The role of hypoxia-induced genes in ovarian angiogenesis

Meidan, Rina; Klipper, Eyal; Zalman, Yulia; Yalu, Ronit

doi:10.1071/rd12139

Cited by 43 publications

(48 citation statements)

References 92 publications

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“…Hypoxia is therefore an important physiological cue in the developing CL. It is well established that hypoxia plays an important role in the up-regulation of VEGF that occurs at this stage and is responsible for the angiogenic process in early CL (Tesone et al 2005, Nishimura & Okuda 2010, Meidan et al 2013). The current study shows that the hypoxia-mimetic compound elevated HIF1A protein and EDN2 mRNA levels, whereas HIF1A silencing (employed herein for the first time in GCs) reduced EDN2 expression and ablated its response to hypoxia.…”

Section: Discussionmentioning

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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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: Discussionmentioning

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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“…Thus, HIF-1α can regulate the expression of numerous target genes and play a critical role in many important biological effects, including ovarian functions (Richards et al, 1995;Luo et al, 2011;Zhang et al, 2011aZhang et al, ,b, 2012aMeidan et al, 2013;Wang et al, 2012Wang et al, , 2013Wu et al, 2012Wu et al, , 2013. Moreover, recent studies found that HIF-1α can be regulated by reproductive hormones (Luo et al, 2011;Zhang et al, 2011a,b;2012a,b;Meidan et al, 2013;Wang et al, 2012Wang et al, , 2013Wu et al, 2012Wu et al, , 2013. These studies indicate that HIF-1α is involved in follicular development in the mammalian ovary.…”

Section: Introductionmentioning

confidence: 99%

“…In female rats, 2 pituitary gonadotropin hormones, follicle-stimulating hormone (FSH) and luteinizing hormone, control reproductive cyclical events through different signaling pathways, including follicular development, maturation, rupture, and release of fertilizable oocytes (Richards et al, 1995;Luo et al, 2011;Zhang et al, 2011aZhang et al, ,b, 2012aMeidan et al, 2013;Wang et al, 2012Wang et al, , 2013Wu et al, 2012Wu et al, , 2013. The understanding of the regulatory mechanisms controlling the growth and final differentiation of a mammalian follicle has advanced exponentially, but our understanding of fundamental pathways remains incomplete during these dynamic processes.…”

Section: Introductionmentioning

confidence: 99%

Expression of hypoxia-inducible factor-1α during ovarian follicular growth and development in Sprague-Dawley rats

et al. 2015

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ABSTRACT. Hypoxia-inducible factor-1α (HIF-1α) has been identified as a transcription factor that is involved in diverse physiological and pathological processes in the ovary. In this study, we examined whether HIF-1α is expressed in a cell-and stage-specific manner during follicular growth and development in the mammalian ovaries. Using immunohistochemistry and Western blot analysis, HIF-1α expression was observed in granulosa cells specifically and was significantly increased during the follicular growth and development of postnatal rats. Furthermore, pregnant mare serum gonadotropin also induced HIF-1α expression in granulosa cells and ovaries during the follicular development of immature rats primed with gonadotropin. Moreover, we also examined proliferation cell nuclear antigen, a cell proliferation marker, during follicular growth and development and found that its expression pattern was similar to that of HIF-1α protein. Granulosa cell culture experiments revealed that proliferation cell nuclear antigen expression may be regulated by HIF-1α. These results indicated that HIF-1α plays an important role in the follicular growth and development of these 2 rat models. The HIF-1α-mediated signaling pathway may be an important mechanism regulating follicular growth and development in mammalian ovaries in vivo.

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“…Angiogenesis during luteal formation was first observed in early 1990s' (Reynolds et al 1992), and has been the subject of several reviews (Reynolds et al 1994;Redmer and Reynolds 7 1996;Reynolds et al 2000;Meidan et al 2013). VEGF, a potent angiogenic factor, has been first identified in 1989 by Ferarra and Henzel (Ferrara and Henzel 1989), and found to be related to the angiogenesis in the luteal formation in cows (Grazul-Bilska et al 1993) and in women (Kamat et al 1995).…”

Section: Roles Of Hypoxic Signaling In Luteal Formationmentioning

confidence: 99%

Multiple roles of hypoxia in ovarian function: roles of hypoxia-inducible factor-related and -unrelated signals during the luteal phase

Nishimura

Okuda

2016

Reprod. Fertil. Dev.

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Promotion of Science (JSPS). 2 Abstract.There is increasing interest in the role of oxygen conditions in the microenvironment of organs, since the discovery of a hypoxia-specific transcription factor, hypoxia-inducible factor-1 (HIF1). Ovarian function has several phases that change day by day, including ovulation, follicular growth, corpus luteum formation and regression. These phases are regulated by many factors, such as pituitary hormones and local hormones including steroids, peptides and cytokines, as well as oxygen conditions. Hypoxia strongly induces angiogenesis because transcription of a potent angiogenic factor, vascular endothelial growth factor, is regulated by HIF1. Follicular development and luteal formation are accompanied by a drastic increase of angiogenesis assisted by the HIF1-VEGF signaling. Hypoxia is also one of the factors for inducing luteolysis by suppressing progesterone synthesis and by promoting apoptosis of luteal cells. This review focuses on recent studies for hypoxic conditions as well as HIF1-regulated genes and proteins in the regulation of ovarian function. Additional keywords Hypoxia, hypoxia-inducible factor IntroductionOvarian function has several phases that change day by day, including follicular growth, ovulation, luteal formation and regression. Follicles progress to ovulation through the proliferation of granulosa and theca cells. After ovulation, the corpus luteum (CL) develops accompanied by active angiogenesis, and when conception does not occur, regresses with the 3 decrease of progesterone (P4) synthesis and apoptosis of luteal cells. During the ovarian cycle, blood flow to the ovary changes, and affects the regulation of ovarian cycles Niswender et al. 1976;Ford and Chenault 1981;Wise et al. 1982;Magness et al. 1983;Acosta et al. 2002). Changes in ovarian blood flow result in the changes in the transport of nutrients, hormones and gases, including O2 to the ovary. In cows, ovarian blood flow has been reported to decrease during luteal regression, and to be kept at low levels during luteal formation after ovulation (Wise et al. 1982). Since a dominant follicle progress to ovulation during luteal regression (McCracken et al. 1999), follicular growth before ovulation occurs in parallel with the decrease of blood flow to the ovary. Furthermore, the oxygen content in ovarian venous blood begins to decrease at the late luteal stage (Wise et al. 1982). These findings indicate that the low oxygen condition (hypoxia) caused by the decreased blood supply is a characteristic part of the ovarian environment during follicular growth, ovulation and luteal formation. as VEGF (Forsythe et al. 1996; Kimura et al. 2001), endothelial nitric oxide synthase (eNOS) (Coulet et al. 2003), and heme oxygenase-1 (HOX-1) (Lee et al. 1997). VEGF stimulates angiogenesis and increases the permeability of blood vessels (Ferrara et al. 2003). eNOS and HOX-1 generate NO and carbon monoxide, which are potent vasodilatory substances that augment perfusion of the hypoxic tissue. At the cellular leve...

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The role of hypoxia-induced genes in ovarian angiogenesis

Cited by 43 publications

References 92 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 of hypoxia-inducible factor-1α during ovarian follicular growth and development in Sprague-Dawley rats

Multiple roles of hypoxia in ovarian function: roles of hypoxia-inducible factor-related and -unrelated signals during the luteal phase

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