Hypoxia induces cardiac malformations via A1 adenosine receptor activation in chicken embryos

Ghatpande, Satish; Billington, Charles J.; Rivkees, Scott A.; Wendler, Christopher C.

doi:10.1002/bdra.20438

Cited by 24 publications

(22 citation statements)

References 29 publications

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“…Vascular changes could Table 4 Study 2 Cesarean Section Parameters also have an impact on subsequent bone development, as vascularization of the cartilaginous anlage is necessary for the recruitment or differentiation of osteoblast precursors and the subsequent deposition of calcium to form ossified bone (Colnot and Helms, 2001;Maes et al, 2002). Alternatively, depletion of erythroblasts could lead to hypoxia, which has been shown to cause abnormal cardiovascular development and growth retardation in mouse (Wendler et al, 2007) and chick embryos (Ghatpande et al, 2008). Further investigations would be needed to determine if any of these mechanisms are responsible for artesunate-induced developmental abnormalities.…”

Section: Discussionmentioning

confidence: 97%

Sensitive periods for developmental toxicity of orally administered artesunate in the rat

White

Clark²

2008

Birth Defects Research Pt B

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The sensitive window for developmental toxicity of artesunate in the rat was identified as days 10 to 14 pc. Single oral doses produced embryolethality and similar cardiovascular and skeletal malformations as previously reported in longer term dosing experiments. These single dose treatment regimens could be useful to further investigate the mechanistic basis for artesunate-induced developmental toxicity.

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Section: Discussionmentioning

confidence: 97%

Sensitive periods for developmental toxicity of orally administered artesunate in the rat

White

Clark²

2008

Birth Defects Research Pt B

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“…Hypoxia is a common fetal stressor that can induce increased mortality, decreased BW, as well as profound abnormalities in the developing cardiovascular and other systems, and even embryogenesis in the earliest developmental stage, all as a result of restricted oxygen delivery to somatic tissues (Dzialowski et al, 2002;Rouwet et al, 2002;Chan and Burggren, 2005;Wendler et al, 2007;Ghatpande et al, 2008). However, hypoxic stress may impose quite different effects on development, depending on the timing (duration and onset) of the hypoxic bout within incubation, because different organ systems have different critical windows during which environmental perturbation will exert maximal effects (see Burggren, 1999).…”

Section: Introductionmentioning

confidence: 99%

Hypoxic level and duration differentially affect embryonic organ system development of the chicken (Gallus gallus)

Zhang

Burggren

2012

Poultry Science

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Hypoxia inhibits avian embryonic development, as well as increases embryonic mortality. However, the key organ systems affected by hypoxia, and their critical windows for development, are poorly understood. Consequently, chicken embryos were continuously exposed to 3 levels of oxygen (21, 15, or 13% O(2)) throughout d 0 to 10, d 11 to 18, or d 0 to 18 of incubation, followed by morphometric and blood physiological measurements. Hypoxia occurring early during incubation (d 0 to 10) had larger effects on embryonic mortality and organ growth than hypoxia occurring at later stages (d 10 to 18). Growth of the heart and chorioallantoic membrane was stimulated by chronic hypoxia, whereas the lung, brain, eye, liver, stomach, beak, and toes showed no disruption. Sustained hypoxia from the beginning of incubation decreased blood hemoglobin, hematocrit, and red blood cell concentration of embryos at d 10, but the values among hypoxic and normoxic groups were not significantly different at d 18. Blood partial pressure of O(2) and partial pressure of CO(2) were dependent upon incubation O(2) level at a given day of development. These results indicated that either modest hypoxia (15% O(2)) throughout development, or hypoxia at any level during the late stages (d 11 to 18), increased the heart and chorioallantoic membrane weight, which partly compensated for the detrimental effects of hypoxia on embryonic development. We conclude that the first half of embryonic development contained the critical windows for the detrimental effects of hypoxia, and the second half contained the critical windows for the compensatory response of hypoxia in key organs.

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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). 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.…”

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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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Hypoxia induces cardiac malformations via A1 adenosine receptor activation in chicken embryos

Abstract: BACKGROUND-The current understanding of the effects of hypoxia on early embryogenesis is limited. Potential mediators of hypoxic effects include adenosine, which increases dramatically during hypoxic conditions and activates A 1 adenosine receptors (A 1 ARs).

Cited by 24 publications

References 29 publications

Sensitive periods for developmental toxicity of orally administered artesunate in the rat

Sensitive periods for developmental toxicity of orally administered artesunate in the rat

Hypoxic level and duration differentially affect embryonic organ system development of the chicken (Gallus gallus)

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

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