ReviewThe role of redox changes in oxygen sensing☆
Introduction
Although all tissues are sensitive to oxygen there are a number of specialized tissues in the body that sense oxygen and serve the function of optimizing oxygen uptake and delivery. These tissues, which can be considered as the Homeostatic Oxygen System, include the carotid body, neuroepithelial bodies in the lungs (NEBs), chromaffin cells of the fetal adrenal medulla and smooth muscle cells in a variety of vessels (the ductus arteriosus and resistance pulmonary, fetoplacental and systemic arteries) (Fig. 1). In the case of the carotid body type 1 cells, NEBs or chromaffin cells, hypoxia leads to exocytosis of neurotransmitters. In the vessels, hypoxia changes tone but interestingly in opposite directions in different vessels. Hypoxia causes relaxation in the ductus arteriosus (DA) and most systemic arteries, while stimulating vasoconstriction in the resistance pulmonary and fetoplacental arteries. There are teleologic reasons why these differences are advantageous, basically in each case the effect is to enhance O2 uptake or optimize O2 delivery (Weir et al., 2005), but the physiology of these tissues is outside the scope of this review.
The effector mechanisms responsible for causing exocytosis in carotid body type 1 cells during hypoxia involve inhibition of potassium current (IK), depolarization of the cell membrane and calcium entry through the voltage-gated L-type calcium channels. In the pulmonary artery smooth muscle cells (PASMCs), in addition to inhibition of IK, hypoxia also increases calcium and reinforces hypoxic pulmonary vasoconstriction (HPV) by three redox-dependent mechanisms (1) enhancing entry through the L-type calcium channel independent of membrane depolarization (Franco-Obregon and Lopez-Barneo, 1996), (2) causing release of intracellular calcium from the sarcoplasmic reticulum and associated repletion through store-operated channels, and (3) causing calcium sensitization by activating small G proteins, such as RhoA (reviewed in Weir et al., 2008). In the DASMCs it is the shift from hypoxia to normoxia (as occurs at birth), rather than from normoxia to hypoxia, which causes inhibition of IK, release of SR calcium and calcium sensitization. If the executive mechanisms are the same, the question remains, what is different about oxygen sensing in the PASMCs and DASMCs that explains their diametrically opposite responses? In response to most stimuli, other than oxygen, the PA and DA have similar vasomotor responses; both contract when stimulated with vasoconstrictors such as phenylephrine, endothelin or potassium chloride. They both relax in response to prostaglandin E2, prostacyclin and nitric oxide. Thus there is something about PO2 which is interpreted differently by the two tissues. The Redox Hypothesis holds that changes in the reduction/oxidation balance in these specialized cells reflects changes in PO2 and changes the function of redox sensitive targets by altering the oxidation of susceptible amino acids, notably cysteines and methionines. The sensors (such as mitochondria or oxidases) are connected to the effectors (ion channels/SR/small G proteins) by signaling molecules (which include reactive oxygen species, such as hydrogen peroxide and superoxide; redox couples, such as nicotinamide adenine dinucleotide and glutathione and probably redox-sensitive enzymes, such as thioredoxin, tyrosine kinases and phosphatases). This hypothesis which dates from the early 1980s holds that there are non-energetic signals derived from mitochondria, that ROS are physiologic signaling molecules and that ion channels have a conserved role in oxygen sensing (Archer et al., 1993, Archer et al., 1986, Weir and Archer, 1995, Weir et al., 2005). One early impediment that hindered acceptance of this theory was a misconception of the structure of mitochondria. Modern imaging of mitochondria using mitochondria-targeted green fluorescent protein shows that the mitochondria permeate the PASMC much like electrical wiring and are ideally positioned to control the function of both membrane and cytosolic factors by the release of redox signaling molecules (Fig. 2).
Section snippets
Redox history
In the fetus, the pulmonary and systemic arteries are exposed to similar pressures and oxygen tensions. Yet, when a pregnant ewe is exposed to hyperbaric oxygen, fetal pulmonary vascular resistance falls dramatically (down 68%), with no change in systemic arterial pressure or resistance (Assali et al., 1968). This observation led to the concept of active, normoxic pulmonary vasodilatation (Weir, 1978). Reactive oxygen species (ROS), such as hydrogen peroxide, are known to be formed in the
Oxygen sensing in DA and PA
As mentioned before, hypoxia causes pulmonary vasoconstriction but dilatation of the DA. Both DAMSCs and PASMCs are, in redox terms, more reduced during hypoxia (Michelakis et al., 2002, Kajimoto et al., 2007). In the hypoxic fetal environment the DA is dilated and in the DAMSCs potassium channels are open. As in the AMCs, rotenone mimics hypoxia, decreasing H2O2 production but in this instance, the fall in H2O2 increases potassium current and causes relaxation (Michelakis et al., 2002b). At
Lessons from heart failure
In type 1 cells taken from the carotid body of rabbits in which heart failure (CHF) has been induced, IK is reduced (Li and Schultz, 2006). Interestingly, the inhibition of IK and the depolarization caused by hypoxia is greater in the CHF cells than in control type 1 cells. Two observations have followed. One is that angiotensin II signaling increases the sensitivity of the Kv channels to hypoxia. This reminds the reader of the priming of HPV seen with angiotensin II and other vasoconstrictors.
Pathophysiology of oxygen sensing
There are several conditions which seem to be related to abnormalities of oxygen sensing. In one example, an inherited overactive sensing of hypoxia leads to chronic hypoxic pulmonary hypertension (CHPHT) (brisket disease) (Weir et al., 1974). The important role of SOD in CHPHT, in which supplementation of SOD reduces pulmonary hypertension, has already been discussed. Perhaps related to this, is the finding of low levels of SOD in the blood of patients with acute high altitude pulmonary edema
Conclusions
The evidence that redox changes are a key link in the cascade of oxygen sensing is strong. In neonatal adrenomedullary cells and neuroepithelial bodies a decrease in H2O2 (a more reduced environment) signals the onset of hypoxia and results in a decrease in IK, calcium entry and secretion. In PASMCs the effector mechanism for hypoxia has more components, including release of intracellular calcium, activation of RhoA and activation of the L-type calcium channel unrelated to membrane potential,
Acknowledgements
This work is supported by Veterans Administration Research funding, NIH-RO1-HL65322, NIH-RO1-HL071115 and 1RC1HL099462-01, theAmerican Heart Association (AHA) and the Roche Foundation for Anemia Research.
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This paper is part of a special issue entitled “Physiological Redox: Regulation in Respiratory, Vascular, and Neural Cells”, guest-edited by Paul T. Schumacker and Jeremy P.T. Ward.