Am J Physiol Heart Circ Physiol 290: H2169 –H2171, 2006;
doi:10.1152/ajpheart.00161.2006.
Editorial Focus
Hypoxia, coronary dilation, and the pentose phosphate pathway
Brandon T. Larsen1,3 and David D. Gutterman1,2,3,4
Departments of 1Pharmacology and Toxicology and 2Medicine and 3Cardiovascular Center, Medical
College of Wisconsin, and 4Department of Veterans Affairs Medical Center, Milwaukee, Wisconsin
Address for reprint requests and other correspondence: D. D. Gutterman,
Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI
53226 (e-mail: [email protected]).
http://www.ajpheart.org
promotes the accumulation of NADP⫹ and the depletion of
NADPH.
The PPP is an important modulator of the overall redox state
of the cell through reduction of NADP⫹ to NADPH, a key
cofactor for several cellular enzymes. Flux through this pathway may regulate a number of redox-sensitive cellular targets
that affect vasomotor function, including soluble guanylyl
cyclase, potassium channels, and the SERCA pump (3, 19).
The present report (5) provides evidence that hypoxia may
indirectly modulate the activity of the SERCA pump via an
effect on the PPP to lower intracellular calcium. Importantly,
this effect on the PPP occurs in the absence of alterations in
cellular ATP, suggesting that hypoxia-induced relaxation of
the BCA is independent of alterations in mitochondrial energy
metabolism. This response may therefore represent an important initial feedback mechanism under conditions of mild to
moderate hypoxia, whereby blood flow is increased, tissue PO2
is restored, and mitochondrial impairment is prevented.
The endothelium plays a prominent regulatory role in many
aspects of vascular biology by functioning as a sensor for
neurotransmitters and hormones, such as acetylcholine, bradykinin, or angiotensin II, or as a sensor for shear stress across its
luminal surface. The endothelium transduces these signals to
the underlying muscle layer by releasing vasoactive constricting or relaxing factors. These factors modulate vasomotor tone
and local tissue perfusion. In the isolated BCA, Gupte and
Wolin (5) report that hypoxia promotes relaxation in the
absence of the endothelium. This is consistent with a previous
study from this laboratory (12) showing that hypoxic vasorelaxation of the BCA is not mediated by NO or prostaglandins
and is not altered by endothelial denudation. Other reports
confirm that hypoxic vasorelaxation can occur in isolated
vessels in the absence of a functional endothelium (2, 15).
Although the endothelium is not required for hypoxic vasorelaxation of the BCA in vitro, this cell layer is also sensitive to
changes in PO2 and may release vasoactive metabolites that
could potentially contribute to the functional response to hypoxia in vivo (2, 14). In any case, a vascular smooth musclespecific oxygen sensor may be particularly important in cardiovascular disease when the endothelium is dysfunctional,
and should therefore be studied in greater depth.
An interesting finding of the present study (5) is that hypoxia
promotes the oxidation of NADPH in the BCA, a redox
phenomenon that is somewhat counterintuitive, as low PO2 is
usually associated with reductive potential. The associated
decrease in cellular NADPH is coupled with lower intracellular
calcium, which probably initiates relaxation. However, an
alternative explanation is that the decrease in NADPH may
reduce NAD(P)H oxidase activity, thereby lowering superoxide and hydrogen peroxide generation by this enzyme. Because
these ROS can inhibit potassium channels and other proteins
involved in the mechanism of vasodilation (6), reduced ROS
levels would be expected to facilitate vasorelaxation. ConsisH2169
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of resistance arteries is an important
feedback control mechanism to maintain adequate oxygenation
of metabolically active tissues and is essential in tissues where
oxygen extraction is nearly maximized, as it is in the heart.
Although the physiological importance of this response has
been appreciated for decades, the underlying cellular and
molecular mechanisms remain incompletely understood.
Under conditions of low arterial PO2, a number of factors act
to match coronary blood flow with oxygen consumption (Fig.
1). The hypoxic environment elicits neural stimuli and release
of humoral substances from adjacent cardiac tissue that stimulate vasodilation. Adenosine, potassium ions, hydrogen ions,
and sympathetic activation can all contribute to dilation during
hypoxia (1, 10). However, these factors do not fully account
for hypoxic dilation (17) and do not address the direct relaxing
effect of hypoxia on isolated vessels. This is important because, in contrast to metabolic regulation of vasomotor tone, it
is important for hypoxia to elicit a direct vasodilator response
from cardiac resistance vessels. Systemic vessels are intrinsically sensitive to changes in PO2, and identification of the
vascular oxygen sensor has been the subject of intense investigation. In recent studies, intracellular reactive oxygen species
(ROS)-generating systems including NAD(P)H oxidase (7, 20)
and the mitochondrial electron transport chain (9, 18) have
been implicated as vascular oxygen sensors (16).
As reported in this issue of the American Journal of Physiology-Heart and Circulatory Physiology, Gupte and Wolin (5)
have identified a novel mechanism whereby hypoxia induces
relaxation of the isolated, endothelium-denuded bovine coronary artery (BCA) by decreasing NADPH and glutathione
(GSH) concentrations in the vascular smooth muscle. This new
mechanism nicely links two prior observations made by the
same group. First, hypoxia relaxes BCA by a mechanism that
does not appear to involve a release of endothelial nitric oxide
or prostaglandins or changes in ROS (12). Second, relaxation
of the BCA to pentose phosphate pathway (PPP) inhibitors
involves decreased NADPH and GSH and reduced intracellular
calcium (3). The present study links hypoxia-induced relaxation with inhibition of the PPP by showing that hypoxic
vasodilation is associated with reduced flux through the PPP,
decreased cytosolic NADPH, decreased Ca2⫹ influx, and accelerated activity of the sarco(endo)plasmic reticulum Ca2⫹ATPase (SERCA) pump. Modulation of this pathway implicates PPP inhibition as an intrinsic mechanism of hypoxic
dilation. Although the specific molecular mechanism underlying this effect of low PO2 on the PPP remains unclear, it may
involve a hypoxia-induced depletion of glucose-6-phosphate,
the substrate for the rate-limiting enzyme of the PPP, that then
HYPOXIC VASORELAXATION
Editorial Focus
H2170
tent with this hypothesis, Wolin’s group (4) has shown that
inhibition of the PPP reduces ROS generation in the bovine
coronary vasculature. However, the situation is more complex.
Previous reports from Wolin’s group (11, 12) indicate that
hypoxic vasorelaxation of the BCA occurs without changes in
ROS production. Thus, although the mechanism whereby hypoxia induces oxidation independent of ROS production remains unknown, it would be intriguing to examine whether
apocynin, an inhibitor of NAD(P)H oxidase, alters hypoxic
dilation in this model.
There are potential clinical ramifications of the study by
Gupte and Wolin (5). They observed that hypoxic vasorelaxation is enhanced under glucose-free conditions and attenuated
with addition of pyruvate, consistent with a sensitivity to the
availability of substrate for the PPP. Although the inhibitory
effects of hyperglycemia on endothelial function are well
established and involve enhanced oxidative stress (13), the
present study suggests that high glucose concentrations may
also impair the intrinsic oxygen sensor in the vascular smooth
muscle. This could have adverse effects in diabetic patients
with cardiovascular disease, in which both endothelium-mediated and endothelium-independent dilator mechanisms could
be simultaneously impaired, possibly explaining the increased
cardiovascular morbidity and mortality observed in diabetic
patients. In contrast, it is interesting to speculate that subjects
with the common biochemical absence of glucose-6-phosphate
dehydrogenase may demonstrate a greater sensitivity to the
AJP-Heart Circ Physiol • VOL
vasodilator effects of hypoxia. Additional studies are needed to
determine the physiological and pathological significance of
the inhibitory effect of glucose on this particular mechanism in
the broader context of vascular biology.
In conclusion, the present report by Gupte and Wolin (5)
identifies the PPP as a novel oxygen sensor in the vascular
smooth muscle that modulates hypoxic coronary vasodilation.
This study expands our understanding of the complex mechanism underlying this fundamental physiological response of the
vasculature to low PO2. Future studies are needed to determine
the functional significance of this redox signaling pathway in
various physiological and pathological conditions.
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Fig. 1. Proposed signaling pathways of hypoxic vasorelaxation in the coronary circulation. Endothelial cells, vascular smooth muscle cells, and cardiomyocytes
are all intrinsically sensitive to low PO2. The endothelium may be activated by hypoxia to release the vasodilator compounds nitric oxide (NO) and prostacyclin
(PGI2) (14). As outlined in the present study by Gupte and Wolin (5), hypoxia diminishes flux through the pentose phosphate pathway (PPP) in the vascular
smooth muscle, leading to decreased NADPH, decreased Ca2⫹ influx, and enhanced Ca2⫹ uptake into the sarcoplasmic reticulum (bold arrows). The subsequent
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to induce relaxation. A2R, adenosine 2 receptor; AA, arachidonic acid; AC, adenylate cyclase; Cox, cyclooxygenase; Em, membrane electrical potential; eNOS,
endothelial NO synthase; G6PD, glucose-6-phosphate (glucose-6-P) dehydrogenase; GC, guanylyl cyclase; GSH, glutathione; IPR, prostacyclin receptor; L-arg,
L-arginine; L-cit, L-citrulline; SERCA, sarco(endo)plasmic reticulum Ca2⫹-ATPase pump.
Editorial Focus
H2171
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