Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Diego, California 92103
HYPOXIC PULMONARY VASOCONSTRICTION
(HPV) serves as an important regulatory mechanism to match perfusion to
ventilation by directing blood flow away from poorly ventilated regions
of the lung to ensure maximal oxygenation of the venous blood.
Persistent HPV, however, causes pulmonary hypertension that may lead to
right heart failure in patients with obstructive pulmonary diseases and
congenital heart defects as well as in dwellers residing in high-altitude areas. The cellular and molecular mechanisms involved in
HPV have been extensively investigated since 1876 when HPV was first
observed, but the precise sequence of events by which hypoxia causes
pulmonary vasoconstriction is still unclear. The observations
that hypoxia causes vasoconstriction in endothelium-denuded pulmonary artery (PA) rings (29, 48, 60) and induces
contraction in single PA smooth muscle cells (SMCs) (28, 34, 55,
62) suggest that HPV is an intrinsic property of the pulmonary
vasculature and that the mechanism of HPV involves direct oxygen
sensing by PASMCs. The full in vivo expression of HPV, however, might
involve an interaction of PASMCs with the endothelium (23,
48).
A rise in cytoplasmic free Ca2+ concentration
([Ca2+]cyt) in PASMCs is a major trigger for
pulmonary vasoconstriction. [Ca2+]cyt is
increased by Ca2+ influx through Ca2+-permeable
channels in the plasma membrane and/or by Ca2+ mobilization
from intracellular Ca2+ stores (e.g.,
sarcoplasmic/endoplasmic reticulum). There are at least three classes
of Ca2+-permeable channels in PASMCs: 1)
voltage-dependent Ca2+ channels (VDCCs), 2)
receptor-operated Ca2+ channels, and 3)
store-operated Ca2+ channels. By governing Ca2+
influx via VDCCs, the membrane potential (Em)
plays a critical role in regulating [Ca2+]cyt
and vascular tone (35). One of the well-defined mechanisms in eliciting HPV involves the membrane depolarization-mediated opening
of VDCCs, which subsequently increases
[Ca2+]cyt in PASMCs and induces pulmonary
vasoconstriction (18, 27). Indeed, blockade of
Ca2+ channels with nifedipine and verapamil inhibits and
removal of external Ca2+ abolishes the hypoxia-induced
pulmonary vasoconstriction and contraction in single PASMCs (28,
32, 51, 60). In contrast, activation of VDCCs with BAY K 8644 potentiates HPV (31).
The Em is primarily controlled by activity of
the Na+-K+-ATPase and K+ channels
in the plasma membrane. A decrease in K+ currents through
plasmalemmal K+ channels (due to blockade of the
channel conductance and/or downregulation of the channel expression)
causes membrane depolarization, whereas an increase in K+
currents causes membrane hyperpolarization. Functionally,
K+ channels are classified into five families:
1) voltage-gated K+ (KV) channels,
2) Ca2+-activated K+ channels,
3) ATP-sensitive K+ channels, 4)
inward rectifier K+ channels, and 5)
voltage-insensitive background K+ channels (20,
22). When based on molecular structure, K+ channels
are categorized into three families: 1) channels with one-pore and six-transmembrane domains (e.g., KV and
Ca2+-activated K+ channels), 2)
channels with one-pore and two-transmembrane domains (e.g.,
ATP-sensitive K+ and inward rectifier K+
channels), and 3) channels with two-pore and
four-transmembrane domains [e.g., voltage-insensitive background
K+ channels, like weakly inward rectifying K+
channels (TWIK)] (20, 22).
Transmembrane K+ current through KV channels
[IK(V)] is thought to primarily determine the
level of Em in PASMCs (13, 44, 58).
Thus Em is directly related to the level of
whole cell IK(V), which is determined by
IK(V) = N × i × Po, where N is
the number of membrane KV channels, i is the
single-channel KV current, and Po is
the steady-state open probability of the KV channel. When
KV channels close (i or
Po is decreased) or KV channel
expression declines (N is decreased),
Em becomes less negative and depolarization occurs as a result of decreased whole cell
IK(V). When KV channels open
(i or Po is increased) or
KV channel expression rises (N is increased),
the Em becomes more negative and
hyperpolarization occurs as a result of increased
IK(V). Due to the important role of
K+ channel activity in regulating the
Em, [Ca2+]cyt, and
vascular tone, McMurtry et al. (33) proposed almost 20 years ago that HPV might be induced by inhibition of membrane K+ channels.
In 1988, Lopez-Barneo et al. (24) first described a
hypoxia-inhibited K+ current in rabbit carotid body
chemoreceptor cells, which provoked many investigators to study the
effect of hypoxia on K+ currents in PASMCs. Several years
later, Post et al. (45) and Yuan et al. (59)
provided direct evidence that acute hypoxia did indeed decrease
K+ currents and caused membrane depolarization in PASMCs
isolated from canines and rats. Since then, there have been many
studies attempting to characterize the electrophysiological
properties and specify the molecular identities of the so-called
oxygen-sensitive K+ channels in oxygen-sensitive cells such
as carotid body chemoreceptor cells (26), central neurons
(17), pulmonary neuroepithelial cells (15, 36,
53), pheochromocytoma (PC12) cells (5, 6), and
PASMCs (1-3, 19, 37, 38, 40, 43, 44, 49, 50, 54, 59).
Based on what we know so far, KV channels appear to be a
top candidate as the oxygen-sensitive K+ channels in PASMCs
(1-3, 19, 37, 38, 40, 43, 44, 49, 50, 54, 59),
although other types of K+ and Ca2+ channels
are also regulated by hypoxia (17, 25, 41).
At the molecular level, KV channels are heteromeric or
homomeric tetramers composed of the pore-forming
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-subunits and the cytoplasmic regulatory (auxiliary)
-subunits (20).
Using RT-PCR and immunoblot analyses, investigators have identified a
number of KV channel
- and
-subunits expressed in
isolated pulmonary arteries and in PASMCs from humans and animals
(e.g., rat, rabbit, canine, and cow; Table
1) (3, 7-9, 19, 38, 40, 52, 61). Characterization of cloned KV channels
indicates that the native KV channels are most likely
heteromultimers formed by both
- and
-subunits in a 1:1 molar
ratio. In other words, each
-subunit associates with a
-subunit
to form
4
4 heteromultimers in native Shaker-related KV channels (39).
The KV channel
-subunits tightly bind to the cytoplasmic
side of the
-subunits through an NAB domain (57). The
major function of the
-subunits when associated with the
-subunits includes conferring rapid inactivation onto the non- or
slowly inactivating KV channel
-subunits (e.g., Kv1.1, Kv1.2, and Kv1.5) (46) and blocking the
-subunits as an
open channel blocker (10). Which of these KV
channel
- and/or
-subunits form the oxygen-sensitive
KV channels in vivo that are responsible for HPV has been
studied extensively during last 5 years.
Table 1.
KV channel - and
-subunits expressed in pulmonary
vasculature and channels potentially involved in oxygen sensing
A number of studies have been focused to determine the sensitivity to
hypoxia of the channels formed by recombinant KV channel subunits in heterologous expression systems, including
Xenopus oocytes, mouse L-cell line, Chinese hamster ovary
cells, rat adrenal PC12 cells, COS-7 cells, and HEK-293 cells (7,
25). The potential candidates of the KV channel
-subunits that could form oxygen-sensitive, homomeric, or
heteromeric channels have been demonstrated to include Kv1.2 (5,
19), Kv1.5 (2, 3), Kv1.2/Kv1.5 (19),
Kv2.1 (5, 25, 40), Kv2.1/Kv9.3 (19, 40),
Kv3.1b (38), Kv3.3 (24, 53), and
Kv4.2/Kv
1.2 (42) (Table 1). Acute hypoxia (<3 min)
significantly reduces the K+ currents generated by these
homomeric or heteromeric channels, and the hypoxic sensitivity of these
channels appears to be independent of the expression systems.
Furthermore, chronic exposure to hypoxia for 1-2 days has been
demonstrated to downregulate the expression of KV channel
-subunits (e.g., Kv1.1, Kv1.2, Kv1.5, Kv2.1, Kv4.3, and Kv9.3) and
reduce whole cell IK(V) in PASMCs (43, 50, 54). These observations indicate that acute (
3-min) and
chronic (
24-h) hypoxia both decrease the activity of KV
channels, likely via different mechanisms and targeting on different
channel subtypes.
In PASMCs and other oxygen-sensitive cells, hypoxia alters the redox
status as determined by the ratio of the reduced to the oxidized forms
of glutathione (GSH/GSSG) and/or nicotinamide adenine dinucleotide
phosphate (NADPH/NADP+ or NADH/NAD+) and shifts
the cells to a more reduced state (1, 56). There are
8-14 cysteine residues in each of the KV channel
-subunits (e.g., Kv1.1, Kv1.2, Kv1.5, and Kv2.1), and 5-7
cysteine residues in each of the
-subunits (e.g., Kv
1.1 and
Kv
1.2). Cysteine residues in KV channel
- and
-subunits are sensitive to redox change; therefore, both the
-
and
-subunits can be potentially regulated by the hypoxia-mediated
redox change.
Since 1992 when Parcej et al. (39) first described a
KV channel -subunit, there are at least four families of
-subunits that have been cloned and described in mammals and humans:
1) Kv
1 (Kv
1.1, Kv
1.2, and Kv
1.3), 2)
Kv
2 (Kv
2.1 and Kv
2.2), 3) Kv
3 (Kv
3.1), and
4) Kv
4 (Kv
4.1) (12, 14). Based on the
gene sequence (4, 30) and crystal structure
(16), the KV channel
-subunits are similar
to the redox-sensitive NAD(P)H-dependent oxidoreductase proteins. In
1994, Rettig et al. (46) identified a cysteine residue in
the
-subunit that is sensitive to oxidation and critical in binding
the NH2-terminal inactivating domain in the
-subunit to
the inner mouth of the channel pore formed by the
-subunits. When
the cysteine residue is reduced, the NH2-terminal inactivating domain occludes the opened channel pore and the
KV channels inactivate rapidly. In contrast, when the
cysteine residue is oxidized, the inactivating domain cannot bind to
the channel pore and the KV channels do not inactivate or
slowly inactivate (46). Thus the
-subunits have been
demonstrated to be a redox sensor, which couples cellular redox status
to KV channel function (16). Indeed,
coexpression of Kv
1.2 subunit confers oxygen sensitivity to Kv4.2 in
HEK-293 cells (42), whereas reducing agents affect
KV channel activity via the
-subunits (46).
HPV occurs predominantly in small resistance pulmonary arteries.
Therefore, if KV channel - and
-subunits are
responsible for HPV, the expression of these subunits as well as the
function of KV channels should be greater in PASMCs from
resistance pulmonary arteries than cells from conduit pulmonary
arteries. To this end, Coppock and Tamkun (8) compared the
protein expression of various KV channel
- and
-subunits between resistance and conduit bovine pulmonary
arteries using immunoblot analysis and immunohistochemistry. They found
that the protein levels of Kv1.5 (~1.5-fold) and Kv3.1b (~12-fold)
were significantly greater in PASMCs isolated from resistance pulmonary
arteries than in cells from conduit pulmonary arteries, whereas Kv2.1
protein levels were comparable. The modest overexpression of Kv1.5
in resistance PA was also confirmed with immunocytochemistry.
Interestingly, the protein expression of Kv
1.1, Kv
1.2, and
Kv
1.3 dramatically increased along the PA tree. The protein levels,
determined by Western blot analysis, of these
-subunits were three-
to sixfold greater in PASMCs isolated from the fourth division of
pulmonary arteries (with an external diameter of 1-2 mm) than
cells isolated from conduit pulmonary arteries (with an external
diameter of 25-30 mm). Immunohistochemical studies also showed a
greater protein expression of Kv
1.2 in resistance pulmonary arteries
than in conduit pulmonary arteries. The differential expression of
Kv
1.1, Kv
1.2, and Kv
1.3 suggest that the auxiliary
-subunits may play an important role in oxygen sensing in PASMCs
(8).
Using total RNA isolated from freshly dissected rat pulmonary arteries
and mesenteric arteries, Davies and Kozlowski (9) recently
found that the mRNA expression of Kv1.2, Kv1.5, Kv2.1, Kv1.1, and
Kv
2.1 was similar between small and large pulmonary arteries,
whereas the mRNA expression of Kv3.4 and Kv4.1 was significantly greater in small pulmonary arteries than in large pulmonary arteries. Furthermore, the mRNA levels of Kv1.2, Kv2.1, Kv9.2, and Kv
1.1 were
much higher in pulmonary arteries (both large and small) than in the
mesenteric arteries. Qualitative differences in KV channel
- and
-subunits in SMCs isolated from pulmonary arteries and
systemic arteries (e.g., coronary and mesenteric arteries) have
not thus far been observed, but the divergent responses of the
pulmonary and systemic vasculatures to hypoxia have been well documented. The quantitative difference in mRNA expression of Kv1.2,
Kv2.1, Kv9.2, and Kv
1.1 between pulmonary arteries and mesenteric
arteries does suggest that these channel subunits may have an important
role in HPV (although it needs to be reconciled with immunoblot
analysis). Whether these subunits form the native KV
channels that are dominantly involved in the regulation of resting
Em and why hypoxia only inhibits these homomeric
and heteromeric KV channels in PASMCs but not in systemic
arterial SMCs require further investigation.
The differential expression of KV channel -subunits
(especially Kv
1.1) in bovine PASMCs as indicated by Coppock and
Tamkun (8) may provide an explanation for the differential
hypoxic sensitivities of conduit and resistance pulmonary arteries. To confirm that the
-subunits are the oxygen sensor responsible for HPV
needs further study with the combined approaches of electrophysiology and molecular biology. The observations by Coppock and Tamkun provide
us with a new concept in searching for the oxygen sensor and strongly
suggest that the auxiliary proteins (e.g.,
-subunits) and the
chaperones (e.g., K+ channel-associated protein)
(21) of the pore-forming
-subunits as well as their
heterologous assembly with different
-subunits may play a critical
role in determining the oxygen or redox sensitivity of KV
channels in PASMCs.
Using mice lacking Kv1.5, Archer et al. (2) recently
provided compelling evidence that the -subunit was also required in
hypoxia-induced reduction of K+ currents and in HPV. They
found that deletion of the Kv1.5 gene was associated with 1)
an impaired HPV in isolated perfused lungs and in isolated PA rings,
2) a reduced sensitivity of whole cell IK(V) to hypoxia, and 3) a decreased
sensitivity of the Em to hypoxia. These
observations indicate that Kv1.5 is definitely involved in
hypoxia-induced membrane depolarization and HPV (2, 3) and
that function of the native oxygen-sensitive heteromeric KV
channels (e.g., Kv1.5/Kv1.2, Kv1.5/Kv
1.1, Kv1.5/Kv
1.2,
Kv1.5/Kv
1.3, and/or Kv1.5/Kv
3.1) in PASMCs relies on Kv1.5.
Whether Kv1.5 is the oxygen sensor per se or is an effector subunit of
an unknown oxygen sensor is still unclear and needs further investigation.
In summary, there are currently three schools of thought regarding
where and what the oxygen sensor(s) is in hypoxia-mediated regulation
of KV channels: 1) the pore-forming -subunits
per se are the oxygen sensor, 2) the auxiliary or chaperone
proteins binding to the
-subunits are the oxygen sensor, and
3) an unknown molecule or protein complex (e.g., NADPH
oxidase) senses oxygen tension and regulates the KV channel
function by affecting either the
- or
-subunits (17, 25,
53). The candidate for the oxygen sensor may be heterogeneous
and should not be limited to the different channel subunits. The oxygen
sensor responsible for HPV may include multiple membrane channels
(e.g., K+ and Ca2+ channels), membrane
receptors, NADPH oxidase (15, 53), and intracellular
organelles (e.g., mitochondria and sarcoplasmic reticulum) (11,
54). Thus the oxygen sensor in PASMCs responsible for HPV would
be better defined as an oxygen-sensing system in which multiple
"oxygen sensors" coordinate with each other and transduce hypoxic
signals to different "effectors" to ensure efficacy.
It has to be emphasized that HPV or the hypoxia-mediated increase in [Ca2+]cyt is not only due to the membrane depolarization-induced opening of VDCCs. Indeed, Robertson et al. (47) demonstrated that in rat intrapulmonary arteries, the membrane depolarization-mediated Ca2+ influx played a minor role in the transient phase I constriction of HPV and was not involved in the sustained phase II constriction. Under physiological conditions, the transmural pressure and oxygen tension in different segments of PA tree vary dramatically. This suggests that HPV may be caused by different mechanisms in different PA segments (e.g., conduit, resistance, and precapillary pulmonary arteries). Inhibition of KV channels (1, 37, 45, 59), mobilization of stored Ca2+ in the sarcoplasmic reticulum (11, 44), activation of voltage-independent Ca2+ channels (47), and generation of reactive oxygen species from mitochondria (55) may all participate in the development of HPV.
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ACKNOWLEDGEMENTS |
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I appreciate the helpful comments on this review by Dr. I. F. McMurtry.
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FOOTNOTES |
---|
Address for reprint requests and other correspondence: J. X.-J. Yuan, Dept. of Medicine, UCSD Medical Center, 200 W. Arbor Dr., San Diego, CA 92103-8382 (E-mail: xiyuan{at}ucsd.edu).
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