Circulation Research. 2001
Published online before print July 5, 2001,
doi: 10.1161/hh1401.094367
A more recent version of this article appeared on July 20, 2001
(Circulation Research. 2001;0:hh1401.094367.)
© 2001 American Heart Association, Inc.
Redox Signaling of the Arteriolar Myogenic Response
P. T. Nowicki,
S. Flavahan,
H. Hassanain,
S. Mitra,
S. Holland,
P. J. Goldschmidt-Clermont
N. A. Flavahan
From the Heart and Lung Research Institute (P.T.N., S.F., H.H., S.M.,
N.A.F.), Ohio State University, Columbus, Ohio; National Institute of Allergy
and Infectious Diseases (S.H.), Bethesda, Md; and Duke University (P.J.G.-C.),
Durham, NC.
Correspondence to N.A. Flavahan, PhD, Heart and Lung Research Institute, 473 West 12th Ave, Room 110E, Columbus, OH 43210. E-mail flavahan-1{at}medctr.osu.edu
Abstract
Arteriolar
vascular smooth muscle cells (VSMCs) are mechanosensitive, constricting
to elevations in transmural pressure (PTM). The
goal of the present study was to determine using mouse isolated
tail arterioles and arteries whether oxidant signaling regulates this
myogenic response. In response to PTM elevation,
VSMCs of arterioles but not arteries generated constriction and
increased reactive oxygen species (ROS) activity (using the
H2O2-sensitive probe
dichlorodihydrofluorescein).
Arterioles had increased expression of NADPH oxidase components
compared with arteries. Inhibition of NADPH oxidase, using mice with
targeted impairment of enzyme components
(p47phox
or rac1) or diphenyleneiodonium, prevented the pressure-induced
generation of ROS. When ROS activity was inhibited, either by
inhibiting NADPH oxidase or with
N-acetylcysteine, the myogenic
constriction was abolished. The myogenic constriction was also
inhibited by catalase, which inactivates
H2O2, but was unaffected
by a cell-permeant mimic of superoxide dismutase (MnTMPyP).
1-Adrenergic constriction was not associated
with altered ROS activity and was not affected by inhibition of NADPH
oxidase or ROS. Exogenous
H2O2 constricted VSMCs of
arterioles but not arteries. Thus, NADPH oxidase and ROS, in particular
H2O2, contribute to the
myogenic response of arteriolar VSMCs.
Key Words: KEY WORDS: H2O2 • smooth muscle • pressure
Vascular
smooth muscle cells (VSMCs) of arterioles, but not arteries, are
mechanosensitive, constricting to elevations in transmural pressure
(PTM). This myogenic response contributes to
blood flow autoregulation and the establishment of basal vascular
tone.1 The response is an
inherent property of arteriolar VSMCs involving calcium-dependent
actin/myosin interaction, but the more proximal signaling components
have not been clearly
defined.1 In cultured cells,
mechanical stress initiates integrin-dependent activation of rho
GTPases (rho, rac1, and CDC42), leading to reorganization of the
cytoskeleton.2 3
Cytoskeleton reorganization by rac1 is mediated by NADPH oxidase and
generation of reactive oxygen species
(ROS).4 This enzyme complex,
comprising Nox1,
p47phox,
p67phox,
p22phox,
and rac1, is a key signaling system in cultured, noncontractile
VSMCs.5 6 The aim
of the present study was to determine whether the rac1/NADPH
oxidase/ROS signaling pathway regulates the myogenic response of
arteriolar VSMCs.
Materials and Methods
Vasomotor Responses
Mouse-tail arterioles and arteries were
cannulated in a microperfusion chamber (Living Systems) and studied in
the absence of flow as
described.7 Unless stated
otherwise, arterioles with intact endothelium were
analyzed. Involvement of animals in the study was approved by
the Ohio State University Animal Care and Use
Committee.
ROS Determination
Endothelium-denuded
vessels7 were incubated with
the H2O2-sensitive probe
5-(and 6)-chloromethyl-2',7'-dichlorodihydro-fluorescein
diacetate (DCF), 5 µg/mL, for 30 minutes (37°C,
PTM of 10 mm Hg). Because activation of
DCF fluorescence is irreversible, fluorescent images
(Zeiss, LSM 410) were captured at a
PTM of 10 mm Hg before and after
PTM had been increased (90 mm Hg, 1
minute). Maintaining vessels at 10 mm Hg did not change DCF
fluorescence. Images were quantified using Metamorph
software.
Mice
Transgenic mice expressing a dominant-negative mutant
of human rac1 (rac-DN, cDNA; gift of Alan Hall, London, England), with
threonine17 to asparagine substitution, were generated in FVB/N mice
using the smooth muscle -actin promoter (gift of Art Strauch, Ohio
State University, Columbus, Ohio). The genome of the mice incorporated
the cDNA of rac-DN, including its polyadenylation site. Founder mice
were selected on the basis of Southern blot analysis, and one
confirmed to have the highest number of human rac-DN gene copies used
to establish a stable transgenic line by breeding it with nontransgenic
FVB/N mates. Reverse transcriptase–polymerase chain reaction
analysis confirmed expression of rac-DN in smooth muscle,
including blood vessels and intestine, whereas the transcript was not
detected in control mice nor in the brain, heart, liver, skeletal
muscle, and testis of transgenic mice. Responses in rac-DN mice were
compared with nontransgenic littermates. All other experiments were
performed on C57Bl6 mice;
p47phox-/-
mice8 were congenic to
C57Bl6.
Western Blot Analysis
Endothelium-denuded vessels from 20
mice were processed as
described.7 Antibodies were
ß-actin (Sigma),
p47phox,
p67phox
(Transduction Laboratories), and rac-1
(Upstate Biotechnology).
Data Analysis
Data are expressed as mean±SEM for n number of
animals. Vasomotor responses were expressed as percentage change in the
basal diameter at 10 mm Hg. Statistical evaluation was by
Student’s t test, except for
multiple comparisons, when ANOVA followed by Scheffe’s
analysis was used.
Results
At a PTM of 10 mm Hg, the
internal diameters of arterioles and arteries were 88.5±5.4 µm
(n=18) and 184.4±13.4 µm, respectively (n=8). An increase in
PTM (10 to 90 mm Hg) caused arterioles to
dilate, then constrict and initiate vasomotion, maintaining a diameter
similar to that at a PTM of 10 mm Hg
(Figure 1A
). The dilation represented passive
opening and was dramatically increased by vasodilators
(Figure 1A). Increasing PTM in
arteries caused only passive dilation, and vasodilators had no effect
(Figure 1A).
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Figure 1. A, Increased PTM (10 to 90 mm Hg, •) caused dilatation (upward movement) and then constriction of arterioles. Vasodilators (papaverine 100 µmol/L plus nitroprusside 10 µmol/L) abolished the myogenic response. In arteries, elevated PTM caused passive dilation that was unaffected by vasodilators. B, Increased PTM (10 to 90 mm Hg) increased ROS activity in arteriolar VSMCs, assessed by LSM analysis of DCF fluorescence. Inhibition of ROS (catalase 3000 U/mL) or impaired activity of NADPH oxidase (DPI 1 µmol/L; p47phox-/- or rac-DN arterioles) reduced basal ROS activity and prevented the increase to elevated PTM. Arteries had reduced ROS activity, which did not increase after PTM elevation. Bar=50 µm.
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Elevating PTM in arterioles increased
ROS activity in VSMCs (2.53±0.30-fold increase in DCF
fluorescence, n=13)
(Figure 1B
). The basal level of ROS was reduced and the
pressure-induced elevation was abolished by the antioxidant
N-acetylcysteine (NAC) (20
mmol/L, data not shown) or by impairment of NADPH oxidase using
arterioles from
p47phox-/-
or rac-DN mice or using the nonselective inhibitor
diphenyleneiodonium (DPI) (1 µmol/L)
(Figure 1B). In contrast, arteries had low levels of ROS
activity, which did not increase after PTM
elevation
(Figure 1B). Arteries had decreased expression of the NADPH
oxidase components rac1,
p47phox,
and
p67phox
compared with arterioles
(Figure 2D).
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Figure 2. NADPH oxidase and myogenic responses. A and B, Myogenic response to PTM elevation (10 to 90 mm Hg, •) was reduced by DPI and in arterioles from p47phox-/- or rac-DN mice. Traces (A) and mean data (±SEM, for n=3 to 13) (B) are presented. C, Impaired activity of NADPH oxidase (DPI; p47phox-/- and rac-DN mice) did not affect constriction to the 1-adrenergic agonist phenylephrine (n=3 to 4). D, Immunoblots demonstrate increased expression of rac1, p67phox, and p47phox in arterioles compared with arteries (representative of 4 experiments). E, Inhibition of NO synthase with L-NAME (10-4 mol/L) did not affect the response of control or p47phox-/- arterioles to PTM elevation (10 to 90 mm Hg, •) (representative of 4 experiments).
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The myogenic constriction to elevated
PTM was inhibited by impairment of NADPH oxidase
(rac-DN or
p47phox-/-
arterioles; DPI, 1 µmol/L), and only passive dilation was observed
(Figures 2A and 2B). Similar results were obtained by
inhibiting ROS with NAC (20 mmol/L)
(Figures 3A and 3B). Inhibition of NADPH oxidase and decreased
ROS activity, in particular superoxide, might depress constriction
indirectly by augmenting endothelium-derived nitric
oxide (NO).9 However,
inhibition of NADPH oxidase (DPI;
p47phox-/-
or rac-DN arterioles) or ROS activity (NAC) also inhibited the myogenic
response in endothelium-denuded arterioles or in the
presence of
NG-nitro-L-arginine
methyl ester (L-NAME) (100 µmol/L), an NO synthase
inhibitor
(Figure 2E and data not shown). Furthermore, the myogenic
constrictor response was not affected by a cell-permeant mimic of
superoxide dismutase (SOD),
MnTMPyP,4 which catalyzes the
dismutation of superoxide to
H2O2, but was abolished
by catalase, which inactivates
H2O2
(Figures 3A and 3B). The inhibitory effect of
catalase on myogenic constriction and DCF fluorescence
(Figures 1B, 3A, and 3B) was maximal after 4 hours,
consistent with intracellular accumulation in
VSMCs.10 Exogenous
H2O2 constricted
endothelium-denuded arterioles but not arteries
(Figure 3D).
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Figure 3. ROS and myogenic responses. A and B, Myogenic response to elevation in PTM (10 to 90 mm Hg, •) was not affected by the SOD mimic MnTMPyP (25 µmol/L, SODm) but was abolished by NAC (20 mmol/L) or catalase (3000 U/mL). Traces (A) and mean data (±SEM, for n=3 to 5) (B) are presented. C, Constriction to phenylephrine was not altered by NAC or catalase (n=3 to 5). D, Exogenous H2O2 (10 µmol/L) constricted endothelium-denuded arterioles but not arteries (representative of 5 experiments).
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Constriction to the 1-adrenergic
agonist phenylephrine was not associated with increased ROS
activity (data not shown) and was not affected by inhibition of NADPH
oxidase (DPI; rac-DN or
p47phox-/-
arterioles) or of ROS (NAC, catalase)
(Figures 2C and 3C).
Discussion
Elevation in PTM increased ROS
activity in arteriolar VSMCs. The source of ROS was likely to be NADPH
oxidase based on the reduced activity in
p47phox-/-
or rac-DN arterioles and the inhibitory effect of DPI. When
the increase in ROS was inhibited, either by the antioxidant NAC or by
inhibition of NADPH oxidase, the myogenic constriction to elevated
PTM was abolished. Therefore, oxidant signaling
by the rac/NADPH oxidase/ROS pathway is essential for the myogenic
response of arterioles. Because 1-adrenergic
constriction was not associated with nor affected by changes in ROS
activity, the role of this pathway may be restricted to
mechanotransduction and myogenic constriction.
In cultured, noncontractile VSMCs, oxidant regulation of
cell growth is mediated by
H2O2.10 11
H2O2 also seems to be the
predominant species involved in myogenic constriction, because (1) the
myogenic response was associated with increased activity of
H2O2, as detected by DCF;
(2) the responses were inhibited by catalase but unaffected by a SOD
mimic; and (3) exogenous
H2O2 was a potent
constrictor of arteriolar VSMCs. Studies in large arteries have
suggested that oxidant signaling is associated predominantly with
diseased phenotypes of
VSMCs,10 11 12
compatible with oxidant regulation of VSMC
growth.10 11 Our
observations on small arteries are consistent with this
proposal and suggest that under physiological
conditions, oxidant signaling may be more important in arteriolar
compared with arterial VSMCs.
Mouse-tail arterioles represent a novel model of the
microcirculation. They demonstrated robust myogenic responses and
remarkable spontaneous vasomotion, suggesting that they are a useful
and somewhat unique model of the terminal arteriolar vasculature.
Several mechanisms have been proposed for the arteriolar myogenic
response,1 and there is
heterogeneous regulation between different vascular
beds.13 The applicability of
the present results to other vascular beds is not known. Indeed,
although H2O2 can cause
constriction through multiple
mechanisms,14 it can also
act as a vasodilator.15 This
suggests that ROS contribution to myogenic constriction may not be
universal or indicates a complex regulation of vasomotor responses by
ROS.
In conclusion, elevation in PTM
causes an NADPH oxidase–dependent generation of ROS in VSMCs of tail
arterioles, and these ROS, in particular
H2O2, initiate myogenic
constriction. Proximal arteries do not participate in this response
because of decreased expression of NADPH oxidase, reduced
production of
H2O2, and decreased
ability to constrict to
H2O2. Altered regulation
of this mechanism may contribute to heightened constriction and oxidant
stress in
hypertension.5
Acknowledgments
This work was supported by grants from
the Scleroderma Research Foundation and National Institutes of Health
(AR46126, HL67331, and HL56091) to
N.A.F.
Footnotes
Original received February 16, 2001; revision received June 12, 2001; accepted June 12, 2001.
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R. A. Oeckler, P. M. Kaminski, and M. S. Wolin
Stretch Enhances Contraction of Bovine Coronary Arteries via an NAD(P)H Oxidase-Mediated Activation of the Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase Cascade
Circ. Res.,
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92(1):
23 - 31.
[Abstract]
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B. Lassegue and K. K. Griendling
Out Phoxing the Endothelium: What's Left Without p47?
Circ. Res.,
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T. Aizawa, N. Ishizaka, S.-I. Usui, N. Ohashi, M. Ohno, and R. Nagai
Angiotensin II and Catecholamines Increase Plasma Levels of 8-Epi-Prostaglandin F2{alpha} With Different Pressor Dependencies in Rats
Hypertension,
January 1, 2002;
39(1):
149 - 154.
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