1 Department of Internal Medicine and 2 Department of Anesthesiology and Intensive Care Medicine, Justus-Liebig-University Giessen, 35392 Giessen, Germany
HYPOXIC PULMONARY
VASOCONSTRICTION (HPV) is an essential mechanism that matches
lung perfusion to ventilation to optimize pulmonary gas exchange (for
reviews, see Refs. 9, 28, 31). Even if early reports observed that alveolar hypoxia induces pulmonary arterial hypertension, the modern era of HPV research started with the
description of this mechanism by von Euler and Liljestrand (32) in 1946. Since then, considerable effort has been
spent to identify the cell(s) responsible for O2 sensing,
the sensor mechanism(s), and the pathway(s) of signal transduction
leading to contraction of the vascular smooth muscle cells in the
precapillary resistance vessels, which are suggested to be the
predominant site of HPV (12, 28). However, we are still
far from a complete understanding of the HPV mechanism.
From the ontogenetic point of view, HPV may better be designated as
normoxic pulmonary vasodilatation. Before birth, HPV helps to divert
blood flow away from the fetal lung through the ductus arteriosus and
thus supports the fetal circulation. Postpartum, in concert with
inflation of the lungs, the pulmonary vasculature relaxes and allows
perfusion of the pulmonary vessels.
The size of the hypoxic lung area and the duration of hypoxia are
important determinants for the characteristics of the lung vascular
response. The following categories may be differentiated: 1)
the acute hypoxic response (occurring within seconds), which matches lung perfusion to ventilation and optimizes pulmonary gas
exchange, and 2) the response to sustained or prolonged
alveolar hypoxia (developing within minutes to hours), also playing a
role in ventilation-perfusion matching and possibly leading to
3) the vascular response to generalized chronic hypoxia,
which is believed to result in extensive vascular remodeling, pulmonary
hypertension, and cor pulmonale. For all three categories, the
underlying biochemical mechanisms remain obscure.
In recent years, evidence has been provided that pulmonary arterial
smooth muscle cells themselves respond to hypoxia, thus representing
both sensor and effector cells with respect to this fundamental
stimulus. Exposure of pulmonary arterial smooth muscle cells to hypoxia
in vitro decreases K+ current through voltage-gated
K+ (KV) channels (1, 24, 43) and
membrane potential (10, 11, 24) and increases
intracellular Ca2+ concentration and myosin light chain
phosphorylation, causing contraction. (5, 6, 10, 16, 20, 24,
30, 45).
Although numerous investigations focused on the acute hypoxic response
in intact animals, isolated perfused lung models, and isolated
pulmonary arteries, comparatively few studies addressed the prolonged
(>10-15 min) vasoconstrictor response to hypoxia. Typically,
sustained hypoxia provokes an initial rapid vasoconstriction followed
by a (partial) vasodilatation and a secondary more or less pronounced
sustained pressor response. Such reactions have been reported from
studies on isolated vessels, isolated perfused lungs, and intact or
open chests of animals of several species (e.g., Refs. 3,
8, 14, 15, 22,
25, 26, 39, 41, 46). However, the magnitude and the time course of the
secondary vasoconstrictor response vary in different investigations and may also be completely absent or reversed into vasodilatation depending
on the pretone of the vessels investigated (21). Moreover, there is still debate whether the first and second vasoconstrictor responses to sustained alveolar hypoxia are regulated by identical or
independent mechanisms. This is of interest because the sustained vasoconstrictor response may lead to the vascular remodeling process characterizing chronic hypoxia such as that occurring in obstructive and restrictive lung disease and at high altitude. From a therapeutic point of view, it would be of major interest to block such processes without loss of ventilation-perfusion matching.
Against this background, the current paper by Dipp et al.
(7) in this issue of the American Journal of
Physiology-Lung Cellular and Molecular Physiology addresses the
role of intracellular Ca2+ stores for the regulation of
sustained HPV. They investigated small intrapulmonary arteries of the
rabbit challenged with hypoxia for a period of 30 min. HPV in these
vessels is composed of an initial transient vasoconstrictor phase
followed by a slowly developing increase in vascular tone (second
phase). The increase during the second phase was noted to be dependent
on the presence of endothelium and extracellular Ca2+.
However, extracellular Ca2+ was not needed for phase
1 constriction and the basal constriction during phase
2. Application of ryanodine and caffeine completely blocked the
biphasic hypoxic response. This inhibition was specific for HPV because
the vasoconstrictive reaction to KCl was still present under such
conditions. These general features were independent from precontraction
of the vessels by PGF2 Reviewing the literature shows that parts of previous investigations
(10, 13) addressing the underlying idea of this paper are
in accordance with the results of Dipp et al. (7) in this issue. However, none of the hitherto existing data are fully in line
with their findings (e.g., Refs. 3, 14,
26, 41, 46). In particular, it
is not entirely clear to date why the first and second phases of
sustained HPV are differentially affected by experimental modulation of
Ca2+ and the presence or absence of endothelium (for a
review, see Ref. 33). Obviously, there are great
variations between different investigations as to this issue (10,
33) . What is the reason for such different results? As also
discussed in the current paper by Dipp et al. (7),
variations in the experimental protocol or the impact of the anesthetic
drugs used during explantation of the lungs may partly be responsible.
For example, it has been convincingly shown that the biphasic response
is largely dependent on the degree of vessel wall pretone
(21). In addition to these suggestions, differences in
species and gender may play a major role (22, 35), which
is also true for the different experimental setups (e.g., comparison of
investigations in intact animals, isolated blood- or buffer-perfused
lungs, and isolated arteries of conductance or resistance vessel
origin). Moreover, many of the conclusions forwarded as the
mechanism(s) of HPV are dependent on inhibitor studies, with tools that
may not be specific for the hypoxic response. Thus although the paper
of Dipp et al. (7) provides an elegant concept for the
regulation of HPV, many questions remain unresolved.
Even if release of Ca2+ from intracellular stores and, in
particular, the SR is the basic mechanism of HPV, it is not clear how
oxygen partial pressure is sensed. Are the stores themselves the oxygen
sensor or is there a more remote sensor, triggering Ca2+
release by some intermediate signaling sequence? The same group from
which the paper by Dipp et al. (7) in this issue of the American Journal of Physiology-Lung Cellular and Molecular
Physiology originates very recently provided evidence for a new
concept of oxygen sensing (40). They propose that
cADP-ribosyl cyclase and cyclic ADP-ribose (cADPR) hydrolase work as
redox sensors. According to this concept, hypoxia increases Moreover, there is a body of literature favoring different sensor and
signaling mechanisms in HPV, and data supporting these alternative concepts are to be reconciled with the concept
forwarded by Dipp et al. (7).
In concept 1, KV channels have been proposed as
the primary oxygen sensors. These channels are inhibited by hypoxia,
which leads to membrane depolarization, activation of L-type
Ca2+ channels, Ca2+ influx, an increase in
intracellular Ca2+ concentration, and cell contraction.
However, it is not clear how the KV channels are gated. It
is likely that the K+ current is controlled by changes in
the cellular redox status, with mitochondrial- and/or NAD(P)H
oxidase-dependent oxygen radical formation or the ratios of redox
couples affected by mitochondrial metabolism possibly being involved
(2, 34). Alternatively, hypoxia-induced elevation in
intracellular Ca2+ levels might secondarily affect the
K+ channels, thereby inducing the hypoxia-provoked membrane
depolarization (23, 33).
In concept 2, the pulmonary oxygen sensor may be represented
by a NADH oxidoreductase, which, via superoxide, generates hydrogen peroxide (H2O2). H2O2
then stimulates guanylate cyclase to release vasodilatating cGMP. The
nitric oxide pathway synergistically contributes to cGMP synthesis via
guanylate cyclase. According to this concept, there is tonic
stimulation of cGMP formation during normoxia. Under hypoxic
conditions, release of H2O2 by the
oxidoreductase is decreased, and the subsequent loss of vasodilatation contributes to HPV (18, 19).
Concept 3 proposes a nonphagocytic (low-output) NADPH
oxidase as the oxygen sensor. The idea of NADPH oxidase as a pulmonary oxygen sensor was initially related to the work of Thomas et al. (29) and Youngson et al. (42). Investigations
by Marshall et al. (17) and investigations by our
laboratory (36, 37) suggest that this system may
paradoxically be activated during hypoxia, with a subsequent increase
in superoxide and H2O2 levels during hypoxia.
The increase in H2O2 levels then elicits
vasoconstriction by a still unidentified mechanism that may involve
hydroxyl radicals.
Recently, Chandel and Schumacker (4) proposed mitochondria
as cellular oxygen sensors as concept 4. They provided
evidence that the hypoxic signal is transduced by a hypoxic blockade of mitochondrial electron transport distal of complex III and a subsequent rise in superoxide levels during hypoxia. Although this concept was
primarily forwarded for gene regulation during chronic hypoxia, it also
has to be taken into account for acute and sustained oxygen sensing.
As concept 5, it has been suggested that cytochrome
P-450-dependent arachidonic acid metabolism with, for
example, the appearance of hydroxyeicosatetraenoic acids is involved in
HPV (44, 47).
Thus we are apparently far from establishing a unifying hypothesis for
the sequelae underlying hypoxic vasoconstriction in the pulmonary
vasculature. One common aspect of the various concepts depicted above
is the role of changes in the cellular redox potential; however, this
may still be part of a multifactorial response. We do not even know
whether the acute and sustained responses to alveolar hypoxia as well
as the mechanisms leading to the vascular remodeling process during
chronic hypoxia are triggered by identical or different (initial)
pathways. An interesting aspect in this context is the dependence of
the progressive increase in vascular tone on the endothelium (and
extracellular Ca2+) during phase 2 that was
found in the paper by Dipp et al. (7). This may point to a
prominent role of the endothelium for the transition of the increase in
vascular tone during sustained hypoxia to the vascular remodeling
process occurring during chronic hypoxia (38). However,
this finding, too, has to be reconciled with various controversial
observations as to the role of the endothelium in HPV (e.g., Ref.
27; for a review, see Ref. 33).
One major reason for the discrepancies in the current concepts of HPV
may be related to the use of nonspecific inhibitors. Additionally,
there are methodological uncertainties concerning the measurement of
reactive oxygen species and their specific role for hypoxia sensing.
Thus more than 50 years after the investigations of von Euler and
Liljestrand (32), we are still in doubt about the
underlying mechanisms of hypoxic vascular responses of the lung.
Hopefully, new technologies and investigations in (conditioned) transgenic and gene-deficient mice may clarify the controversies we are
currently facing.
ARTICLE
TOP
ARTICLE
REFERENCES
. Dipp et al. conclude 1) that hypoxia releases Ca2+ from the
sarcoplasmic reticulum (SR) and that this is the underlying mechanism
of HPV, 2) that Ca2+ flux across the plasmalemma
is not essential for HPV, and 3) that the endothelium is not
needed for basal Ca2+ release from the SR during hypoxia
but may sensitize the contractile response to Ca2+.
-NADH
levels, which then increase the net amount of cADPR synthesized from
-NAD+ by cADP-ribosyl cyclase, and simultaneously
inhibit cADPR degradation by cADPR hydrolase. cADPR promotes
Ca2+ release from ryanodine-sensitive SR stores and elicits
vasoconstriction. This concept is suggested to be responsible for the
sustained vasoconstrictive phase of HPV, whereas phase 1 of
HPV may result from an initial fall in ATP levels and inhibition of SR
Ca2+-ATPase by hypoxia. However, this concept has to be
settled in further investigations.
![]() |
FOOTNOTES |
---|
Address for reprint requests and other correspondence: W. Seeger, Dept. of Internal Medicine, Justus-Liebig-Univ. Giessen, Klinikstrasse 36, 35392 Giessen, Germany (E-mail: Werner.Seeger{at}innere.med.uni-giessen.de).
![]() |
REFERENCES |
---|
![]() ![]() ![]() |
---|
1.
Archer, SL,
Huang J,
Henry T,
Peterson D,
and
Weir EK.
A redox-based O2 sensor in rat pulmonary vasculature.
Circ Res
73:
1100-1112,
1993[Abstract].
2.
Archer, SL,
Weir EK,
Reeve HL,
and
Michelakis E.
Molecular identification of O2 sensors and O2-sensitive potassium channels in the pulmonary circulation.
Adv Exp Med Biol
475:
219-240,
2000[ISI][Medline].
3.
Bennie, RE,
Packer CS,
Powell DR,
Jin N,
and
Rhoades RA.
Biphasic contractile response of pulmonary artery to hypoxia.
Am J Physiol Lung Cell Mol Physiol
261:
L156-L163,
1991
4.
Chandel, NS,
and
Schumacker PT.
Cellular oxygen sensing by mitochondria: old questions, new insight.
J Appl Physiol
88:
1880-1889,
2000
5.
Cornfield, DN,
Stevens T,
McMurtry IF,
Abman SH,
and
Rodman DM.
Acute hypoxia increases cytosolic calcium in fetal pulmonary artery smooth muscle cells.
Am J Physiol Lung Cell Mol Physiol
265:
L53-L56,
1993
6.
Cornfield, DN,
Stevens T,
McMurtry IF,
Abman SH,
and
Rodman DM.
Acute hypoxia causes membrane depolarization and calcium influx in fetal pulmonary artery smooth muscle cells.
Am J Physiol Lung Cell Mol Physiol
266:
L469-L475,
1994
7.
Dipp, M,
Nye PCG,
and
Evans AM.
Hypoxic release of calcium from sarcoplasmic reticulum of pulmonary artery smooth muscle.
Am J Physiol Lung Cell Mol Physiol
281:
L318-L325,
2001
8.
Domino, KB,
Chen L,
Alexander CM,
Williams JJ,
Marshall C,
and
Marshall BE.
Time course and responses of sustained hypoxic pulmonary vasoconstriction in the dog.
Anesthesiology
60:
562-566,
1984[ISI][Medline].
9.
Fishman, AP.
Hypoxia on the pulmonary circulation. How and where it acts.
Circ Res
38:
221-231,
1976[ISI][Medline].
10.
Gelband, CH,
and
Gelband H.
Ca2+ release from intracellular stores is an initial step in hypoxic pulmonary vasoconstriction of rat pulmonary artery resistance vessels.
Circulation
96:
3647-3654,
1997
11.
Harder, DR,
Madden JA,
and
Dawson C.
Hypoxic induction of Ca2+-dependent action potentials in small pulmonary arteries of the cat.
J Appl Physiol
59:
1389-1393,
1985
12.
Hillier, SC,
Graham JA,
Hanger CC,
Godbey PS,
Glenny RW,
and
Wagner WW, Jr.
Hypoxic vasoconstriction in pulmonary arterioles and venules.
J Appl Physiol
82:
1084-1090,
1997
13.
Jabr, RI,
Toland H,
Gelband CH,
Wang XX,
and
Hume JR.
Prominent role of intracellular Ca2+ release in hypoxic vasoconstriction of canine pulmonary artery.
Br J Pharmacol
122:
21-30,
1997[Abstract].
14.
Jin, N,
Packer CS,
and
Rhoades RA.
Pulmonary arterial hypoxic contraction: signal transduction.
Am J Physiol Lung Cell Mol Physiol
263:
L73-L78,
1992
15.
Leach, RM,
Robertson TP,
Twort CH,
and
Ward JP.
Hypoxic vasoconstriction in rat pulmonary and mesenteric arteries.
Am J Physiol Lung Cell Mol Physiol
266:
L223-L231,
1994
16.
Madden, JA,
Vadula MS,
and
Kurup VP.
Effects of hypoxia and other vasoactive agents on pulmonary and cerebral artery smooth muscle cells.
Am J Physiol Lung Cell Mol Physiol
263:
L384-L393,
1992
17.
Marshall, C,
Mamary AJ,
Verhoeven AJ,
and
Marshall BE.
Pulmonary artery NADPH-oxidase is activated in hypoxic pulmonary vasoconstriction.
Am J Respir Cell Mol Biol
15:
633-644,
1996[Abstract].
18.
Mohazzab-H, KM,
and
Wolin MS.
Properties of a superoxide anion-generating microsomal NADH oxidoreductase, a potential pulmonary artery PO2 sensor.
Am J Physiol Lung Cell Mol Physiol
267:
L823-L831,
1994
19.
Monaco, JA,
and
Burke-Wolin T.
NO and H2O2 mechanisms of guanylate cyclase activation in oxygen-dependent response of rat pulmonary circulation.
Am J Physiol Lung Cell Mol Physiol
268:
L546-L550,
1995
20.
Murray, TR,
Chen L,
Marshall BE,
and
Macarak EJ.
Hypoxic contraction of cultured pulmonary vascular smooth muscle cells.
Am J Respir Cell Mol Biol
3:
457-465,
1990[ISI][Medline].
21.
Ozaki, M,
Marshall C,
Amaki Y,
and
Marshall BE.
Role of wall tension in hypoxic responses of isolated rat pulmonary arteries.
Am J Physiol Lung Cell Mol Physiol
275:
L1069-L1077,
1998
22.
Peake, MD,
Harabin AL,
Brennan NJ,
and
Sylvester JT.
Steady-state vascular responses to graded hypoxia in isolated lungs of five species.
J Appl Physiol
51:
1214-1219,
1981
23.
Post, JM,
Gelband CH,
and
Hume JR.
[Ca2+]i inhibition of K+ channels in canine pulmonary artery: novel mechanism for hypoxia-induced membrane depolarization.
Circ Res
77:
131-139,
1995
24.
Post, JM,
Hume JR,
Archer SL,
and
Weir EK.
Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction.
Am J Physiol Cell Physiol
262:
C882-C890,
1992
25.
Robertson, TP,
Aaronson PI,
and
Ward JP.
Hypoxic vasoconstriction and intracellular Ca2+ in pulmonary arteries: evidence for PKC-independent Ca2+ sensitization.
Am J Physiol Heart Circ Physiol
268:
H301-H307,
1995
26.
Robertson, TP,
Hague D,
Aaronson PI,
and
Ward JP.
Voltage-independent calcium entry in hypoxic pulmonary vasoconstriction of intrapulmonary arteries of the rat.
J Physiol (Lond)
525:
669-680,
2000
27.
Sham, JS,
Crenshaw BR,
Deng LH,
Shimoda LA,
and
Sylvester JT.
Effects of hypoxia in porcine pulmonary arterial myocytes: roles of KV channel and endothelin-1.
Am J Physiol Lung Cell Mol Physiol
279:
L262-L272,
2000
28.
Staub, NC.
Site of hypoxic pulmonary vasoconstriction.
Chest
88:
240S-245S,
1985[Medline].
29.
Thomas, HM, III,
Carson RC,
Fried ED,
and
Novitch RS.
Inhibition of hypoxic pulmonary vasoconstriction by diphenyleneiodonium.
Biochem Pharmacol
42:
R9-R12,
1991[ISI][Medline].
30.
Vadula, MS,
Kleinman JG,
and
Madden JA.
Effect of hypoxia and norepinephrine on cytoplasmic free Ca2+ in pulmonary and cerebral arterial myocytes.
Am J Physiol Lung Cell Mol Physiol
265:
L591-L597,
1993
31.
Voelkel, NF.
Mechanisms of hypoxic pulmonary vasoconstriction.
Am Rev Respir Dis
133:
1186-1194,
1986[ISI][Medline].
32.
Von Euler, US,
and
Liljestrand G.
Observations on the pulmonary arterial blood pressure in the cat.
Acta Physiol Scand
12:
301-320,
1946.
33.
Ward, JPT,
and
Aaronson PI.
Mechanisms of hypoxic pulmonary vasoconstriction: can anyone be right?
Respir Physiol
115:
261-271,
1999[ISI][Medline].
34.
Weir, EK,
and
Archer SL.
The mechanism of acute hypoxic pulmonary vasoconstriction: the tale of two channels.
FASEB J
9:
183-189,
1995
35.
Wetzel, RC,
and
Sylvester JT.
Gender differences in hypoxic vascular response of isolated sheep lungs.
J Appl Physiol
55:
100-104,
1985[ISI].
36.
Weissmann, N,
Grimminger F,
Voswinckel R,
Conzen J,
and
Seeger W.
Nitro blue tetrazolium inhibits but does not mimic hypoxic vasoconstriction in isolated rabbit lungs.
Am J Physiol Lung Cell Mol Physiol
274:
L721-L727,
1998
37.
Weissmann, N,
Tadi A,
Hänze J,
Rose F,
Winterhalder S,
Nollen M,
Schermuly RT,
Ghofrani HA,
Seeger W,
and
Grimminger F.
Hypoxic vasoconstriction in intact lungs: a role for NADPH oxidase-derived H2O2?
Am J Physiol Lung Cell Mol Physiol
279:
L683-L690,
2000
38.
Weissmann, N,
Winterhalder S,
Nollen M,
Voswinckel R,
Quanz K,
Ghofrani HA,
Schermuly RT,
Seeger W,
and
Grimminger F.
NO and reactive oxygen species are involved in biphasic hypoxic vasoconstriction of isolated rabbit lungs.
Am J Physiol Lung Cell Mol Physiol
280:
L638-L645,
2001
39.
Welling, KL,
Sanchez R,
Ravn JB,
Larsen B,
and
Amtorp O.
Effect of prolonged alveolar hypoxia on pulmonary arterial pressure and segmental vascular resistance.
J Appl Physiol
75:
1194-1200,
1993[Abstract].
40.
Wilson, HL,
Dipp M,
Thomas JM,
Lad C,
Galione A,
and
Evans AM.
ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase act as a redox sensor: a primary role for cADPR in hypoxic pulmonary vasoconstriction.
J Biol Chem
276:
11180-11188,
2001
41.
Woodmansey, PA,
Zhang F,
Channer KS,
and
Morice AH.
Effect of the calcium antagonist amlodipine on the two phases of hypoxic pulmonary vasoconstriction in rat large and small isolated pulmonary arteries.
J Cardiovasc Pharmacol
25:
324-329,
1995[ISI][Medline].
42.
Youngson, C,
Nurse C,
Yeger H,
and
Cutz E.
Oxygen sensing in airway chemoreceptors.
Nature
365:
153-155,
1993[ISI][Medline].
43.
Yuan, XJ,
Goldman WF,
Tod ML,
Rubin LJ,
and
Blaustein MP.
Hypoxia reduces potassium currents in cultured rat pulmonary but not mesenteric arterial myocytes.
Am J Physiol Lung Cell Mol Physiol
264:
L116-L123,
1993
44.
Yuan, XJ,
Tod ML,
Rubin LJ,
and
Blaustein MP.
Inhibition of cytochrome P-450 reduces voltage-gated K+ currents in pulmonary arterial myocytes.
Am J Physiol Cell Physiol
268:
C259-C270,
1995
45.
Zhang, F,
Carson RC,
Zhang H,
Gibson G,
and
Thomas HM, III.
Pulmonary artery smooth muscle cell [Ca2+]i and contraction: responses to diphenyleneiodonium and hypoxia.
Am J Physiol Lung Cell Mol Physiol
273:
L603-L611,
1997
46.
Zhang, F,
Woodmansey A,
and
Morice AH.
Acute hypoxic vasoconstriction in isolated rat small and large pulmonary arteries.
Physiol Res
44:
7-18,
1995[ISI][Medline].
47.
Zhu, D,
Birks EK,
Dawson CA,
Patel M,
Falck JR,
Presberg K,
Roman RJ,
and
Jacobs ER.
Hypoxic pulmonary vasoconstriction is modified by P-450 metabolites.
Am J Physiol Heart Circ Physiol
279:
H1526-H1533,
2000