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Department of Medicine (Cardiology) and the Vascular Biology Group, University of Alberta, Edmonton, Alberta T6G 2B7, Canada
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Abstract |
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Introduction |
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 Top Introduction Properties of HPVO2-sensitive Kv channels: the...Oxygen sensors: the redox...ControversiesConclusionReferences |
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O2-sensing systems consist of a sensor that alters the production of a mediator in response to changes in PO2. The mediator, in turn, alters the function of one or more effectors, which ultimately mediate the physiological response of the system. Teleologically, it is optimal that the sensor monitors a variable that is rapidly modified by mild hypoxia before ATP levels decline or tissue damage occurs. O2-sensing systems maintain systemic PO2 within a tight physiological range and thus stabilize ATP production and promote survival during the periodic exposures to hypoxia that occur in most aerobic lives. Often the sensor, mediator, and effector are linked in a functional unit. This review will focus on the proposed sensing unit involved in HPV, in which the sensor is the proximal portion of the mitochondrial electron transport chain (ETC); the mediators are ETC-derived, activated O2 species (AOS); and the effectors are redox-sensitive, voltage-gated K+ channels (Kv channels). Although it is unlikely that there is a single, universal O2 sensor, there is evidence suggesting that the proximal mitochondrial ETC is involved in O2 sensing in several tissues and species. The potential contribution of a similar putative redox sensor, membrane-bound NADPH, will also be considered. In most of the O2-sensitive cardiovascular tissues, H2O2 or other AOS have been proposed as diffusible mediators. This brief review will deal with identifying the molecular mechanism of HPV, highlighting controversies where they exist. We apologize to the many authors whose work has helped shape our understanding of HPV but who were not cited because of space constraints, and we also acknowledge that other theories for the mechanism of HPV exist.
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Properties of HPV |
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TopIntroductionProperties of HPVO2-sensitive Kv channels: the...Oxygen sensors: the redox...ControversiesConclusionReferences |
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HPV is intrinsic to resistance PAs.
HPV occurs in isolated lungs, small PA rings, and even in isolated PA smooth muscle cells (SMCs; Fig. 1
). HPV is strongest in small muscular PAs (>3rd generation). Although most segments of the pulmonary circulation, including pulmonary veins, constrict in response to hypoxia, proximal PAs dilate (3).
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).
HPV is triggered by hypoxia, not anoxia.
Because of the unique location of resistance PAs, near the terminal airways and alveoli, they preferentially respond to alveolar rather than intravascular PO2. In humans, HPV onsets with inspired O2 concentrations 
12%. In vivo, HPV is uniphasic, a plateau pressure being attained within minutes that is not increased by repeated challenges or altered when hypoxic ventilation is sustained for hours. This is also true in isolated lungs perfused with blood; however, HPV increases with repeated challenges when Krebs-albumin perfusate is used.
Although HPV is modulated by numerous mediators, its core mechanism is independent of endothelial and neurohumoral factors.
Although the core mechanism of HPV is postulated to reside within PA SMCs, the magnitude of HPV is modulated by circulating mediators and the autonomic nervous system. HPV is diminished by inhibitors of the endothelin, leukotriene, or serotonin pathways and is enhanced by inhibitors of prostaglandin or nitric oxide synthesis. To date, it seems that none of these mediators is essential to HPV (for review, see Ref. 8).
Dependence on extracellular Ca.2+
HPV is inhibited by antagonists (Fig. 1C) and enhanced by agonists of the voltage-dependent, L-type Ca2+ channel (e.g., BAY K 8644; for review, see Ref. 8). Although this suggests that HPV is dependent on the influx of extracellular Ca2+, there is debate as to the relative contribution of release of intracellular Ca2+ vs. Ca2+ influx through the L-type Ca2+ channel. However, most of the reports suggesting a major role for Ca2+ release derive from studies of isolated arteries in which pretreatment with a vasoconstrictor, which might itself trigger release of Ca2+, has been used to "prime" HPV.
Hypoxia inhibits whole cell K+current in PA but not systemic arterial SMCs
Interestingly, hypoxia dilates systemic arteries (Fig. 1A) and either increases or fails to inhibit K+ current (IK) in systemic arterial SMCs (for review, see Ref. 8). However, 4-aminopyridine (4-AP) inhibits IK in SMC from both PA and renal arteries. The opposing hypoxic responses of the PA vs. systemic arteries may result either from tissue-specific differences in the O2 sensor or in the response of the K+ channels to a common redox mediator.
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O2-sensitive Kv channels: the effector mechanism of HPV |
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TopIntroductionProperties of HPVO2-sensitive Kv channels: the...Oxygen sensors: the redox...ControversiesConclusionReferences |
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). The activity of the L-type Ca2+ channel is largely regulated by membrane potential (EM), which is established by K+ channels. The more Kv inhibition occurs, the more depolarized the PA SMC, and the more opening of the L-type channels (a pathway leading to influx of extracellular Ca2+). As predicted by this hypothesis (Fig. 1G), Ca2+ channel blockers substantially reduce HPV (Fig. 1C), whereas Kv channel inhibitors, such as 4-AP, cause pulmonary vasoconstriction. Inhibitors of the large-conductance Ca2+-sensitive K+ channel (BKCa) and ATP-sensitive K+ channels (KATP) do not increase normoxic pulmonary vascular resistance in adult mammals, suggesting that these channel types do not control basal PA tone. The electrophysiology of the PA SMC parallels the hemodynamics of the pulmonary circulation, in that PA SMCs from resistance PAs depolarize in response to 4-AP but not in response to BKCa or KATP blockers (reviewed in Ref. 8).
There has recently been significant progress in establishing the molecular identity of the O2-sensitive K+ channels involved in HPV. This task is difficult because the IK is an ensemble of current conducted through many channel types. However, comparing the pharmacology of the O2-sensitive K+ current (IKvO2) with that of clonal K+ channels in expression systems has been useful in suggesting candidate O2-sensitive channels. IKvO2 in PA SMCs is slowly inactivating, 4-AP sensitive, and resistant to charybdotoxin (8). This profile tends to exclude a role for 4-AP-insensitive channels (i.e., BKCa), rapidly inactivating channels (e.g., Kv1.4 and Kv4.3), and charybdotoxin-sensitive channels (e.g., homotetrameric Kv1.2 and Kv1.6 channels). Furthermore, Kv1.2 homotetramers have a current morphology (slowly activating with run-up on repeat stimulation) quite distinct from that seen in PA SMCs and are exquisitely sensitive to charybdotoxin, suggesting that the role of Kv1.2 in HPV is most likely through its involvement in charybdotoxin-insensitive heterotetramers with Kv1.5 (for review, see Ref. 8). Kv2.1, alone or in combination with Kv9.2 
-subunits, also has a pharmacological profile and O2 sensitivity consistent with a role in HPV.
Several groups have proposed that multiple Kv channels are involved in HPV, including homo- and heterotetramers comprised of Kv1.2, Kv1.5, Kv2.1, and Kv3.1b (for review, see Ref. 8). To identify which of the clonal Kv channels accounts for HPV, we developed an immunoelectropharmacological approach to identifying the channels involved in creating the O2-sensitive IK mosaic. This approach utilized the specificity of anti-Kv channel antibodies to functionally inhibit Kv current in PA SMCs from resistance PAs. Introduction of anti-Kv2.1 or anti-Kv1.5 (but not anti-inward rectifier K+ channel antibodies) via the patch pipette technique inhibits a portion of IK and partially depolarizes EM (reviewed in Ref. 7). Kv1.5 is an appealing candidate for involvement in HPV because it is 4-AP sensitive and charybdotoxin insensitive. Furthermore, in rodents exposed to chronic hypoxia, acute HPV is selectively suppressed, whereas response to other vasoconstrictors is preserved. Loss of acute HPV persists for several days after return to normoxia and is associated with decreased Kv1.5 expression in cultured PA SMCs (18) and in vivo (data from our laboratory show reduced Kv1.5 and Kv2.1). Kv1.5 expression is also reduced in other forms of PHT. In addition, anorexigens, such as dexfenfluramine, that cause vasoconstriction and outbreaks of PHT inhibit IK (others have shown that they directly block both Kv1.5 and Kv2.1). Because pharmacological and immunologic probes lack the specificity to distinguish the contribution of candidate channels to IK, we examined the effects of targeted deletion of Kv1.5 in mice. The Kv1.5 knockout mouse displays reduced HPV (Fig. 2) and a loss of IKv1.5, a hypoxia- and 4-AP-sensitive component of IK (4). There is still residual HPV in Kv1.5 knockout mice and some O2-sensitive Kv current in their PA SMCs, perhaps reflecting contributions of other types of K+ channels.
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Oxygen sensors: the redox theory of HPV |
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TopIntroductionProperties of HPVO2-sensitive Kv channels: the...Oxygen sensors: the redox...ControversiesConclusionReferences |
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Redox potential is a measure of the relative tendency of a substance to acquire or donate electrons. In the case of mitochondrial ETC, electrons flow from electron donors, NADH and FADH, to distal electron recipients because of the dinucleotide’s more negative reduction-oxidation potential. The more negative this potential, the more likely a substance is to donate an electron. In the mitochondrial ETC, electrons flow down a potential gradient of redox potential ranging from –0.35 for NADH/NAD+ to +0.82 for O2/H2O. Physiological generation of AOS occurs during normal electron shuttling by cytochromes within the ETC. Although most of the O2 used by the mitochondrial ETC is eventually reduced to H2O, ~2% is incompletely reduced, due to single electron reductions, and yields AOS, particularly the superoxide radical.
AOS were originally thought to be too toxic to serve a physiological role, but like nitric oxide, in low amounts these species are important signaling molecules. Although AOS can be produced by xanthine oxidase, cyclooxygenase, and nitric oxide synthase, the PO2-responsive production of AOS primarily occurs in the mitochondrial ETC and several vascular oxidases, including NAD(P)H and novel vascular oxidases (NOX). Both the mitochondrial ETC and vascular oxidases generate the superoxide radical. Superoxide radical is very unstable, and its short diffusion radius makes it a poor signaling molecule; however, it is rapidly converted to the more stable and diffusible H2O2 by Mn superoxide dismutase (SOD) in the mitochondria and Cu/Zn SOD in the cytoplasm. H2O2 production is thereby still linked to PO2 and is an attractive mediator.
AOS can regulate the function of target proteins by donating electrons to highly negatively charged residues. Reduction or oxidation of the sulfhydryl groups of amino acids, such as cysteine or methionine, may cause conformational changes in the K+ channel that change channel gating and open probability. A number of other important signaling substances such as kinases and phosphatases are now also known to be redox sensitive. Therefore, AOS, whether diffusing out of mitochondria or produced by membrane-bound oxidases, can affect target proteins that control vascular tone, including Kv channels. Because the production of AOS changes rapidly in response to changes in ambient O2 within the physiological range (Fig. 3D), these molecules are attractive mediator candidates for the mechanism of HPV.
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). The concept that AOS can serve as physiological signals, rather than mediators of toxic injury, was controversial when it was initially proposed (1) and perhaps still is. Under conditions of alveolar hypoxia, production of AOS falls in proportion to the inspired O2 concentration (FiO2). The PA SMCs respond to the withdrawal of the tonic oxidant signal with redox inhibition of K+ channels (Fig. 4).
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) (2). Furthermore, unlike other drug classes, including distal ETC inhibitors, proximal ETC inhibitors (such as rotenone and antimycin A) cause PA constriction (2), carotid body activation, and the relaxation of systemic arteries and the ductus arteriosus (unpublished data; see Ref. 8 for review). Although it is tempting to explain hypoxia and metabolic inhibitor-induced pulmonary vasoconstriction on the basis of the ability of these stimuli to eventually cause ATP depletion, Buescher et al. (see Ref. 8) used nuclear magnetic resonance spectroscopy to show that ATP is preserved in isolated lungs during moderate hypoxia. Teleologically, the role of the lung as a net supplier, rather than a consumer, of O2 (in marked contrast to all other organs) may explain the unique occurrence of hypoxia-induced vasoconstriction in PAs. A third line of support for the redox theory is that AOS alter IK and vascular tone much as O2 does. There are several means by which changes in PO2 might alter the function of ion channels. In the simplest scenario, hypoxia could directly inhibit the K+ channel by a redox mechanism. Certainly, some (but not all) K+ channels can be directly (i.e., in excised patches) opened or closed by redox modulation in vitro (see Ref. 8 for review). Reducing agents, such as GSH, NADH, and dithionite, inhibit K+ channels in PA SMCs, whereas oxidants, such as diamide or GSSG, activate K+ channels (see Ref. 8 for review). However, the concept of a redox-sensitive K+ channel is also essential to hypotheses that place the O2 sensor at a distance from the Kv channel (i.e., in the mitochondrial ETC or NADPH oxidase). In both the mitochondrial and membrane oxidase sensor models, a freely diffusible electron donor or AOS, such as H2O2, signals the change in PO2 and initiates a redox modulation of the K+ channel (Fig. 4). However, this signal, by definition, requires a receptive or "redox-sensitive" Kv channel.
It is also possible that redox sensitivity may be conferred to Kv channels by coassociation of Kv -subunits with ß-subunits, smaller subunits that have significant homology to the NADPH oxidoreductases. Three ß-subunit genes (Kvß1.1, Kvß2, and Kvß3) are expressed in PA SMC. Although they can increase inactivation of Kv1.x channels or shift the activation of channels toward more negative potentials, their role in HPV is unknown. Hulme et al. (see Ref. 8) found that Kv1.2, -1.5, and -2.1/9.3 are O2 sensitive even when expressed in expression systems, presumably without ß-subunits. Another means by which Kv channels may become more O2 sensitive relates to the association between functional Kv channel -subunits and electrically nonconducting -subunits in families Kv5–9. Kv5–9 homotetramers do not conduct current; however, when associated with functional Kv channel proteins, they form heterotetramers with altered activation and inactivation properties, which may be important in conferring O2 sensitivity (e.g., the Kv2.1/9.3; see Ref. 6).
Mitochondria as O.2 sensors.
Inhibitors of the mitochondrial ETC mimic hypoxia’s effects on the carotid body (e.g., increase sinus nerve activity) and PA (cause vasoconstriction; Fig. 3). Both hypoxia and mitochondrial ETC inhibitors reduce the production of AOS in the lung, inhibit a Kv current (2), and elicit pulmonary vasoconstriction (Fig. 3D). As early as 1986, a link was proposed between mitochondrial AOS production, cellular redox status, K+ currents, and HPV (1). Subsequently, it was confirmed that inhibitors of complex I and III, but not complex IV, cause pulmonary vasoconstriction, inhibit IK, and prevent further HPV, suggesting the existence of a mitochondrial O2 sensor (2). The mitochondria generate a superoxide anion at complexes I and III that is dismutated by mitochondrial-specific MnSOD, generating the diffusible signaling molecule H2O2. Recently, another group (19) has offered supportive evidence for the role of mitochondria, with findings indicating that mitochondria complex III is important in HPV. They showed that proximal ETC blockers suppressed HPV without affecting the response to other vasoconstrictors. Their conclusions, implicating the proximal ETC in oxygen sensing, are in agreement with our hypothesis. However, they found that AOS were increased by hypoxia and ETC inhibition, whereas others found that, in the pulmonary circulation, hypoxia decreases AOS (5, 10, 14). This discrepancy may relate to the fluorescent probe they used to measure AOS, which is sensitive to nitric oxide and can itself generate AOS (see below). Inhibition of ETC function not only decreases the production of AOS but also shifts the ratio of cytosolic redox couples, such as NADH/NAD and GSH/GSSG, to a more reduced ratio (15). This "backup" of reduced substances in the cytosol occurs rapidly and at a physiologically relevant range of PO2 (15). Thus when mitochondrial electron shuttling is diminished by hypoxia, there is both less AOS production and an accumulation of the reduced form of several electron donors in the cytosol. Either or both of these interrelated redox changes could also serve an O2 sensor function.
"The NAPDH oxidase uses both flavin and heme groups to shuttle electrons from NADPH to oxygen, yielding superoxide radical."
NADPH oxidase.
NADPH oxidase, another putative source of signaling AOS for HPV, is a flavocytochrome present in phagocytes, carotid body type 1 cells, neuroepithelial bodies, PA SMCs, and endothelial cells. It includes a membrane-bound flavocytochrome containing two subunits, gp91phox and p22phox, and the cytosolic proteins p47phox and p67phox, which bind to the flavocytochrome to form the active enzyme complex (Fig. 3, A–C, and Fig. 4) (5). The NADPH oxidase uses both flavin and heme groups to shuttle electrons from NADPH to oxygen, yielding superoxide radical. NADPH oxidase produces AOS in proportion to PO2 and has been touted as a possible redox O2 sensor (14). Both NADPH and NADH oxidase, named according to their substrate preference, are present in PA SMCs. AOS formation by the NADH isoform decreases as PO2 falls and is inhibited by diphenyleneiodonium (DPI; see Ref. 8 for review). These are features consistent with the oxidase acting as a redox O2 sensor. Although DPI inhibits IK, it causes minimal vasoconstriction and inhibits HPV (see Ref. 8 for review). However, the lack of a greater constrictor effect may be because DPI is also a L-type Ca2+ channel blocker (see Ref. 8 for review). Unfortunately, DPI nonspecifically inhibits flavoprotein-containing enzymes, including NADPH oxidases, nitric oxide synthase, and complex I of the mitochondrial ETC (see Ref. 8 for review). Thus DPI is a poor tool for assessing the physiological role of NADPH oxidase in regulating vascular tone. The development of mice deficient in NADPH oxidase activity due to mutation of the X-linked gene for gp91phox provided an opportunity to study the role of NAD(P)H oxidase in HPV. Most O2-responsive cell types contain a similar form of the oxidase, containing the gp91phox component. HPV is preserved in mice lacking a functional gp91phox despite a marked reduction in AOS production in their lungs (Fig. 3, A–C) (5). This suggests that NADPH oxidases containing gp91phox are not required for HPV (5). Moreover, rotenone constriction is enhanced in these mice, consistent with the mitochondrial O2 sensor hypothesis (5). Preserved O2 sensing has also been reported in the type 1 cell of the carotid body from gp91phox knockout mice, although the O2 sensing is impaired in their neuroepithelial bodies.
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Controversies |
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TopIntroductionProperties of HPVO2-sensitive Kv channels: the...Oxygen sensors: the redox...ControversiesConclusionReferences |
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Controversies regarding the molecular identity of the redox sensor.
Vascular SMCs contain gp91phox homologs, called NOX, which also preferentially use NADPH as a substrate. NOXs are inhibited by DPI and are important sources of AOS in systemic vascular SMCs (11). However, most studies of NOX have been performed in systemic arteries and have measured AOS production in response to vasoconstrictors (e.g., angiotensin II) or mitogens (e.g., platelet-derived growth factor). There is little evidence that NOX are involved AOS production in PA SMC. It is noteworthy that angiotensin II does not cause an acute change in AOS production in mouse lungs at doses that cause vasoconstriction (5). Perhaps the predominant source of AOS differs between PAs, in which AOS may be signaling molecules serving to optimize O2 uptake from the environment, vs. systemic arteries, in which AOS may be involved in the pathogenesis of atherosclerosis (which is rare in PAs).
Effects of hypoxia and ETC inhibitors on PA SMC AOS production.
There is debate as to whether hypoxia and ETC inhibitors decrease (2, 5) or increase (19) production of AOS. As discussed in the section on mitochondrial O2 sensors, much of the controversy results from the use of 2’,7’-dichlorodihydrofluorescein diacetate (DCF), an agent that preferentially detects nitric oxide (as mentioned in the product insert) and that can itself increase generation of one of the species it is often used to detect, namely H2O2 (16). Rota et al. (16) studied DCF by using several techniques, including electron spin resonance, and concluded that "DCF cannot be used conclusively to measure superoxide or hydrogen peroxide formation in cells undergoing oxidative stress."
Controversy regarding endothelin and the mechanism of HPV.
In rats, the endothelin (ET)A-receptor antagonist BQ-123, but not the ETB-receptor antagonist BQ-788, inhibits HPV. However, the KATP antagonist glibenclamide prevents BQ-123 inhibition of HPV. Thus ET-1 reinforces HPV by suppressing compensatory, vasodilator KATP channel activity (17) and also can inhibit Kv current via a protein kinase C-dependent mechanism. Although endothelin’s role in HPV remains unclear, it may be an important mechanism in reinforcing the hypoxic response.
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Conclusion |
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TopIntroductionProperties of HPVO2-sensitive Kv channels: the...Oxygen sensors: the redox...ControversiesConclusionReferences |
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Acknowledgments |
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E. Michelakis and S. Archer are supported by the Alberta Heritage Foundation for Medical Research, the Canadian Institutes for Health Research, the Heart and Stroke Foundation of Canada, and the Canadian Foundation for Innovation.
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References |
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TopIntroductionProperties of HPVO2-sensitive Kv channels: the...Oxygen sensors: the redox...ControversiesConclusionReferences |
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-subunits in pulmonary artery smooth muscle cells. J Clin Invest 100: 2347–2353, 1997.[Web of Science][Medline]
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