The Role of Hypoxia in Development of the Mammalian Embryo

Dunwoodie, Sally L.

doi:10.1016/j.devcel.2009.11.008

Cited by 536 publications

(549 citation statements)

References 126 publications

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“…The response to cellular hypoxia in mammalian embryos is mediated by hypoxia inducible factor (HIF1) (reviewed by Dunwoodie, 2009). The HIF1α subunit of this transcription factor is rapidly degraded in normoxia (Wang et al, 1995), but it is stabilized and transported to the nucleus when cellular oxygen levels fall below 2% (Jiang et al, 1996).…”

Section: Low Oxygen Exposure Reduces Fgf Signaling In the Shfmentioning

confidence: 99%

Gestational stress induces the unfolded protein response, resulting in heart defects

et al. 2016

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Congenital heart disease (CHD) is an enigma. It is the most common human birth defect and yet, even with the application of modern genetic and genomic technologies, only a minority of cases can be explained genetically. This is because environmental stressors also cause CHD. Here we propose a plausible non-genetic mechanism for induction of CHD by environmental stressors. We show that exposure of mouse embryos to short-term gestational hypoxia induces the most common types of heart defect. This is mediated by the rapid induction of the unfolded protein response (UPR), which profoundly reduces FGF signaling in cardiac progenitor cells of the second heart field. Thus, UPR activation during human pregnancy might be a common cause of CHD. Our findings have far-reaching consequences because the UPR is activated by a myriad of environmental or pathophysiological conditions. Ultimately, our discovery could lead to preventative strategies to reduce the incidence of human CHD.

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Section: Low Oxygen Exposure Reduces Fgf Signaling In the Shfmentioning

confidence: 99%

Gestational stress induces the unfolded protein response, resulting in heart defects

et al. 2016

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“…Such changes initiate the transition from fetal to postnatal circulatory patterns, including closure of the foramen ovale and the ductus arteriosus. Closure of the ductus is directly triggered by increased oxygen tension (via prostaglandins), and many other events in the newborn are triggered by the transition to normoxia (28). Thus, we hypothesized that the transition from the intrauterine hypoxic environment to the extrauterine normoxic environment might participate in initiating the rapid changes in adrenal steroidogenesis that follow birth.…”

Section: Discussionmentioning

confidence: 99%

Potential role of increased oxygenation in altering perinatal adrenal steroidogenesis

et al. 2014

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Background: At birth, the large fetal adrenal involutes rapidly, and the patterns of steroidogenesis change dramatically; the event(s) triggering these changes remain largely unexplored. Fetal abdominal viscera receive hypoxic blood having a partial pressure of oxygen of only ~2 kPa (20-23 mm Hg); perinatal circulatory changes change this to adult values (~20 kPa). We hypothesized that transition from fetal hypoxia to postnatal normoxia participates in altering perinatal steroidogenesis. Methods: We grew midgestation human fetal adrenal cells and human NCI-H295A adrenocortical carcinoma cells in 2% O 2 , then transitioned them to 20% O 2 and quantitated steroidogenic mRNAs by quantitative PCR and microarrays. results: Transitioning fetal adrenal cells from hypoxia to normoxia increased mRNAs for 17α-hydroxylase/17,20 lyase (P450c17), 3β-hydroxysteroid dehydrogenase (3βHSD2), and steroidogenic acute regulatory protein (StAR). We repeated the protocol with NCI-H295A cells acclimated to hypoxia for 15 d, quantitating 31,255 transcripts by microarray. Using an arbitrary 1.5-fold difference, 1 d of normoxia increased 4 transcripts and decreased 56, whereas 2 d of normoxia increased 62 transcripts and decreased 105. P450c17, 3βHSD2, and StAR were ranked among the top eight increased transcripts. conclusion: These data suggest that the hypoxic/normoxic transition at birth contributes to perinatal changes in adrenal steroidogenesis.

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“…HIF1α is expressed ubiquitously, while the expression of HIF2α and HIF3α are more restricted (Chen et al 2009). HIF1α and HIF2α dimerise with HIF1β forming HIF1 and HIF2, both of which activate key transcription factors (Chen et al 2009;Dunwoodie 2009). HIF3α is found in three isoforms (HIF3α, neonatal and embryonic PAS (NEPAS) and inhibitory PAS protein (IPAS)) (Chen et al 2009;Dunwoodie 2009).…”

Section: Hypoxia-inducible Factors (Hifs)mentioning

confidence: 99%

“…HIF1α and HIF2α dimerise with HIF1β forming HIF1 and HIF2, both of which activate key transcription factors (Chen et al 2009;Dunwoodie 2009). HIF3α is found in three isoforms (HIF3α, neonatal and embryonic PAS (NEPAS) and inhibitory PAS protein (IPAS)) (Chen et al 2009;Dunwoodie 2009). HIF3α isoforms dimerise with HIF1β forming HIF3 and HIF3NEPAS (Chen et al 2009;Dunwoodie 2009).…”

Section: Hypoxia-inducible Factors (Hifs)mentioning

confidence: 99%

“…They are hetero-dimers consisting of two subunits, HIF-α and aryl hydrocarbon receptor nuclear translocator (ARNT; also called HIF1β) (Chen et al 2009). Both subunits contain basic helix-loop-helix (bHLH)-Per Arnt-Sim (PAS) domains that mediate heterodimerization and DNA binding (Dunwoodie 2009). HIF1β is constitutively expressed whereas the activity and expression of HIF1α depends on cellular oxygen concentrations Wenger 2002;Bruick 2003).…”

Section: Hypoxia-inducible Factors (Hifs)mentioning

confidence: 99%

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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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The Role of Hypoxia in Development of the Mammalian Embryo

Cited by 536 publications

References 126 publications

Gestational stress induces the unfolded protein response, resulting in heart defects

Gestational stress induces the unfolded protein response, resulting in heart defects

Potential role of increased oxygenation in altering perinatal adrenal steroidogenesis

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

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