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

2016 ◽  
Vol 28 (10) ◽  
pp. 1479 ◽  
Author(s):  
Ryo Nishimura ◽  
Kiyoshi Okuda
Keyword(s):  
Ovarian Function ◽  
Hypoxia Inducible Factor ◽  
Follicular Development ◽  
Pituitary Hormones ◽  
Multiple Roles ◽  
Angiogenic Factor ◽  
Hypoxic Conditions ◽  
Progesterone Synthesis ◽  
Oxygen Conditions ◽  
Endothelial Growth Factor

There is increasing interest in the role of oxygen conditions in the microenvironment of organs because of the discovery of a hypoxia-specific transcription factor, namely hypoxia-inducible factor (HIF) 1. Ovarian function has several phases that change day by day, including ovulation, follicular growth and corpus luteum formation and regression. These phases are regulated by many factors, including pituitary hormones and local hormones, such as steroids, peptides and cytokines, as well as oxygen conditions. Hypoxia strongly induces angiogenesis because transcription of the potent angiogenic factor vascular endothelial growth factor (VEGF) is regulated by HIF1. Follicular development and luteal formation are accompanied by a marked increase in angiogenesis assisted by HIF1–VEGF signalling. Hypoxia is also one of the factors that induces luteolysis by suppressing progesterone synthesis and by promoting apoptosis of luteal cells. The present review focuses on recent studies of hypoxic conditions, as well as HIF1-regulated genes and proteins, in the regulation of ovarian function.

scholarly journals The effect of alpha-v integrin inhibition on the malignant characteristics of medulloblastoma

2013 ◽  
Vol 11 (1) ◽  
pp. 60-67 ◽  
Author(s):  
Eric M. Thompson ◽  
Nathaniel L. Whitney ◽  
Y. Jeffrey Wu ◽  
Edward A. Neuwelt
Keyword(s):  
Cell Proliferation ◽  
Cell Lines ◽  
Stress Responses ◽  
Hypoxia Inducible Factor ◽  
Aggressive Phenotype ◽  
Hypoxic Conditions ◽  
Oxygen Conditions ◽  
Cellular Stress Responses ◽  
Dose Dependent Decrease ◽  
And Migration

Object Hypoxia induces an aggressive phenotype in some brain tumors in part due to hypoxia-inducible factor–1α (HIF-1α) and integrin expression. The importance of hypoxia in medulloblastoma is unclear and the interaction of HIF-1α and c-Myc in medulloblastoma has not been explored. The objective of this study was to determine if hypoxia induces an aggressive phenotype in human medulloblastoma cells that constitutively express high (D283 Med) or low (DAOY) levels of c-Myc and to determine if blocking αv integrins with the monoclonal antibody intetumumab inhibits hypoxia-induced cellular stress responses. Methods Cells were grown at 21% and 1% O2 and in the presence or absence of intetumumab. Measures of malignancy evaluated included cell proliferation, cell migration, and expression of vascular endothelial growth factor (VEGF), αv integrins, HIF-1α, and c-Myc. Results Both cell lines robustly expressed αv integrins. Hypoxic DAOY cells showed significantly increased proliferation compared with normoxic controls (p < 0.05), whereas D283 Med cells did not. Both cell lines exhibited a dose-dependent decrease in proliferation when treated with intetumumab (p < 0.05). Hypoxia did not increase DAOY migration, but intetumumab significantly inhibited migration at both oxygen conditions (p < 0.05). Intetumumab significantly decreased VEGF levels in DAOY cells at both oxygen conditions (p < 0.05) and in normoxic D283 cells (p < 0.01). Neither cell line demonstrated increased HIF-1α expression in response to hypoxia. However, hypoxic D283 Med cells grown in the presence of intetumumab demonstrated significantly decreased c-Myc expression (p < 0.05). Conclusions Hypoxia did not clearly induce a more aggressive phenotype in medulloblastoma cells. Despite this result, intetumumab decreased medulloblastoma cell proliferation and migration and variably decreased VEGF and c-Myc expression in hypoxic conditions. Targeting αv integrins represents a promising potential adjuvant modality in the treatment of medulloblastoma, particularly subtypes that metastasize and overexpress VEGF and c-Myc.

scholarly journals A Fairy Chemical Suppresses Retinal Angiogenesis as a HIF Inhibitor

Biomolecules ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1405
Author(s):  
Deokho Lee ◽  
Yukihiro Miwa ◽  
Jing Wu ◽  
Chiho Shoda ◽  
Heonuk Jeong ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Inhibitory Effect ◽  
Retinal Neovascularization ◽  
Vascular Endothelial ◽  
Vegf Mrna ◽  
Oxygen Induced Retinopathy ◽  
Hypoxic Conditions ◽  
Chronic Therapy ◽  
Retinal Angiogenesis ◽  
Endothelial Growth Factor

Neovascular retinal degeneration is a leading cause of blindness in advanced countries. Anti-vascular endothelial growth factor (VEGF) drugs have been used for neovascular retinal diseases; however, anti-VEGF drugs may cause the development of chorioretinal atrophy in chronic therapy as they affect the physiological amount of VEGF needed for retinal homeostasis. Hypoxia-inducible factor (HIF) is a transcription factor inducing VEGF expression under hypoxic and other stress conditions. Previously, we demonstrated that HIF was involved with pathological retinal angiogenesis in murine models of oxygen-induced retinopathy (OIR), and pharmacological HIF inhibition prevented retinal neovascularization by reducing an ectopic amount of VEGF. Along with this, we attempted to find novel effective HIF inhibitors. Compounds originally isolated from mushroom-forming fungi were screened for prospective HIF inhibitors utilizing cell lines of 3T3, ARPE-19 and 661W. A murine OIR model was used to examine the anti-angiogenic effects of the compounds. As a result, 2-azahypoxanthine (AHX) showed an inhibitory effect on HIF activation and suppressed Vegf mRNA upregulation under CoCl2-induced pseudo-hypoxic conditions. Oral administration of AHX significantly suppressed retinal neovascular tufts in the OIR model. These data suggest that AHX could be a promising anti-angiogenic agent in retinal neovascularization by inhibiting HIF activation.

Bortezomib inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated repression of hypoxia-inducible factor-1

Blood ◽  
2008 ◽  
Vol 111 (6) ◽  
pp. 3131-3136 ◽  
Author(s):  
Dong Hoon Shin ◽  
Yang-Sook Chun ◽  
Dong Soon Lee ◽  
L. Eric Huang ◽  
Jong-Wan Park
Keyword(s):  
Multiple Myeloma ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Hypoxia Inducible Factor ◽  
Adaptation To Hypoxia ◽  
Vascular Endothelial ◽  
Transactivation Domain ◽  
Tumor Cell Death ◽  
Hypoxic Conditions ◽  
Endothelial Growth Factor

Abstract Bortezomib (PS-341), a proteasome inhibitor, has been examined clinically for the treatment of multiple myeloma and several solid tumors. Bortezomib directly induces tumor cell death and has also been reported to inhibit tumor adaptation to hypoxia by functionally inhibiting hypoxia-inducible factor-1α (HIF-1α). However, the mechanism underlying HIF-1 inhibition by bortezomib remains obscure. In the present study, we demonstrated that bortezomib attenuated the hypoxic induction of erythropoietin and vascular endothelial growth factor at subnanomolar concentrations in multiple myeloma and liver cancer cell lines, regardless of cytotoxic concentrations of bortezomib. Bortezomib repressed HIF-1α activity by inhibiting the recruitment of p300 coactivator. Specifically, bortezomib targeted HIF-1α C-terminal transactivation domain (CAD) but not the CAD lacking Asn803, which is a hydroxylation site by the factor inhibiting HIF-1 (FIH). Accordingly, this effect of bortezomib on CAD was augmented by FIH expression and abolished by FIH knock-down. Furthermore, bortezomib stimulated the interaction between CAD and FIH under hypoxic conditions, and FIH inhibition reversed the suppressions of erythropoietin and vascular endothelial growth factor by bortezomib. We propose that the mechanism underlying the inhibitory effects of bortezomib on tumor angiogenesis and hypoxic adaptation involves the repression of HIF-1α transcriptional activity by reinforcing the FIH-mediated inhibition of p300 recruitment.

scholarly journals RSUME is implicated in HIF-1-induced VEGF-A production in pituitary tumour cells

2011 ◽  
Vol 19 (1) ◽  
pp. 13-27 ◽  
Author(s):  
B Shan ◽  
J Gerez ◽  
M Haedo ◽  
M Fuertes ◽  
M Theodoropoulou ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Hypoxia Inducible Factor ◽  
Pituitary Tumour ◽  
Mrna Levels ◽  
Human Pituitary ◽  
Human Pituitary Adenoma ◽  
Protein Levels ◽  
Hypoxic Conditions ◽  
Adaptive Processes ◽  
Endothelial Growth Factor

The recently cloned small RWD-domain containing protein RSUME was shown to increase protein levels of hypoxia-inducible factor-1α (HIF-1α). The latter is the oxygen-regulated subunit of HIF-1, the most important transcription factor of the cellular adaptive processes to hypoxic conditions. It is also a major regulator of vascular endothelial growth factor-A (VEGF-A), which is critically involved in the complex process of tumour neovascularisation. In this study, the expression and role of RSUME in pituitary tumours was studied. We found that RSUME mRNA was up-regulated in pituitary adenomas and significantly correlated with HIF-1α mRNA levels. Hypoxia (1% O2) or treatment with hypoxia-mimicking CoCl2enhanced RSUME and HIF-1α expression, induced translocation of HIF-1α to the nuclei and stimulated VEGF-A production both in pituitary tumour cell lines and primary human pituitary adenoma cell cultures. When RSUME expression was specifically down-regulated by siRNA, the CoCl2-induced increase VEGF-A secretion was strongly reduced which was shown to be a consequence of the RSUME knockdown-associated reduction of HIF-1α synthesis. Thus, RSUME plays an important role in initiating pituitary tumour neovascularisation through regulating HIF-1α levels and subsequent VEGF-A production and may therefore be critically involved in pituitary adenoma progression.

scholarly journals Hypoxia and Dysregulated Angiogenesis in Kidney Disease

2015 ◽  
Vol 1 (1) ◽  
pp. 80-89 ◽  
Author(s):  
Shinji Tanaka ◽  
Tetsuhiro Tanaka ◽  
Masaomi Nangaku
Keyword(s):  
Kidney Disease ◽  
Adoptive Transfer ◽  
Kidney Diseases ◽  
Hypoxia Inducible Factor ◽  
Kidney Injury ◽  
Angiogenic Factor ◽  
Vegf Expression ◽  
Peritubular Capillaries ◽  
End Stage ◽  
Endothelial Growth Factor

Background: Accumulating evidence has demonstrated that renal hypoxia has a crucial role in the pathogenesis of acute kidney injury (AKI), chronic kidney disease (CKD), and AKI-to-CKD transition, ultimately culminating in end-stage kidney disease. Renal hypoxia in progressive CKD is intricately linked to persisting capillary loss, which is mainly due to dysregulated angiogenesis. Summary: In CKD, hypoxia-inducible factor (HIF) accumulates in the ischemic tubulointerstitium but fails to sufficiently stimulate angiogenic responses, partly because of blunted activation of HIF, which is best exemplified in diabetic kidney disease. In addition, vascular endothelial growth factor (VEGF) expression is downregulated, possibly because injured tubules are not able to express sufficient VEGF and inflammatory circumstances inhibit VEGF expression. The upregulation of antiangiogenic factors and the incompetence of endothelial progenitor cells (EPCs) may also play some roles in the inadequacy of capillary restoration. Administration of VEGF or angiopoietin-1 maintains peritubular capillaries in several kidney diseases; however, administration of a single angiogenic factor may lead to the formation of abnormal vessels and induce inflammation, resulting in worsening of hypoxia and tubulointerstitial fibrosis. HIF stabilization, which aims to achieve the formation of mature and stable vessels by inducing coordinated angiogenesis, is a promising strategy. Given that the effect of systemic HIF activation is highly context-dependent, further studies are needed to elucidate the precise roles of HIF in various kidney diseases. The adoptive transfer of EPCs or mesenchymal stem cells (MSCs) is a fascinating alternative strategy to restore the peritubular capillaries. Key Messages: Suppressed HIF activation and VEGF expression may be responsible for the dysregulated angiogenesis in progressive CKD. Administration of a single angiogenic factor can cause abnormal vessel formation and inflammation, leading to a detrimental result. Although further studies are warranted, HIF stabilization and adoptive transfer of EPCs or MSCs appear to be promising strategies to restore normal capillaries.

scholarly journals Transcriptome sequencing revealed differences in the response of renal cancer cells to hypoxia and CoCl2 treatment

F1000Research ◽  
2015 ◽  
Vol 4 ◽  
pp. 1518 ◽  
Author(s):  
Nadezhda Zhigalova ◽  
Artem Artemov ◽  
Alexander M. Mazur ◽  
Egor B. Prokhortchouk
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Hypoxia Inducible Factor ◽  
Low Oxygen ◽  
Human Cancer Cells ◽  
Hypoxic Conditions ◽  
Pathway Activation ◽  
Oxygen Conditions ◽  
Order Of Magnitude ◽  
Transcriptional Changes

Human cancer cells are subjected to hypoxic conditions in many tumours. Hypoxia causes alterations in the glycolytic pathway activation through stabilization of hypoxia-inducible factor 1. Currently, two approaches are commonly used to model hypoxia: an alternative to generating low-oxygen conditions in an incubator, cells can be treated with CoCl2. We performed RNA-seq experiments to study transcriptomes of human Caki-1 cells under real hypoxia and after CoCl2 treatment. Despite causing transcriptional changes of a much higher order of magnitude for the genes in the hypoxia regulation pathway, CoCl2 treatment fails to induce alterations in the glycolysis / gluconeogenesis pathway. Moreover, CoCl2 caused aberrant activation of other oxidoreductases in glycine, serine and threonine metabolism pathways.

scholarly journals Hypoxia-Inducible Factor-1 in Physiological and Pathophysiological Angiogenesis: Applications and Therapies

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Agnieszka Zimna ◽  
Maciej Kurpisz
Keyword(s):  
Growth Factor ◽  
Transcriptional Activation ◽  
Hypoxia Inducible Factor ◽  
Vascular Endothelial ◽  
Hypoxia Inducible Factor 1 ◽  
Hypoxic Conditions ◽  
Promising Target ◽  
Oxygen Sensitive ◽  
Endothelial Growth Factor ◽  
Extended Exposure

The cardiovascular system ensures the delivery of oxygen and nutrients to all cells, tissues, and organs. Under extended exposure to reduced oxygen levels, cells are able to survive through the transcriptional activation of a series of genes that participate in angiogenesis, glucose metabolism, and cell proliferation. The oxygen-sensitive transcriptional activator HIF-1 (hypoxia-inducible factor-1) is a key transcriptional mediator of the response to hypoxic conditions. The HIF-1 pathway was found to be a master regulator of angiogenesis. Whether the process is physiological or pathological, HIF-1 seems to participate in vasculature formation by synergistic correlations with other proangiogenic factors such as VEGF (vascular endothelial growth factor), PlGF (placental growth factor), or angiopoietins. Considering the important contributions of HIF-1 in angiogenesis and vasculogenesis, it should be considered a promising target for treating ischaemic diseases or cancer. In this review, we discuss the roles of HIF-1 in both physiological/pathophysiological angiogenesis and potential strategies for clinical therapy.

scholarly journals The Multiple Roles of EG-VEGF/PROK1 in Normal and Pathological Placental Angiogenesis

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Nadia Alfaidy ◽  
Pascale Hoffmann ◽  
Houssine Boufettal ◽  
Naima Samouh ◽  
Touria Aboussaouira ◽  
...  
Keyword(s):  
Multiple Roles ◽  
Angiogenic Factor ◽  
Endocrine Gland ◽  
Placental Development ◽  
Placental Angiogenesis ◽  
Trophoblastic Diseases ◽  
Potential Biomarker ◽  
Gestational Trophoblastic Diseases ◽  
Vasculogenesis And Angiogenesis ◽  
Endothelial Growth Factor

Placentation is associated with several steps of vascular adaptations throughout pregnancy. These vascular changes occur both on the maternal and fetal sides, consisting of maternal uterine spiral arteries remodeling and placental vasculogenesis and angiogenesis, respectively. Placental angiogenesis is a pivotal process for efficient fetomaternal exchanges and placental development. This process is finely controlled throughout pregnancy, and it involves ubiquitous and pregnancy-specific angiogenic factors. In the last decade, endocrine gland derived vascular endothelial growth factor (EG-VEGF), also called prokineticin 1 (PROK1), has emerged as specific placental angiogenic factor that controls many aspects of normal and pathological placental angiogenesis such as recurrent pregnancy loss (RPL), gestational trophoblastic diseases (GTD), fetal growth restriction (FGR), and preeclampsia (PE). This review recapitulates EG-VEGF mediated-angiogenesis within the placenta and at the fetomaternal interface and proposes that its deregulation might contribute to the pathogenesis of several placental diseases including FGR and PE. More importantly this paper argues for EG-VEGF clinical relevance as a potential biomarker of the onset of pregnancy pathologies and discusses its potential usefulness for future therapeutic directions.

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