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-hydroxylase: a potential
O2 sensor in rat arterioles and skeletal muscle
cells
Medical College of Wisconsin and Marquette University, Milwaukee, Wisconsin 53226
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The purposes
of this study were to 1) further evaluate the possible role
that vasoconstrictor metabolites of cytochrome P-450 (CYP)
-hydroxylase plays in O2-induced constriction of
arterioles in the rat skeletal muscle microcirculation, 2)
determine whether -hydroxylases are expressed in rat cremaster
muscle, and 3) determine whether the enzyme is located in
the parenchyma or the arterioles. O2-induced constriction
of third-order arterioles in the in situ cremaster muscle of
Sprague-Dawley rats was significantly inhibited by the CYP inhibitors
N-methyl-sulfonyl-12,12-dibromododec-11-enamide (DDMS; 50 µM) and 17-octadecynoic acid (ODYA; 10 µM). Immunoblot analysis
with antibody raised against CYP4A protein indicated the presence of
immunoreactive proteins in the cremaster muscle and in isolated
arterioles and muscle fibers from this tissue. However, the molecular
mass of the immunoreactive proteins was 85 kDa instead of the expected
50-52 kDa for CYP4A -hydroxylase isolated from rat liver or
kidney. Treatment of the cremaster muscle with deglycosidases
shifted the bands to the expected range which indicates that these
proteins are likely glycosylated in skeletal muscle.
Immunohistochemistry revealed intense staining of both muscle fibers
and microvessels in the cremaster muscle. The results of this study
indicate that O2 sensing in the skeletal muscle
microcirculation may be mediated by CYP4A -hydroxylases in both
arterioles and parenchymal cells.
microcirculation; 20-hydroxyeicosatetraenoic acid; autoregulation; vascular smooth muscle
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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OXYGEN-DEPENDENT AUTOREGULATORY MECHANISMS are critical in regulating organ blood flow and vascular resistance, and numerous studies have investigated the response of the vasculature to changes in O2 availability. Although the mechanisms that contribute to vasodilation in response to reduced PO2 have been widely studied (5, 7-8, 10, 22, 26, 28), much less is known regarding the mechanisms that mediate the constriction of arterioles in response to elevated PO2.
A major question that has remained unanswered for decades is the
location of the "sensor" for the vasoconstrictor response to
increased O2 availability in the microcirculation.
Specifically, is it located in the parenchymal cells or in the blood
vessels? Recent studies have suggested that 20-hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P-450 (CYP) metabolite of
arachidonic acid, is an important mediator of the vasoconstrictor
response to increased O2 availability in the skeletal
muscle microcirculation of rats (13) and hamsters
(19). Although the original studies of the role of 20-HETE
as a possible O2 sensor indicated that mRNA for CYP
-hydroxylase was present in the cremaster muscle, it has yet to be
determined whether the protein itself is expressed in this vascular
bed, and nothing is known about the cell types that express the enzyme
in the cremaster muscle. In this respect identification of the sites of
CYP -hydroxylase expression will provide crucial information
regarding the possible sensor for O2-induced constriction
of arterioles in the skeletal muscle microcirculation.
In the present study, Western blotting and immunohistochemistry were
used to determine the location of CYP4A enzymes in rat skeletal muscle
microcirculation. The results of this study indicate that CYP4A
-hydroxylases are expressed in skeletal muscle cells and arterioles
of rat cremaster muscle. This suggests that either or both of these
locations can sense changes in O2 availability via this
enzyme system.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal preparation.
Twelve male Sprague-Dawley rats (weight 330 ± 10 g) were
anesthetized with pentobarbital sodium (50-60 mg/kg ip). A carotid artery was cannulated for measurement of mean arterial pressure (MAP),
and a jugular vein was cannulated for administration of supplemental
anesthesia as necessary. The trachea was cannulated to ensure a patent
airway, and the animal was maintained on a temperature-controlled board
on the stage of a Leitz Laborlux microscope. The in situ
transilluminated cremaster muscle was prepared as previously described
(2). Throughout the experiment the tissue was superfused
at 35°C with a bicarbonate-buffered physiological salt solution (PSS;
pH 7.35) equilibrated with a 0% O2-5%
CO2-95% N2 gas mixture, which ensures that
O2 delivery to the tissue is controlled by the
microcirculation. Arteriolar responses to elevated
PO2 were tested by superfusing the preparation with PSS equilibrated with a 21% O2-5%
CO2-74% N2 gas mixture. Internal diameters of
third-order arterioles were measured by television microscopy
(2) utilizing a moveable reference-line system operated
via a video micrometer (For-A Video Microscaler, For-A Instruments;
Tokyo, Japan). Active tone in the vessels was verified by measuring the
increase in diameter during maximal dilation of the arteriole produced
by a local application of 10
3 M adenosine using a Pasteur
pipette. Arteriolar responses to increased O2 availability
were determined by measuring vessel diameter before and after the
O2 concentration of the superfusion solution was increased
from 0 to 21% O2.
Blockade of 20-HETE formation. After a 1-h equilibration period during which the superfusion solution was equilibrated with a 0% O2-5% CO2-95% N2 gas mixture, control measurements of arteriolar diameter and MAP were obtained for 5 min. The superfusion solution was then equilibrated with a 21% O2-5% CO2-74% N2 gas mixture, and arteriolar diameter and MAP were measured for 10 min to determine the magnitude of the O2-induced vasoconstriction during the control period (before the vessels were treated with the CYP4A inhibitors or vehicle). The superfusion solution was then equilibrated with a 0% O2 mixture to allow the vessel to recover to control diameter.
Once recovery of arteriolar diameter under 0% O2 superfusion was achieved, arteriolar responses to elevation of superfusion solution PO2 were determined after inhibition of CYP4A-hydroxylase. In these experiments
either 10 µM ODYA, 50 µM DDMS, or the vehicle for the inhibitor (a
0.1% solution of absolute ethanol in PSS) was applied over the
preparation utilizing a Razel syringe pump (model A99, Razel Scientific
Instruments) at a rate of 0.3 ml/min for 30 min. During this period of
time the superfusion solution was stopped and the preparation was kept
evenly moist by a top dressing of tissue paper. After the application
of 17-octadecynoic acid (ODYA),
N-methyl-sulfonyl-12,12-dibromododec-11-enamide (DDMS), or
vehicle, superfusion with PSS equilibrated with the 0% O2
gas mixture was restored. After the initial exposure to DDMS, the preparation was superfused with PSS containing 1 µM DDMS for the duration of the experiment, because DDMS is a reversible inhibitor of
CYP4A -hydroxylase. Arteriolar diameter and MAP were measured every
minute for a 5-min control period, and then the superfusion solution
was equilibrated with a 21% O2-5% CO2-74%
N2 gas mixture. Arteriolar diameter and MAP were measured
each minute for 10 min to determine the magnitude of
O2-induced constriction of the arterioles after vehicle
treatment or inhibition of CYP4A -hydroxylase.
In another series of experiments, we tested the effect of ODYA and DDMS
on the ability of the vessels to constrict in response to either
elevated K+ or norepinephrine (NE) to verify that the
blockade of O2-induced constriction of the arterioles by
these inhibitors was not due to a nonspecific reduction in the ability
of the vessels to respond to contractile activation. In those
experiments the preparation was superfused for 1 h with control
PSS equilibrated with the 0% O2-5% CO2-95%
N2 gas mixture. At the end of the equilibration period, arteriolar diameters were measured during superfusion of the
preparation with PSS containing either 30 mM K+ or
increasing concentrations of NE (108 M-106
M). After determination of arteriolar constriction in response to
elevated K+ or NE, the preparation was superfused with
normal PSS to allow vessel diameters to recover to control values.
CYP4A -hydroxylase enzymes were then inhibited with ODYA or DDMS as
described above, and arteriolar constriction in response to elevated
K+ or NE was retested.
Western blot for CYP4A -hydroxylase.
To verify the presence of CYP4A -hydroxylase protein in the
cremaster muscle of rats, we performed Western blots on whole cremaster
muscles and on individual arterioles and skeletal muscle fibers that
were isolated from the tissue via microdissection. In these
experiments, rats were anesthetized with pentobarbital sodium and the
cremaster muscle was excised and placed in ice-cold methanol to inhibit
protease activity. The muscle was then fast-frozen in liquid nitrogen
and stored at 
80°C until homogenization. To isolate the arterioles
and skeletal muscle fibers, the cremaster muscle was pinned out flat in
a petri dish containing ice-cold methanol that was placed in a
Plexiglas chamber with circulating ice-cold water. The arterioles and
individual muscle fibers were removed by microdissection, placed on a
stainless steel plate on dry ice, fast-frozen in liquid nitrogen, and
stored at 80°C until homogenization.
-hydroxylase proteins from cremasteric muscle fibers and arterioles
are glycosylated, the blots were stained with an Immun-Blot kit for
glycoprotein detection (Bio-Rad; Hercules, CA). In this protocol (which
is completed on a nitrocellulose membrane after electrophoretic
separation of the proteins) all the glycoproteins in the sample are
biotinylated and subsequently visualized after incubation in
streptavidin-alkaline phosphatase and color-development reagents.
Immunohistochemical studies.
Immunohistochemical techniques were used to localize the CYP4A
-hydroxylase more precisely in the cremaster muscle. Frozen tissue
sections 7-10-µm thick were air dried and then fixed in cold
acetone (20°C). The samples were then rehydrated in Tris buffer (50 mM Tris and 150 mM NaCl, pH 7.4) for 10 min and blocked in a solution
of 2% normal rabbit serum (Santa Cruz Biolaboratory) in Tris and 2%
BSA for 20 min. A 1:125 dilution of CYP4A1, a CYP polyclonal antibody
(Daiichi Pure Chemical) in PBS with 1% normal serum, was applied to
some of the slides for 1 h at room temperature. Control
slides were incubated with normal rabbit serum only. The slides were
then rinsed in PBS for 5 min and the secondary antibody, a 1:500
dilution of biotinylated anti-goat IgG in PBS with 1% normal serum,
was applied for 30 min (Vector Laboratories; Burlingame, CA) and rinsed
in PBS for 5 min. The sections were then incubated for 30 min
with Vectastain Elite ABC reagent, washed in buffer for 5 min,
incubated in peroxidase substrate solution, and counterstained with
Biomeda hematoxylin for 1 min.
80°C freezer. At the
time of use the tissue was transferred to a 16°C cryostat and
mounted on a cryostat stub with OCT compound. Sections (3-4 µm
thick) were cut, mounted on glass slides, and allowed to dry overnight
at room temperature. The next day the sections were fixed for 5 min in
a mixture of 75% acetone-25% ethanol and rinsed twice (5 min each) in
PBS. The sections were initially blocked with an avidin-biotin blocking
kit (Vector Laboratories) and then blocked with normal rabbit serum.
After avidin blocking, the slides were exposed to a 1:125 dilution of
CYP4A1 antibody for 4 h at room temperature. After a 5-min rinse
in PBS, the tissue was incubated in biotinylated anti-goat IgG (ABC
Elite kit, Vector Laboratories) for 30 min and then rinsed for 5 min in
PBS. The tissue was incubated in Vectastain ABC reagent for 30 min and
rinsed for 5 min in PBS. The CYP4A1 peroxidase was localized with
3,3'-diaminobenzidine (Vector Laboratories) for 10 min. The
sections were then rinsed in water, dehydrated, covered with
coverslips, and subsequently viewed with a Nikon E600 microscope
equipped with a Princeton Instrument digital camera.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The response of third-order arterioles in rat cremaster muscle to
superfusion with 21% O2 solution before and after ODYA, DDMS, or vehicle is summarized in Fig. 1.
ODYA and DDMS significantly inhibited the O2-induced
constriction of the arterioles from 7 ± 2 to 0.8 ± 0.5 µm (ODYA) and from 5 ± 0.7 to 0.1 ± 0.4 µm (DDMS).
O2-induced constriction of the arterioles was unaffected by
superfusion with the vehicle alone.
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Figure 2 summarizes the magnitude of
arteriolar constriction in response to 30 mM K+ and
increasing concentrations of NE (108-106 M)
before and after inhibition of CYP4A -hydroxylases with ODYA and
DDMS. Constriction of the arterioles in response to K+ (30 mM) and NE was unaffected by ODYA and DDMS (Fig. 2) or the vehicle for
ODYA and DDMS (data not shown).
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Figure 3 is a representative Western blot
of the whole cremaster muscle, isolated cremasteric arterioles, and
individual skeletal muscle fibers. Immunoreactivity for CYP4A isoforms
was present in the whole muscle, the arterioles, and the skeletal
muscle cells. However, these immunoreactive bands ran at a
molecular mass of 85 kDa, which is 30 kDa heavier than that typically
found in the rat liver and kidney microsomes (positive control) and in
vessels isolated from the brain and kidney (12, 25).
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Figure 4 is a representative Western blot
of the whole cremaster muscle after the deglycosylation procedure.
After treatment with the various deglycosylation enzymes (PGNase F,
sialidase A, and endo-O-glycosylase), the immunoreactive
band that originally migrated to a molecular mass of 85 kDa shifted to
a molecular mass position on the gel that corresponds with that of the
positive control for the CYP4A1 enzyme.
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Figure 5 is an immunoblot of whole
cremaster muscle after completion of the glycoprotein detection
protocol. Glycoprotein bands are clearly visible at 85 kDa, the
position corresponding to the molecular mass marker of the CYP4A1
immunoreactive protein isolated from the cremaster muscle. These bands
are absent after incubation of the cremaster muscle microsomes with
PGNase F, sialidase A, and endo-O-glycosylase.
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The result of a typical immunohistochemical experiment on tissue
sections from rat cremaster muscle and liver is presented in Fig.
6. In these experiments immunoreactivity
for CYP4A protein in the cremaster muscle appears in both the
microvessels and the skeletal muscle fibers. In sections stained with
the CYP4A antibody, the arteriolar smooth muscle cells exhibited dense
staining; however, the skeletal muscle cells in the tissue parenchyma
exhibited a diffuse staining throughout the cytoplasm with a darker
area of staining in the cell membrane. Sections of liver incubated with the CYP4A antibody as a positive control exhibited dense staining throughout the tissue. In the tissue sections incubated with
normal rabbit serum, staining is absent in the parenchymal cells of the cremaster muscle and liver and in the cremasteric microvessels, demonstrating the lack of nonspecific binding in the tissue.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Very little is known about the nature and location of the O2 sensor mediating the constriction of resistance vessels during increases in O2 availability. There is some evidence that elevated PO2 causes constriction of skeletal muscle arterioles by reducing the release of vasodilator prostaglandins from the endothelium (23). In other studies, Jackson (16, 17) demonstrated that leukotriene antagonists and lipoxygenase inhibitors block the constriction of arterioles in response to increased superfusion solution PO2 in the epithelial portion of the hamster cheek pouch. However, in a subsequent study Jackson (18) reported that O2-induced constriction of arterioles in the hamster cremaster muscle is not blocked by leukotriene antagonists and lipoxygenase inhibitors, indicating that some other mechanism mediates O2-induced constriction of arterioles in that vascular bed.
Although there has been some support for the hypothesis that
O2-induced constriction of arterioles is mediated by the
formation of a vasoconstrictor metabolite in response to elevated
PO2, a major limitation of this hypothesis has
been the lack of suitable candidate metabolites that are
vasoconstrictors and, most importantly, are formed in response to
elevations of PO2 through the physiological range. However, recent studies have demonstrated that increases in
PO2 over the physiological range cause a
progressive increase in the formation of 20-HETE by CYP4A
-hydroxylase (13) and that blockade of CYP4A
-hydroxylase inhibits O2-induced constriction in several
vascular beds, namely the rat cremaster muscle (13), the
hamster cremaster muscle (19), and the hamster cheek pouch retractor muscle (19). The observations that
1) CYP4A -hydroxylase produces a vasoconstrictor
metabolite (20-HETE) that depends on O2 concentration over
the physiological range of PO2, and
2) O2-induced constriction in the skeletal
muscle microcirculation is blocked by inhibiting CYP4A -hydroxylase
suggest that 20-HETE may be a candidate for the vasoconstrictor
substance that mediates the local control of blood flow during
increased O2 availability in this vascular bed. In
the present study we demonstrated that the O2-induced
constriction of arterioles in the rat cremaster muscle is inhibited by
both ODYA and DDMS, two mechanistically different inhibitors of the
formation of 20-HETE. Taken together these observations provide further
support for the hypothesis that O2-induced constriction of
skeletal muscle arterioles is mediated via the formation of 20-HETE by
CYP4A -hydroxylase.
In the present study Western blots as well as immunohistochemistry
demonstrated that CYP4A -hydroxylase, a potential sensor for
O2-induced constriction of arterioles, is localized in the arterioles themselves and in the surrounding skeletal muscle cells. Taken together these observations indicate that elevations in PO2 in the cremaster muscle can be sensed by
the microvessels and the surrounding parenchymal tissue.
A particularly interesting finding of this study is that CYP4A
-hydroxylase appears to be glycosylated in the cremaster muscle of
the Sprague-Dawley rat. This finding differs from previous studies of renal tissues (1) and raises a number of
interesting questions. One possible interpretation of this finding is
that the enzyme is membrane bound in skeletal muscle. The latter
hypothesis is supported by our immunohistochemistry studies in which
the most intense staining of the skeletal muscle cells appeared at the
level of the plasma membrane. This is an important observation because
the presence of glycosylation suggests the possibility that the protein
is targeted, perhaps within the Golgi apparatus, for the cell membrane
in the skeletal muscle fibers and probably in the vascular smooth
muscle cells. This would not only enable the enzyme to participate in
receptor-mediated vasoconstrictor responses (29) but would
also position the enzyme at a location that would enable it to monitor
PO2 levels at the cell surface. Another
possible interpretation for the findings of the present study is that
the enzyme itself is not glycosylated but that a glycosylated molecule
of some kind is binding to the enzyme. In the latter case, the change
in molecular weight occurring in response to the deglycosylation
enzymes may be due to the enzymatically induced dissociation of the
molecules rather than deglycosylation of the CYP enzyme itself.
Regardless of the presence or absence of direct glycosylation of the
enzyme in skeletal muscle, important questions that remain to be
answered are whether the activity of CYP4A -hydroxylase in this
tissue is similar to that in other tissues and how the activity of this
enzyme is regulated in skeletal muscle.
In summary the results of the present study demonstrate that CYP4A
-hydroxylase protein is present in a vascular bed where O2-induced constriction is blocked by inhibitors of the
formation or action of 20-HETE, providing further evidence in support
of the hypothesis that 20-HETE is an important mediator of
O2-induced constriction in the skeletal muscle
microcirculation. These studies also demonstrated that CYP4A
-hydroxylase is located in both the arterioles and the skeletal
muscle cells surrounding the blood vessels. Because 20-HETE formation
by this enzyme depends on O2 over the physiological range
of PO2, the present studies indicate that
O2 sensing by this enzyme system can occur both in the
microvessels and in the parenchymal tissue. This provides important
insight into the longstanding question of whether the sensor for
O2-induced vasoconstriction in the microcirculation serves
to regulate O2 supply to the parenchymal cells, whether it
detects O2 levels in the blood vessels themselves, or
whether it acts at both sites.
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ACKNOWLEDGEMENTS |
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The technical assistance of Janet DeBruin for the Western blots and the immunohistochemistry and Lourdes de la Cruz for the glycoprotein detection studies is greatly appreciated.
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FOOTNOTES |
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This study was supported by National Institutes of Health Grants HL-37374, HL-29587, NR-00105, and DK-38226.
Address for reprint requests and other correspondence: J. H. Lombard, Dept. of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. (E-mail: jlombard{at}mcw.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 7 July 2000; accepted in final form 15 November 2000.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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  Y.-J. Chen, J. Li, and J. Quilley Deficient renal 20-HETE release in the diabetic rat is not the result of oxidative stress Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2305 - H2312. [Abstract] [Full Text] [PDF]
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P. J. Marvar, J. R. Falck, and M. A. Boegehold High dietary salt reduces the contribution of 20-HETE to arteriolar oxygen responsiveness in skeletal muscle Am J Physiol Heart Circ Physiol, March 1, 2007; 292(3): H1507 - H1515. [Abstract] [Full Text] [PDF]
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 J.-S. Wang, H. Singh, F. Zhang, T. Ishizuka, H. Deng, R. Kemp, M. S. Wolin, T. H. Hintze, N. G. Abraham, A. Nasjletti, et al. Endothelial Dysfunction and Hypertension in Rats Transduced With CYP4A2 Adenovirus Circ. Res., April 14, 2006; 98(7): 962 - 969. [Abstract] [Full Text] [PDF]
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J. Wang, R. J. Roman, J. R. Falck, L. de la Cruz, and J. H. Lombard Effects of high-salt diet on CYP450-4A {omega}-hydroxylase expression and active tone in mesenteric resistance arteries Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1557 - H1565. [Abstract] [Full Text] [PDF]
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 A. D. Baines and P. Ho 20-HETE-mediated vasoconstriction by hemoglobin-O2 carrier in Sprague-Dawley but not Wistar rats J Appl Physiol, March 1, 2005; 98(3): 772 - 779. [Abstract] [Full Text] [PDF]
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F. Zhang, M.-H. Wang, J.-S. Wang, B. Zand, V. R. Gopal, J. R. Falck, M. Laniado-Schwartzman, and A. Nasjletti Transfection of CYP4A1 cDNA decreases diameter and increases responsiveness of gracilis muscle arterioles to constrictor stimuli Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1089 - H1095. [Abstract] [Full Text] [PDF]
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S. L. Amaral, K. G. Maier, D. N. Schippers, R. J. Roman, and A. S. Greene CYP4A metabolites of arachidonic acid and VEGF are mediators of skeletal muscle angiogenesis Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1528 - H1535. [Abstract] [Full Text] [PDF]
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 R. J. Roman P-450 Metabolites of Arachidonic Acid in the Control of Cardiovascular Function Physiol Rev, January 1, 2002; 82(1): 131 - 185. [Abstract] [Full Text] [PDF]
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 F. Zhang, M.-H. Wang, U.M. Krishna, J. R. Falck, M. Laniado-Schwartzman, and A. Nasjletti Modulation by 20-HETE of Phenylephrine-Induced Mesenteric Artery Contraction in Spontaneously Hypertensive and Wistar-Kyoto Rats Hypertension, December 1, 2001; 38(6): 1311 - 1315. [Abstract] [Full Text] [PDF]
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