Hypoxia-Induced Signaling in the Cardiovascular System

Simon, M. Celeste; Liu, Liping; Barnhart, Bryan C.; Young, Regina M.

doi:10.1146/annurev.physiol.70.113006.100526

Cited by 60 publications

(48 citation statements)

References 99 publications

(158 reference statements)

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“…The histological specimens also suggested that tumor cells are exposed to an O 2 gradient ranging from efficient oxygenation near the stroma decreasing gradually to near anoxia bordering the necrotic regions. These varying O 2 concentrations have since been shown to have significantly different effects on cellular processes 4 .…”

Section: Early Demonstrations Of Tumor Hypoxiamentioning

confidence: 99%

The impact of O2 availability on human cancer

2008

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During the last century, it has been established that regions within solid tumors experience mild to severe oxygen deprivation, due to aberrant vascular function. These hypoxic regions are associated with altered cellular metabolism, as well as increased resistance to radiation and chemotherapy. As discussed in this Timeline, over the past decade, work from many laboratories has elucidated the mechanisms by which hypoxia-inducible factors (HIFs) modulate tumor cell metabolism, angiogenesis, growth, and metastasis. The central role played by intra-tumoral hypoxia and HTF in these processes has made them attractive therapeutic targets in the treatment of multiple human malignancies.Oxygen (O 2 ) is required for aerobic metabolism to maintain intracellular bioenergetics and serve as an electron acceptor in many organic and inorganic reactions. Hypoxia, defined as reduced O 2 levels, occurs in a variety of pathological conditions, including stroke, tissue ischemia, inflammation, and the growth of solid tumors. The beginnings of hypoxia research in tumor biology can be traced back to observations made in the early 20 th century by Otto Warburg who demonstrated that, unlike normal cells, tumor cells favor glycolysis, independent of cellular oxygenation levels. He postulated that tumor growth is caused by mitochondrial dysfunction in neoplastic cells, forcing them to generate energy through glycolysis (reviewed in 1 ). This hypothesis appears to be incorrect, but a number of other molecular mechanisms promoting "aerobic glycolysis" have been proposed including mutations and epigenetic changes in genes encoding tumor suppressors (e.g. p53), oncogene activation (e.g. c-Myc), and hypoxic adaptations {Denko, 2008 #6606; Gatenby, 2004 #6608; Deberardinis, 2008 #6609.

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Section: Early Demonstrations Of Tumor Hypoxiamentioning

confidence: 99%

The impact of O2 availability on human cancer

2008

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“…However, hypoxia-induced imbalance between O 2 supply and demand impacts gene expression, metabolism, growth, and function (13,17,20,21,33,45,48,50,53,56). Oxygen deprivation during critical periods of embryogenesis impairs heart development and function with hemodynamic disturbances resulting in fetal growth retardation and increasing the risk of cardiovascular disease in adulthood, the so-called "fetal programming" (8,12,26,38,47,57,59).…”

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confidence: 99%

A hypoxic episode during cardiogenesis downregulates the adenosinergic system and alters the myocardial anoxic tolerance

Robin

Marcillac

Raddatz

2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Robin E, Marcillac F, Raddatz E. A hypoxic episode during cardiogenesis downregulates the adenosinergic system and alters the myocardial anoxic tolerance. Am J Physiol Regul Integr Comp Physiol 308: R614 -R626, 2015. First published January 28, 2015 doi:10.1152/ajpregu.00423.2014.-To what extent hypoxia alters the adenosine (ADO) system and impacts on cardiac function during embryogenesis is not known. Ectonucleoside triphosphate diphosphohydrolase (CD39), ecto-5=-nucleotidase (CD73), adenosine kinase (AdK), adenosine deaminase (ADA), equilibrative (ENT1,3,4), and concentrative (CNT3) transporters and ADO receptors A 1, A2A, A2B, and A3 constitute the adenosinergic system. During the first 4 days of development chick embryos were exposed in ovo to normoxia followed or not followed by 6 h hypoxia. ADO and glycogen content and mRNA expression of the genes were determined in the atria, ventricle, and outflow tract of the normoxic (N) and hypoxic (H) hearts. Electrocardiogram and ventricular shortening of the N and H hearts were recorded ex vivo throughout anoxia/reoxygenation Ϯ ADO. Under basal conditions, CD39, CD73, ADK, ADA, ENT1,3,4, CNT3, and ADO receptors were differentially expressed in the atria, ventricle, and outflow tract. In H hearts ADO level doubled, glycogen decreased, and mRNA expression of all the investigated genes was downregulated by hypoxia, except for A 2A and A3 receptors. The most rapid and marked downregulation was found for ADA in atria. H hearts were arrhythmic and more vulnerable to anoxia-reoxygenation than N hearts. Despite downregulation of the genes, exposure of isolated hearts to ADO 1) preserved glycogen through activation of A1 receptor and Akt-GSK3␤-GS pathway, 2) prolonged activity and improved conduction under anoxia, and 3) restored QT interval in H hearts. Thus hypoxia-induced downregulation of the adenosinergic system can be regarded as a coping response, limiting the detrimental accumulation of ADO without interfering with ADO signaling.anoxia-reoxygenation; arrhythmias; glycogen metabolism; hypoxia; adenosine signaling LOW OXYGEN LEVEL is a prerequisite for normal embryonic and fetal growth including the cardiovascular system. However, hypoxia-induced imbalance between O 2 supply and demand impacts gene expression, metabolism, growth, and function (13,17,20,21,33,45,48,50,53,56). Oxygen deprivation during critical periods of embryogenesis impairs heart development and function with hemodynamic disturbances resulting in fetal growth retardation and increasing the risk of cardiovascular disease in adulthood, the so-called "fetal programming" (8,12,26,38,47,57,59). Maternal hypoxemia, reduction in umbilical blood flow, or placental insufficiency can rapidly lead to acute or chronic ischemia and/or hypoxia, which exacerbates ATP-derived adenosine (ADO) production. Since ADO represents an important regulator of the embryonic cardiovascular function (35), the present study focuses on the modulation of the adenosinergic system by hypoxia and its functional consequences in the d...

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“…HIF-1␣ and HIF-2␣ are the critical mediators of the hypoxia response, and they regulate both overlapping and unique transcriptional targets (47). HIF-2␣ is expressed mainly in vascular endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Activation of the VEGFR1 Chromatin Domain

Dutta

Ray

Vivian

et al. 2008

Journal of Biological Chemistry

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Angiogenesis is induced by multiple growth factors including vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2). In vascular endothelium VEGF signals through two receptor-tyrosine kinases, VEGFR1 and VEGFR2. The VEGFR1 gene encodes both a receptor-tyrosine kinase and a secreted splice variant, soluble VEGFR1. Whereas VEGFR1 is essential for vascular development, mechanisms that regulate VEGFR1 expression in endothelial cells are poorly understood. We demonstrate here that in endothelial cells, FGF2 and epidermal growth factor (EGF) signaling induce VEGFR1 mRNA expression in a combinatorial fashion. EGF/FGF2-mediated VEGFR1 induction is mediated via functional interaction of transcription factors ETS1 and HIF-2␣. Mechanistic analyses revealed that in endothelial cells EGF/FGF2 signaling induces ETS1 expression, increases HIF-2␣ protein level in absence of hypoxia, and recruits both ETS1 and HIF-2␣ to the VEGFR1 chromatin domain. Knockdown of ETS1 and HIF-2␣ by RNA interference inhibits EGF/FGF2-induced VEGFR1 expression, and loss of expression is associated with impaired RNA-polymerase II recruitment and histone modifications at the VEGFR1 promoter region. In addition, using a mouse embryonic stem cell in vitro differentiation system, we found that induction of VEGFR1 in embryoid bodies is also associated with ETS1 and HIF-2␣ recruitment to the VEGFR1 locus. These results establish an angiogenic signal-ETS1/HIF-2␣ axis that regulates the VEGFR1 chromatin domain to induce VEGFR1 transcription in endothelial cells and in differentiating embryonic stem cells.Angiogenesis involves endothelial cell differentiation, proliferation, migration, and cell adhesion, which lead to tubulogenesis to form vessels. VEGFR 2 family of receptor-tyrosine kinases is crucial for vascular development during embryogenesis as well as physiological and pathological angiogenesis (1). VEGFR1 and VEGFR2 are closely related receptor-tyrosine kinases and have both shared and specific ligands. Despite their differential kinase activation potentials, both VEGFR1 and VEGFR2 are required for normal development and angiogenesis (2, 3). Gene targeting studies demonstrate that VEGFR1

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Hypoxia-Induced Signaling in the Cardiovascular System

Cited by 60 publications

References 99 publications

The impact of O2 availability on human cancer

The impact of O2 availability on human cancer

A hypoxic episode during cardiogenesis downregulates the adenosinergic system and alters the myocardial anoxic tolerance

Activation of the VEGFR1 Chromatin Domain

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