12, with an accompanying decrease in CXCR4 expression.…”

Section: Role Of Steroid Hormones and Regulatory Factors In Cxcl12-mementioning

confidence: 99%

“…Belot et al [83] proved that progesterone inhibits the migration of mast cells toward CXCL12, with an accompanying decrease in CXCR4 expression. Subsequently, Okada et al [79] and Glace et al [80] demonstrated that progesterone inhibits estrogen-induced CXCL12 expression in uterine tissue cells and endometrial stromal cells, respectively. Thus, the balance between estrogen and progesterone may result in differential expressions of CXCL12, CXCR4, and CXCR7, and further affect the physiological role of CXCL12-mediated signaling in the human placenta [65,79,81].…”

Section: Role Of Steroid Hormones and Regulatory Factors In Cxcl12-mementioning

confidence: 99%

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Insights into the mechanism of CXCL12-mediated signaling in trophoblast functions and placental angiogenesis

Wang¹,

Li²,

Zhao³

et al. 2015

ABBS

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The chemokine CXCL12 and its receptor CXCR4 are important signaling components required for human blastocyst implantation and the progression of pregnancy. Growing evidence indicates that the CXCL12/CXCR4 axis can regulate trophoblast function and uterine spiral artery remodeling, which plays a fundamental role in placentation and fetal outcome. The orphan receptor CXCR7 is also believed to partly regulate the function of the CXCL12/CXCR4 axis. Additionally, the CXCL12/ CXCR4/CXCR7 axis can enhance the cross-talk between trophoblasts and decidual cells such as uterine natural killer cells and decidual stromal cells which are involved in regulation of trophoblast differentiation and invasion and placental angiogenesis. In addition, recent studies proved that CXCL12 expression is elevated in the placenta and mid-trimester amniotic fluid of pregnant women with preeclampsia, implying that dysregulation of CXCL12 plays a role in the pathogenesis of preeclampsia. Further understanding of the regulatory mechanisms of CXCL12-mediated signaling in trophoblast functions and placental angiogenesis may help to design novel therapeutic approaches for pregnancy-associated diseases.

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Progestins inhibit estradiol-induced vascular endothelial growth factor and stromal cell–derived factor 1 in human endometrial stromal cells

Cited by 35 publications

References 37 publications

Endometrial miR-200c is Altered During Transformation into Cancerous States and Targets the Expression of ZEBs, VEGFA, FLT1, IKKβ, KLF9, and FBLN5

Endometrial miR-200c is Altered During Transformation into Cancerous States and Targets the Expression of ZEBs, VEGFA, FLT1, IKKβ, KLF9, and FBLN5

Differential regulation of endothelium behavior by progesterone and medroxyprogesterone acetate

Insights into the mechanism of CXCL12-mediated signaling in trophoblast functions and placental angiogenesis

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