Hypoxia is Important for Establishing Vascularization During Corpus Luteum Formation in Cattle

Nishimura, Ryo; Okuda, Kiyoshi

doi:10.1262/jrd.09-162e

Cited by 76 publications

(110 citation statements)

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“…PGF2α caused a reduction in blood and oxygen flow to the CL (Nett et al, 1976). Bovine luteal cells when cultured under low oxygen (3%) conditions produce higher amounts of hypoxiainducible factor I (HIF-I) protein and of total VEGF mRNA and protein (Nishimura and Okuda, 2010). Hypoxia has been shown to induce expression of HIF-I mRNA and transduction of its protein in other cell types and tissues as rat embryonic neural stem cells (Crossin, 2012), and HIF-I is a key regulator of VEGF synthesis (Ferrara, 2004).…”

Section: Discussionmentioning

confidence: 99%

The corpora lutea proangiogenic state of VEGF system components is turned to antiangiogenic at the later phase of the oestrous cycle in cows

Guzmán

Macías-Valencia

Fierro

et al. 2015

Animal

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Blood vessel expansion and reduction in the corpus luteum (CL) is regulated by the vascular endothelial growth factor (VEGF) system and linked to the maintenance of the CL. The VEGF system has both angiogenic and antiangiogenic ligands and receptors. Our objective was to evaluate the relationship between the mRNA expression of angiogenic and antiangiogenic members of the VEGF system in the CL, throughout the luteal phase of the oestrous cycle in cows. The CL of 18 cows were collected by transvaginal surgery on days 4, 6, 9, 12, 15 and 18 of the oestrous cycle and the mRNA expression of VEGF system components was evaluated by quantitative real-time PCR. The mRNA expression of VEGF ligands and receptors increased (P < 0.05) from the early-and mid-luteal phase (days 4 to 12) reaching its maximum expression on day 15 of the cycle. We found no expression of VEGF164b throughout the cycle. Expression of sVEGFR1 did not change during the oestrous cycle and exceeded that of the VEGFR1 by 100 times. Nonetheless, as VEGFR1 increased, the relationship between the soluble and membrane receptor decreased (P < 0.01). In contrast, the expression of VEGFR2 was higher than that of its soluble isoform for all days studied, however, the ratio between the membrane-bound and its soluble counterpart decreased continuously throughout the cycle (P < 0.01). Our results show that the expression levels for VEGF ligands, receptors and their antagonistic counterparts are adjusted during CL development and regression, to upregulate angiogenesis early in the oestrous cycle and restrict it at the time of luteolysis.

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Section: Discussionmentioning

confidence: 99%

The corpora lutea proangiogenic state of VEGF system components is turned to antiangiogenic at the later phase of the oestrous cycle in cows

Guzmán

Macías-Valencia

Fierro

et al. 2015

Animal

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“…Immunostaining shows that HIF1α protein is strongly expressed in the primate early CL . In addition, HIF1α protein expression in bovine CL is higher at the early and developing luteal stages than at the other luteal stages (Nishimura and Okuda 2010). Hypoxia also induced that the expression of HIF1α protein, VEGF mRNA and protein increased under hypoxia in cultured 8 bovine developing luteal cells (Nishimura and Okuda 2010).…”

Section: Roles Of Hypoxic Signaling In Luteal Formationmentioning

confidence: 89%

“…The response to hypoxia is important pathologically in the ischemic tissues, and is important physiologically in the process of embryo development in organ formation Wenger 2002;Bruick 2003;Wiesener and Maxwell 2003;Lee et al 2004; 11 Hellwig-Burgel et al 2005;Chen et al 2009;Dunwoodie 2009). We have previously suggested that hypoxia plays roles in both life (luteal formation) (Nishimura and Okuda 2010) and death (luteal regression) (Nishimura et al 2008) of CL. In the formation of CL, hypoxia induces angiogenesis (Nishimura and Okuda 2010), whereas it decreases P4 synthesis (Nishimura et al 2006) and promotes apoptosis during regression of the CL (Nishimura et al 2008).…”

Section: Discussionmentioning

confidence: 99%

“…We have previously suggested that hypoxia plays roles in both life (luteal formation) (Nishimura and Okuda 2010) and death (luteal regression) (Nishimura et al 2008) of CL. In the formation of CL, hypoxia induces angiogenesis (Nishimura and Okuda 2010), whereas it decreases P4 synthesis (Nishimura et al 2006) and promotes apoptosis during regression of the CL (Nishimura et al 2008). These ideas are summarized in Figure 4.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, HIF1α protein expression in bovine CL is higher at the early and developing luteal stages than at the other luteal stages (Nishimura and Okuda 2010). Hypoxia also induced that the expression of HIF1α protein, VEGF mRNA and protein increased under hypoxia in cultured 8 bovine developing luteal cells (Nishimura and Okuda 2010). During the peri-ovulatory period, the blood flow to the ovary is low (Wise et al 1982).…”

Section: Roles Of Hypoxic Signaling In Luteal Formationmentioning

confidence: 94%

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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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Activation of NF‐κB signaling pathway during HCG‐induced VEGF expression in luteal cells

Zhang

Huang

Zhang

et al. 2019

Cell Biology International

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Vascular endothelial growth factor (VEGF) plays an essential role in luteal angiogenesis, the present study therefore utilized luteal cells cultured in vitro to further investigate the activation and contribution of nuclear factor (NF)‐κB to VEGF expression induced by human chorionic gonadotrophin (HCG). The present results showed HCG induced VEGF expression as well as hypoxia‐inducible factor (HIF)‐1α mRNA and protein expressions, which was blocked by NF‐κB inhibitor pyrrolidine dithiocarbamate (PDTC). Further analysis found that these increases of VEGF and HIF‐1α mRNA induced by HCG were also blocked by NF‐κB siRNA transfection, which was consistent with PDTC treatment. However, HIF‐1α siRNA treatment significantly decreased HCG induced‐VEGF expression with no effect on NF‐κB mRNA expression. Furthermore, combination of HIF‐1α siRNA and PDTC treatment did not further decrease VEGF mRNA expression, and the result of chromatin immunoprecipitation indicated NF‐κB may regulate HIF‐1α transcription through binding with its promoter. Taken together, the present results clearly demonstrated that NF‐κB was activated to regulate VEGF expression by increasing HIF‐1α transcription in luteal cells treated with HCG. Therefore, the present study provided a new and important mechanism of luteal angiogenesis during the formation of corpus luteum in mammals.

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Hypoxia is Important for Establishing Vascularization During Corpus Luteum Formation in Cattle

Cited by 76 publications

References 39 publications

The corpora lutea proangiogenic state of VEGF system components is turned to antiangiogenic at the later phase of the oestrous cycle in cows

The corpora lutea proangiogenic state of VEGF system components is turned to antiangiogenic at the later phase of the oestrous cycle in cows

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

Activation of NF‐κB signaling pathway during HCG‐induced VEGF expression in luteal cells

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