Determination of hypoxic region by hypoxia marker in developing mouse embryos in vivo: A possible signal for vessel development

Lee, You Mie; Jeong, Chul‐Ho; Koo, Sunyoung; Son, Myung Jin; Song, Hyun Seok; Bae, Soo-Kyung; Raleigh, James A.; Chung, Habong; Yoo, Mi‐Ae; Kim, Kyu‐Won

doi:10.1002/1097-0177(20010201)220:2<175::aid-dvdy1101>3.0.co;2-f

Cited by 271 publications

(161 citation statements)

References 54 publications

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“…This concentration of O 2 is predicted to give a P O 2 level in the dam of between 25 and 30 mmHg (1 mmHg ϭ 133 Pa) (26). To verify that this condition induced embryonic hypoxia, we used Hypoxyprobe-1, which forms conjugates when tissue O 2 levels are Ͻ10 mmHg (27).…”

Section: Resultsmentioning

confidence: 61%

A1 adenosine receptors play an essential role in protecting the embryo against hypoxia

Wendler

Amatya

McClaskey

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Embryos can be exposed to environmental factors that induce hypoxia. Currently, our understanding of the effects of hypoxia on early mammalian development is modest. Potential mediators of hypoxia action include the nucleoside adenosine, which acts through A 1 adenosine receptors (A1ARs) and mediates adverse effects of hypoxia on the neonatal brain. We hypothesized that A 1ARs may also play a role in mediating effects of hypoxia on the embryo. When pregnant dams were exposed to hypoxia (10% O2) beginning at embryonic day (E) 7.5 or 8.5 and continued for 24 -96 h, A 1AR؉/؉ embryos manifested growth inhibition and a disproportionate reduction in heart size, including thinner ventricular walls. Yet, when dams were exposed to hypoxia, embryos lacking A 1ARs (A1AR؊/؊) had much more severe growth retardation than A 1AR؉/؉ or ؉/؊ embryos. When levels of hypoxia-inducible factor 1␣ (HIF1␣) were examined, A1AR؊/؊ embryos had less stabilized HIF1␣ protein than A1AR؉/؊ littermates. Normal patterns of cardiac gene expression were also disturbed in A1AR؊/؊ embryos exposed to hypoxia. These results show that short periods of hypoxia during early embryogenesis can result in intrauterine growth retardation. We identify adenosine and A1ARs as playing an essential role in protecting the embryo from hypoxia.cardiac ͉ heart development ͉ hypoxia-inducible factor ͉ intrauterine growth retardation

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Section: Resultsmentioning

confidence: 61%

A1 adenosine receptors play an essential role in protecting the embryo against hypoxia

Wendler

Amatya

McClaskey

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Endogenous ORPs appear to be useful as hypoxia markers in normal tissues (e.g. Lee et al, 2001), but without a good understanding of the factors that control ORP expression, heterogeneity of expression of proteins such as involucrin will limit their scope as markers of human tumour hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Evidence that involucrin, a marker for differentiation, is oxygen regulated in human squamous cell carcinomas

Azuma

et al. 2004

Br J Cancer

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The majority of hypoxic cells in squamous cell carcinomas of the head and neck and cervix express involucrin, a molecular marker for differentiation. This raises the question of whether involucrin is an oxygen-regulated protein and, if so, whether it could serve as an endogenous marker for tumour hypoxia. Consistent with oxygen regulation, involucrin protein was found to increase with increasing hypoxia in confluent cultures of moderately differentiated human SCC9 cells. Cells harvested at the point of confluence and exposed to graded concentrations of oxygen revealed a K m of approximately 15 mmHg for involucrin induction. This is similar to K m s for HIF1a, CAIX and VEGF. Involucrin induction showed a steep dependence on pO 2 with a transition from minimum to maximum expression occurring over less than an order of magnitude change in pO 2 . In contrast to SCC9 cells, involucrin was not induced by hypoxia in poorly differentiated SCC4 cells. It is concluded that involucrin is an oxygen-regulated protein, but that differentiation modulates its transcription status with respect to hypoxia induction.

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“…Hypoxia and HIF factors have been implicated as master regulators of cardiovascular development [41,42]. Although HIF-1 and HIF-2 may have overlapping transcriptional regulation of proangiogenic genes, transgenic mouse studies support specific activities for HIF-1 and HIF-2 in vascular development that includes stage-, cell-, and tissuespecific roles.…”

Section: Biological Roles For Hif-1 and Hif-2 In Cardiac Angiogenesismentioning

confidence: 99%

Keeping the engine primed: HIF factors as key regulators of cardiac metabolism and angiogenesis during ischemia

2007

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Myocardial ischemia, the most common cause of cardiac hypoxia in clinical medicine, occurs when oxygen delivery cannot meet myocardial metabolic requirements in the heart. This deficiency can result from either a reduced supply of oxygen (decreased coronary bloodflow) or an increased myocardial demand for oxygen (increased wall stress or afterload). Patients with stable coronary artery disease as well as patients experiencing acute myocardial infarction can experience episodes of severe ischemia. Although hypoxia is an obligatory component, it is not the sole environmental stress experienced by the ischemic heart. Reperfusion after ischemia is associated with increased oxidative stress as the heart reverts to aerobic respiration and thereby generates toxic levels of reactive oxygen species (ROS). During mild ischemia, mitochondrial function is partially compromised and substrate preferences adapt to sustain adequate ATP generation. With severe ischemia, mitochondrial function is markedly compromised and anaerobic metabolism must provide energy no matter what the cost in generation of toxic ROS adducts. Ischemia produces a variety of environmental stresses that impair cardiovascular function. As a result, multiple signaling pathways are activated in mammalian cells during ischemia/reperfusion injury in an attempt to minimize cellular injury and maintain cardiac output. Amongst the transcriptional regulators activated are members of the hypoxia inducible factor (HIF) transcription factor family. HIF factors regulate a variety of genes that affect a myriad of cellular processes including metabolism, angiogenesis, cell survival, and oxygen delivery, all of which are important in the heart. In this review, we will focus on the metabolic and angiogenic aspects of HIF biology as they relate to the heart during ischemia. We will review the metabolic requirements of the heart under normal as well as hypoxic conditions, the effects of preconditioning and its regulation as it pertains to HIF biology, the apparent roles of HIF-1 and HIF-2 in intermediary metabolism, and translational applications of HIF-1 and HIF-2 biology to cardiac angiogenesis. Increased understanding of the role of HIFs in cardiac ischemia will ultimately influence clinical cardiovascular practice.

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Determination of hypoxic region by hypoxia marker in developing mouse embryos in vivo: A possible signal for vessel development

Cited by 271 publications

References 54 publications

A1 adenosine receptors play an essential role in protecting the embryo against hypoxia

A1 adenosine receptors play an essential role in protecting the embryo against hypoxia

Evidence that involucrin, a marker for differentiation, is oxygen regulated in human squamous cell carcinomas

Keeping the engine primed: HIF factors as key regulators of cardiac metabolism and angiogenesis during ischemia

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