Loss of Function of Endothelin-2 Leads to Reduced Ovulation and CL Formation

Cacioppo, Joseph A.; Oh, Sang Wook; Kim, Hey Young; Cho, Jongki; Lin, Po Ching; Yanagisawa, Masashi; Ko, Che Myong

doi:10.1371/journal.pone.0096115

Cited by 30 publications

(37 citation statements)

References 56 publications

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“…Prevention of EDN2 action in rodents using EDN receptor antagonists resulted in unruptured follicles that failed to develop into corpora lutea (CL; Ko et al 2006, Palanisamy et al 2006, Cacioppo et al 2014. Consistent with the contention that EDN2 is essential for CL formation, we reported that EDN2 mRNA levels were transiently expressed immediately after ovulation, in the early, developing bovine CL.…”

Section: Introductionsupporting

confidence: 65%

“…Endothelin 2 (EDN2) is a new player in reproductive processes implicated in ovulation and corpus luteum (CL) formation (Palanisamy et al 2006, Klipper et al 2010, Cacioppo et al 2014. Prevention of EDN2 action in rodents using EDN receptor antagonists resulted in unruptured follicles that failed to develop into corpora lutea (CL; Ko et al 2006, Palanisamy et al 2006, Cacioppo et al 2014.…”

Section: Introductionmentioning

confidence: 99%

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HIF1A-dependent increase in endothelin 2 levels in granulosa cells: role of hypoxia, LH/cAMP, and reactive oxygen species

Yalu¹,

Oyesiji²,

Eisenberg³

et al. 2015

Reproduction

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Hypoxia-inducible factor 1 alpha (HIF1A) and endothelin 2 (EDN2) are transiently expressed during the same time window in the developing corpus luteum (CL). In this study, we sought to investigate the involvement of LH/cAMP, reactive oxygen species (ROS), and a hypoxia-mimetic compound (CoCl 2 ) on HIF1A expression and how it affected EDN2 levels, using transformed human granulosa cells (thGCs) and primary bovine granulosa cells (GCs). CoCl 2 elevated HIF1A protein levels in thGCs in a dose-dependent manner. Forskolin alone had no significant effect; however, forskolin and CoCl 2 together further induced HIF1A protein and EDN2 mRNA expression in thGCs. Similarly, in primary GCs, LH with CoCl 2 synergistically augmented HIF1A protein levels, which resulted in higher expression of EDN2 and another well-known hypoxia-inducible gene, VEGF (VEGFA). Importantly, LH alone elevated HIF1A mRNA but not its protein. The successful knockdown of HIF1A in thGCs using siRNA abolished hypoxia-induced EDN2 and also the additive effect of forskolin and CoCl 2 . We then examined the roles of ROS in thGCs: hydrogen peroxide (20 and 50 mM) elevated HIF1A protein as well as the expression of EDN2, implying that induction of HIF1A protein levels is sufficient to stimulate the expression of EDN2 (and VEGF) in normoxia. A broad-range ROS scavenger, butylated hydroxyanisole, inhibited CoCl 2 -induced HIF1A protein with a concomitant reduction in the mRNA expression of EDN2 and VEGF in thGCs. The results obtained in this study suggest that HIF1A, induced by various stimuli, is an essential mediator of EDN2 mRNA expression. The results may also explain the rise in the levels of HIF1A-dependent genes (EDN2 and VEGF) in the developing CL.

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Section: Introductionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

HIF1A-dependent increase in endothelin 2 levels in granulosa cells: role of hypoxia, LH/cAMP, and reactive oxygen species

Yalu¹,

Oyesiji²,

Eisenberg³

et al. 2015

Reproduction

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“…A similar expression pattern of ET2 was observed in CL of cows (Klipper et al 2010), implying a role of this peptide during luteal formation and angiogenesis. The physiological significance of ET2 in ovarian function was recently demonstrated in knockout mice, in which loss of ET2 expression resulted in impaired ovulation and luteal formation (Cacioppo et al 2014). Importantly, ET2 injection into ovaries of these animals augmented ovulation and increased expression of the cytochrome P450 side chain cleavage Luteal endothelin system in the dog enzyme (P450scc, CYP11A1) (Cacioppo et al 2014).…”

Section: Discussionmentioning

confidence: 99%

“…ET2 is the only ET that is upregulated in pre-ovulatory follicles at the time of ovulation and, as suggested for humans, rats and mice, its elevated levels might result from the hypoxic condition observed within growing follicles (Ko et al 2006, Na et al 2008, Bridges et al 2010, Choi et al 2011. The functional importance of ET2 and ETB for ovulation, CL formation and luteal P4 production was shown in mice (Palanisamy et al 2006, Cacioppo et al 2014. ETs also influence steroidogenesis through the activation of ETA (Iwai et al 1991, Tedeschi et al 1994, Kamada et al 1995, Girsh et al 1996.…”

Section: Introductionmentioning

confidence: 89%

“…It is tightly regulated by numerous locally produced mediators such as angiogenic factors (Reynolds et al 2000, Fraser & Wulff 2003, Zalman et al 2012. Among these, endothelins (ETs) play an important role in regulating many ovarian functions including vascularization, steroidogenesis, ovulation and folliculogenesis, as well as luteal regression and/or luteolysis (Apa et al 1998, Girsh & Dekel 2002, Ko et al 2006, Cacioppo et al 2014. Endothelial-derived ETs consist of three different isoforms, ET1, -2, and -3, which convey their effects through ETA and ETB receptors (Yanagisawa et al 1988, Nussdorfer et al 1999.…”

Section: Introductionmentioning

confidence: 99%

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Expression and functional implications of luteal endothelins in pregnant and non-pregnant dogs

Gram¹,

Latter²,

Boos³

et al. 2015

Reproduction

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Luteal development is regulated by many locally produced mediators, e.g., prostaglandins and angiogenic factors. However, the role and function of vasoactive factors in the canine corpus luteum (CL) remain largely unknown. Consequently, expression of the endothelin (ET) receptors-A and -B (ETA and ETB, revealing vasoconstriction and vasodilator properties respectively), the ET-converting enzyme (ECE1) and ET1, -2 and -3 were investigated in CL from non-pregnant dogs (days 5, 15, 25, 35, 45 and 65 post-ovulation), and at selected stages of pregnancy (pre-implantation, post-implantation, mid-gestation), and during normal and antigestagen-induced prepartum luteolysis/ abortion. The interrelationship between PGE2 and the ET system was investigated in PGE2-treated canine primary lutein cells from early CL. ET1 did not change significantly over time; ET2, ECE1 and ETB were elevated in early CL and were downregulated towards the mid/late-luteal phase. The prepartum increase of ET2 was significant. ET3 increased gradually, and was highest in late CL and/or at prepartum luteolysis. ETA remained constant until the late CL phase and increased only during prepartum luteolysis. ET1 was localized to the luteal cells, and ET2, ET3 and ETA to vascular endothelium. ECE1 and ETB were detected at both locations. Except for upregulated ET1 and lack of effect on ET2, antigestagen applied to mid-pregnant dogs evoked similar changes to those observed during normal luteolysis. PGE2 upregulated ETB in treated cells; ETA and ET1 remained unaffected, and ET2 decreased. A modulatory role of the ETs in canine CL, possibly in association with other factors (e.g., PGE2 and progesterone receptor), is strongly indicated.Reproduction (2015) 150 405-415

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Generation and characterization of an endothelin‐2 iCre mouse

Cacioppo

Koo

Lin

et al. 2015

Genesis

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A novel transgenic mouse line that expresses codon-improved Cre recombinase (iCre) under regulation of the Endothelin-2 gene (edn2) promoter was developed for the conditional deletion of genes in Endothelin-2 lineage cells and for the spatial and temporal localization of Endothelin-2 expression. Endothelin-2 (EDN2, ET-2, previously VIC) is a transcriptionally regulated 21 amino acid peptide implicated in vascular homeostasis, and more recently in female reproduction, gastrointestinal function, immunology, and cancer pathogenesis that acts through membrane receptors and G-protein signaling. A cassette (edn2-iCre) was constructed that contained iCre, a polyadenylation sequence, and a neomycin selection marker in front of the endogenous start codon of the edn2 gene in a mouse genome BAC clone. The cassette was introduced into the C57BL/6 genome by pronuclear injection, and two lines of edn2-iCre positive mice were produced. The edn2-iCre mice were bred with ROSA26-lacZ and Ai9 reporter mice to visualize areas of functional iCre expression. Strong expression was seen in the periovulatory ovary, stomach and small intestine, and colon. Uniquely, we report punctate expression in the corneal epithelium, the liver, the lung, the pituitary, the uterus, and the heart. In the embryo, expression is localized in developing hair follicles and the dermis. Therefore, edn2-iCre mice will serve as a novel line for conditional gene deletion in these tissues.

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Loss of Function of Endothelin-2 Leads to Reduced Ovulation and CL Formation

Cited by 30 publications

References 56 publications

HIF1A-dependent increase in endothelin 2 levels in granulosa cells: role of hypoxia, LH/cAMP, and reactive oxygen species

HIF1A-dependent increase in endothelin 2 levels in granulosa cells: role of hypoxia, LH/cAMP, and reactive oxygen species

Expression and functional implications of luteal endothelins in pregnant and non-pregnant dogs

Generation and characterization of an endothelin‐2 iCre mouse

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