Hypoxic regulation of nitric oxide signaling in vascular smooth muscle
Thomas C. Resta
Vascular Physiology Group, Department of Cell Biology and Physiology,
University of New Mexico Health Sciences Center, Albuquerque, New Mexico
87131-0001
THE CURRENT ARTICLE IN FOCUS by Mingone and colleagues (Ref.
16, see
p. L296 in this issue)
describes a novel permissive effect of hypoxia on cGMP-independent relaxation
to nitric oxide (NO) in bovine pulmonary and coronary arteries. Interestingly,
whereas NO-mediated vasorelaxation appeared to be largely a function of cGMP
at ambient PO2, a cGMP-independent mechanism involving activation
of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)
was revealed during hypoxic exposure. This study emphasizes the emerging
complexity of NO signaling in vascular smooth muscle and raises important new
questions regarding mechanisms by which PO2 regulates
cGMP-independent actions of NO.
Both cGMP-dependent and -independent mechanisms of NO signaling have been
implicated in vascular smooth muscle
(1,
2,
48,
10,
13,
15,
16,
19,
20,
31,
32). It is well established
that soluble guanylyl cyclase is an important target of NO in both the
pulmonary and systemic circulations
(8,
10,
13,
15,
19). Activation of soluble
guanylyl cyclase by NO leads to increased cGMP synthesis and stimulation of
protein kinase G (PKG) (8,
15,
19). PKG, in turn, elicits
relaxation of vascular smooth muscle through a myriad of signaling pathways,
leading to a decrease in the intracellular free Ca2+
concentration ([Ca2+]i) and desensitization
of the contractile apparatus to Ca2+
(8,
15). Those pathways involving
a decrease in [Ca2+]i are, for the most part,
poorly understood. However, evidence exists for PKG-dependent activation of
large-conductance Ca2+-activated K+ (BK)
channels and associated membrane hyperpolarization, inhibition of L-type
voltage-gated Ca2+ channels, stimulation of
Ca2+-ATPases on both the plasma membrane and
sarcoplasmic reticulum, inhibition of inositol trisphosphate receptors, and
decreased inositol trisphosphate synthesis
(8,
15). Those mechanisms
involving a decrease in sensitivity of the contractile apparatus to
Ca2+ in response to PKG activation are even less well
defined but appear to be predominantly mediated by regulation of myosin light
chain phosphorylation subsequent to activation of myosin light chain
phosphatase (8,
15,
19,
21,
22).
In addition, NO signals through cGMP-independent mechanisms in many tissues
by nitrosylation of cysteine thiol groups or transition metals to
posttranslationally modify enzymatic activity
(3,
11,
12,
18,
2325,
29). Many cGMP-independent
influences of NO in vascular smooth muscle appear to involve an increase in
sarcolemmal K+ permeability. For example, NO has been reported to
activate BK channels either directly
(7) or indirectly via
inhibition of 20-hydroxyeicosatet-raenoic (20-HETE) production
(4,
5,
31) or increased calcium spark
activity (20). Additional
evidence supports a role for cGMP-independent activation of delayed rectifier
K+ channels in pulmonary arterial smooth muscle cells
(32). Other direct effects of
NO include stimulation of SERCA in rabbit aortic smooth muscle, leading to
increased Ca2+ reuptake by intracellular stores, a fall
in [Ca2+]i, and consequent inhibition of
store-operated Ca2+ influx
(1,
2,
9). This latter mechanism of
cGMP-independent activation of SERCA is consistent with the findings of
Mingone et al. (16), which
identify regulatory influences of hypoxia on this pathway.
Although the mechanism by which NO mediates cGMP-independent
Ca2+ sequestration by the sarcoplasmic reticulum is not
understood, it is possible that NO modulates SERCA activity by
S-nitrosylation of the enzyme
(25). It is also unclear how
hypoxia functions to modify SERCA activity. Although current debate exists as
to whether hypoxia increases the production of reactive oxygen species or
instead leads to a more reduced cellular state in pulmonary vascular smooth
muscle (14,
17,
2630),
one possible explanation for the permissive effect of hypoxia on NO-dependent
stimulation of SERCA is via an alteration in the redox state of the pump. In
agreement with this hypothesis, Adachi et al.
(2) have demonstrated that
impaired NO-dependent relaxation and SERCA activity in aortas from
hypercholesterolemic rabbits are prevented by long-term administration of the
antioxidant t-butylhydroxytoluene, suggesting that increased
oxidative stress associated with hypercholesterolemia impairs SERCA function.
A more reduced state imposed by hypoxia may, therefore, enhance refilling of
intracellular Ca2+ stores through disinhibition of
SERCA. Whether oxidative stress impairs SERCA activity by preventing
S-nitrosylation of the pump remains to be investigated. However, a
recent report by Sun et al.
(24) has demonstrated a
similar inhibitory effect of increasing PO2 on both NO-dependent
activation and S-nitrosylation of the skeletal muscle ryanodine
receptor. Whereas stimulation of channel activity by NO is inhibited at
ambient PO2 (
150 mmHg), an apparently lower oxidative stress
associated with a more physiological tissue PO2 (
10 mmHg)
permits S-nitrosylation at a specific cysteine residue (Cys-3635) via
an allosteric mechanism and subsequent channel activation. It is noteworthy
that this lower PO2 is similar to the oxygen tension used as a
hypoxic stimulus (810 mmHg) by Mingone et al.
(16), and thus an analogous
mechanism may account for the observed cGMP-independent stimulation of SERCA
by NO under hypoxic conditions. In contrast to potential influences of hypoxia
on the redox state and allosteric regulation of the target enzyme (e.g.,
SERCA), it is alternatively possible that hypoxia limits NO bioinactivation by
oxygen-derived free radicals, thus facilitating S-nitrosylation
reactions through increases in the concentration of NO within relevant
microcellular domains.
In conclusion, the observations of Mingone and colleagues
(16) will likely provide the
basis for intriguing new avenues of investigation to understand mechanisms of
hypoxic modulation of NO signal transduction in vascular smooth muscle.
Challenges of future studies include defining the potential role of
S-nitrosylation of SERCA in regulating pump activity as well as the
mechanism by which hypoxia facilitates cGMP-independent stimulation of SERCA
by NO. The concept of hypoxia as a redox effector of second messenger
signaling has potentially broad physiological and pathophysiological
implications for not only NO regulation of vascular, immunological, and neural
function, but for hypoxic modulation of a diverse spectrum of intracellular
signaling pathways.
 |
FOOTNOTES
|
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Address for reprint requests and other correspondence: T. C. Resta, Vascular
Physiology Group, Dept. of Cell Biology and Physiology, Univ. of New Mexico
Health Sciences Center, MSC08 4750, 1 Univ. of New Mexico, Albuquerque, NM
87131-0001 (E-mail:
tresta{at}salud.unm.edu).
 |
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