Response To Hypoxia Proteins

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 Response To Hypoxia Proteins Background

Here is some information about tissue responses to hypoxia for your research:

Adult tissues require oxygen for aerobic respiration. The delivery of oxygen to body tissues is influenced by a host of variables, an important one of which is the partial pressure of O2 (pO2). pO2 is calculated as the percentage of inspired O2 multiplied by the barometric pressure (mmHg) (pO2elevY=%O2 x barometric pressureelevY). Thus, the pO2 of ambient air (21% O2) at atmospheric pressure at sea level (760 mmHg) is 159 mmHg (0.21 x 760 mmHg=159 mmHg).

Remarkably, eukaryotic systems are able to survive across environmental extremes of inspired pO2. Humans, for example, can survive at altitudes extending from sea level to 4000 m in the Himalayan Mountains where Tibetans have lived for centuries. Animals are also highly adaptive to hypoxic niches, whether at high-altitude or below sea level. A notable example is the subterranean mole rat (Spalax ehrenbergi), which survives underground in a hypoxic environment ~5% O2 (pO2 ~38 mmHg). The molecular modifications underlying these adaptations will be discussed in detail below.

In addition to pO2, another important determinant of oxygen delivery is the diffusion distance of O2 from the capillary network. Although each tissue has distinct oxygen and metabolic needs, this distance remains essentially constant (~100 µm). It is estimated that most tissues are subjected to pO2 of at least 20 mmHg, as it has been observed that pO2 lower than 10 mmHg results in induction of hypoxia inducible factor (HIF)-1α binding to target DNA sequences. In this discussion, hypoxia will be defined as ~1-2% O2 (pO2 ~7 mmHg), and normoxia will be defined as ~21% O2 (>3% O2 = pO2 of >20 mmHg).

Generally, normal adult tissues function under normoxic conditions, although there are a few notable exceptions. Specific regions of the thymus and bone marrow are very hypoxic (5-10 mmHg), which may facilitate maintenance of a less differentiated phenotype of immature T cells and hematopoietic stem cells, respectively. These cells have developed a glycolytic metabolism in order to survive such conditions, thus potentially minimizing the production of ROS, which are byproducts of oxidative phosphorylation. Studies using 2-nitroimidazole drugs, which form adducts with proteins and DNA at <2% O2, have led to an increase in the understanding of the role of hypoxia in developmental, physiological and pathophysiological conditions. For example, it is now estimated that the human embryo develops in an environment of 1-5% O2 (pO2 0.5-30 mmHg). The subsequent expression of HIF-1α in the embryo is required for the formation of many tissues and organs, including the heart, the placenta and the vasculature, among others. HIF-1α is also required for differentiation and migration of key cellular compartments, including trophoblasts and neural crest cells. Although the developing embryo is considered to be chronically hypoxic before complete development of the vasculature, intermittently or acutely hypoxic microenvironments may be more physiologically relevant to adult tissues and pathologies.

More precise methods for measuring tissue oxygenation have revealed the cellular microenvironment to be quite heterogeneous. Complex measurements using a combination of oxygen probes, dyes and microscopy in both normal and tumor tissues have demonstrated cyclical hypoxia of variable duration, from minutes to several hours. As reviewed by Dewhirst et al., tissue oxygenation is simply a balance between oxygen availability and tissue need. Factors such as diffusion distance, the shape and geometry of the blood vessels and flux of red blood cells all determine how well that need is met. These cycles of intermittent hypoxia seem to correlate with red cell flux, as tissue pO2 itself positively correlates with red cell flux. Inconsistent red cell flux may be due to ongoing vascular remodeling, intermittent claudication or changes in arterial pressure or oxygen-carrying capacity of the blood (hypoxemia).

Tissue responses to hypoxia must be robust and rapid given the dynamic nature of oxygen availability. Although the response to hypoxia may be tissue-type specific, there are several general outcomes following a decrease in oxygen tension. In hypoxemic hypoxia, all tissues are affected due to the global decrease in oxygen in the blood. At high altitudes, for example, the decreased availability of O2 is offset by a reduction in the affinity of hemoglobin for oxygen, thereby increasing the delivery efficiency of available oxygen. Hypoxemia results in a series of physiological/molecular changes that result in increased production of red blood cells and hemoglobin to increase the hematocrit, and sprouting of capillaries from existing blood vessels to extend the blood supply. Heart rate and breathing also increase to improve O2 delivery. Athletes commonly train at high altitudes to increase their performance by manipulating this natural process of increasing their oxygen delivery. Cellular energy production mechanisms quickly adapt to hypoxia by switching from oxidative to glycolytic metabolism and conserving ATP where possible, often by halting protein, DNA and mRNA synthesis. If the hypoxic stress is too severe, cellular necrosis and apoptosis occur, eventually resulting in organ failure. The brain is particularly susceptible to hypoxia given its large energy demands.

Hypoxia may also be limited to specific tissues as in ischemic diseases caused by atherosclerotic arterial obstruction, such as coronary artery disease and peripheral artery disease. These conditions affect a variety of cell types, including endothelial and vascular smooth muscle cells, skeletal myocytes, and cardiac myocytes. Data from our lab have shown that endothelial cells are more resistant to oxygen deprivation than skeletal myocytes, which may maintain tissue perfusion to preserve surrounding, more susceptible tissues during hypoxia. Endothelial cells (ECs) subjected to hypoxia rapidly release growth factors and inflammatory cytokines that not only protect the endothelial cell but also recruit inflammatory cells. Intercellular adhesion molecule (ICAM)-1 and other molecules specific to neutrophil attachment are increased on the endothelial cell surface. Pulmonary blood vessels constrict in hypoxic conditions, resulting in increased blood flow velocity, while systemically, vessels vasodilate to improve perfusion. Additionally, vascular smooth muscle cells (VSMC) may respond to hypoxia through increased proliferation and migration, resulting in intimal hyperplasia, or thickening of the muscular layer of the arterial wall. However, this VSMC response is thought to be mediated by ECs through secretion of various soluble growth factors. Survival of VSMCs is also prolonged in hypoxia following activation of the hypoxia-responsive gene telomerase reverse transcriptase (TERT).