(Hypertension. 1997;30:203-208.)
© 1997 American Heart Association, Inc.
Articles |
Myogenic Tone Attenuates Pressure-Induced Gene Expression in Isolated Small Arteries
From the Department of Physiology, Eastern Virginia Medical School, Norfolk, Va.
Correspondence to Russell L. Prewitt, PhD, Department of Physiology, Eastern Virginia Medical School, PO Box 1980, Norfolk, VA 23501. E-mail RLP{at}BORG.EVMS.EDU
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Abstract |
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Abstract This study was designed to determine whether pressure-induced expression of early response genes in the arterial wall is dependent on an increase in cell stretch or an increase in wall stress. Mesenteric arteries (245 to 385 µm in diameter) were isolated from Wistar rats and subjected to static pressures of either 90 mm Hg (control), 140 mm Hg, or 165 mm Hg for a period of 3 hours. Arteries developed a range of myogenic tone such that wall stresses in the 140 and 165 mm Hg arteries (1.60 to 4.44x106 dynes/cm2) were equivalent in some cases to those of controls (1.76 to 2.63x106 dynes/cm2). Vessels subjected to 140 or 165 mm Hg intraluminal pressure had diameters ranging from 74% to 104% of their relaxed diameter at 90 mm Hg, whereas control vessel diameters ranged from 88% to 100%. At the end of each experiment, vessels were fixed in 10% formalin, embedded in paraffin, and sectioned for in situ hybridization. Wall stress significantly correlated with c-myc mRNA and 18S rRNA expression. Gene expression did not correlate with vessel diameter, expressed as a percentage of the relaxed diameter at 90 mm Hg, ie, cell stretch. The expression of ß-actin mRNA did not differ between vessels and showed no correlation with wall stress, suggesting that the induction of c-myc mRNA and 18S rRNA was part of a specific response. These findings show that in an isolated artery, a pressure stimulus can be perceived as an increase in wall stress, independently of cell stretch. Therefore, wall stress may be the signaling parameter in hypertension where arteries are tonically constricted. The inhibition of gene expression by myogenic constriction may explain why hypertrophy takes place in large arteries during hypertension but not in arterioles where increased tone reduces wall stress.
Key Words: arteries • hypertrophy • myogenic tone • pressure • stress
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Introduction |
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In essential hypertension in humans, walls of large arteries hypertrophy, whereas arterioles remodel into vessels with smaller lumens without medial hypertrophy.1 Small arteries located at the transition from conduit to resistance vessels undergo both lumen reduction and hypertrophy, a process of inward hypertrophic remodeling.2 Wall hypertrophy is the dominant structural change in the SHR,3 4 5 but eutrophic inward remodeling of arterioles in renal hypertensive rats6 7 is very similar to that seen in essential hypertension. These structural changes result in an increase in the media to lumen ratio, which helps maintain hypertension by increasing peripheral resistance and responsiveness to vasoconstrictor stimuli.8 In the SHR, the use of antihypertensive drugs3 4 to lower blood pressure and the use of ligatures to protect parts of the vascular system from the increase in pressure5 attenuate these changes, suggesting that pressure itself may be a major stimulus for both hypertrophy and remodeling. The present study addresses the question of how a single mechanical signal of elevated pressure can lead to both hypertrophy of arteries and inward eutrophic remodeling of arterioles.
The second question is how a change in pressure is sensed by the VSMC. Cell stretch has been shown to stimulate second messenger production and growth responses in many different studies, especially those in isolated VSMC9 10 11 12 13 14 15 and segments of whole vessels.16 17 18 19 20 21 While these studies indicate that cell stretch is sufficient stimulus for a growth response, the mechanism by which these cells sense stretch is unclear. In these models, stretching of the cells is invariably associated with an increase in wall tension, and it has been suggested that this factor plays an important role in mechanotransduction.16 18 20 It is unlikely that VSMC in artery walls will actually be stretched during the development of hypertension, although they will experience an increase in circumferential wall stress. A recent study by Wilson et al15 shows that signal transduction of cyclical stretch is mediated through specific integrins recognizing the RGD binding motif. Considering this, stretch-activated phospholipase C19 or opening of ion channels22 by stretch of the cell membrane may not be necessary for signal transduction.
We have shown previously in an isolated pressurized mesenteric artery preparation that a 60% to 80% increase in wall stress with minimal cell stretch (<3%) was sufficient to stimulate proto-oncogene expression and rRNA production, suggesting that wall stress may indeed be the factor sensed in these vessels.23 This present study was therefore undertaken to completely dissociate wall stress from cell stretch by using smaller mesenteric arteries that develop myogenic tone, ie, they are able to constrict as pressure is increased. This made it possible to raise intraluminal pressures such that wall stresses were significantly elevated while the vessels were still constricted; therefore, VSMC were not stretched in these preparations. The results of this study clearly demonstrate a correlation between wall stress and changes in expression of c-myc and 18S rRNA in these arteries. This indicates that wall stress can be sensed independently of cell stretch and suggests that the detection of cell stretch may in fact be dependent on an increase in wall stress.
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Methods |
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Isolation of Mesenteric Arteries
Twenty-three male Wistar rats weighing between 183 and 353 g were anesthetized with a subcutaneous injection of ketamine/xylazine (80/12 mg/kg) and killed by cervical dislocation. The experimental protocol was approved by the institutional animal care and use committee. An incision was made in the abdominal wall, and the mesentery was carefully dissected away from the intestine and placed in cold (4°C) dissection buffer (30 mmol/L MOPS, 1.2 mmol/L NaH2PO4, 5 mmol/L glucose, 2 mmol/L pyruvate, 0.02 mmol/L [disodium salt] EDTA, 145 mmol/L NaCl, 4.7 mmol/L KCl, 2 mmol/L CaCl2, 1.2 mmol/L MgSO4, 10 g/L BSA, pH 7.4, osmolarity 290 to 310). Two arteries per animal were dissected free of fat and excised. Mesenteric arteries of 224 to 385 µm were mounted on pipettes in a dual-vessel chamber. Vessels were superfused at 4 mL/min with HEPES-buffered Krebs (112 mmol/L NaCl, 11.5 mmol/L glucose, 25.5 mmol/L NaHCO3, 10 mmol/L HEPES, 1.2 mmol/L MgSO4, 2.5 mmol/L CaCl2, 1.2 mmol/L KH2PO4, 4.7 mmol/L KCl) gassed with air/CO2 (95%/5%). The medium was maintained at a temperature of 37°C and a pH of 7.4 throughout each experiment. The intraluminal pressure (with no flow) was then increased from 30 mm Hg in steps of 15 mm Hg per 15 minutes over a 1-hour period until a pressure of 90 mm Hg was reached. During this initial pressurization period, many of the vessels typically developed spontaneous myogenic tone. Each vessel was allowed to constrict until it reached a stable diameter at 90 mm Hg.
Experimental Treatment of Vessels
Vessels were assigned to either a control or one of two
high-pressure groups. Intraluminal pressure was left at 90 mm
Hg in controls; pressure in the high-pressure groups was initially
raised to either 140 or 165 mm Hg. Control and high-pressure
vessels were paired until 10 control vessels were obtained, and then
both arteries were maintained at the elevated pressures, resulting in
data from 20 arteries at 140 mm Hg and 10 at 165 mm
Hg. Vessels were maintained at their designated experimental pressure
for a period of 3 hours. At the end of each experiment, the pressure in
all vessels was set to 90 mm Hg while each vessel was
constricted with norepinephrine (2 µmol/L)
and dilated with acetylcholine (2 µmol/L) to check that
the vessels were still viable and the endothelium was
intact. Vessels were immediately fixed in 10% buffered formalin,
processed in graded alcohols and xylene, and embedded in paraffin for
sectioning.
Measurement of Arterial Dimensions
Throughout each experiment, the vessels were observed with
closed-circuit television microscopy using a x10 objective on a Zeiss
ACM microscope. Internal and external diameters of each vessel were
measured with a video image shearer (Vista model 308) and used to
calculate wall thickness. Wall tension was calculated using the La
Place relation, which states that Wall Tension=Transmural
PressurexRadius. Wall stress in each vessel was derived by dividing
wall tension by wall thickness.
In Situ Hybridization and Quantification
The protocols for in situ hybridization with
35S-labeled riboprobe and for quantification have been
described previously.23 Briefly, paraffin sections of
arteries (4 µm) were mounted on Superfrost/Plus slides.
Experimentally paired vessels (4 to 5 sections of each) were mounted on
the same slide so that hybridization conditions were identical. Slides
were deparaffinized, and the vessels were rehydrated in graded alcohol
and then washed with 0.5x SSC (sodium citrate, sodium chloride).
Vessels were treated with proteinase K at room temperature, washed
three times with PBS, and fixed in 4% paraformaldehyde
for 15 minutes at 4°C. Slides were washed three times with PBS and
allowed to air dry. The vessel sections were then covered with 200 µL
prehybridization solution (10% dextran sulfate, 1x Denhardt's
solution, 1 mmol/L EDTA, 10 mmol/L Tris, 0.3
mol/L NaCl, 50% formamide, 0.5 mg/mL yeast tRNA, 10
mmol/L DTT) and incubated for 2 to 3 hours at 38°C to 42°C
in a humidified hybridization box. Slides were briefly washed with
0.5x SSC, covered with 100 µL hybridization solution
(prehybridization solution containing 107 cpm of probe per
milliliter), and incubated overnight at the calculated melting
temperature of the riboprobe (50°C to 55°C) in a humidified
hybridization box. Slides were washed with 2x SSC containing 1
mmol/L EDTA and 10 mmol/L ß-mercaptoethanol, then
treated with RNase A for 30 minutes at room temperature. Slides were
then washed in the following solutions: 2x SSC containing 1
mmol/L EDTA and 10 mmol/L ß-mercaptoethanol, 0.1x
SSC containing 1 mmol/L EDTA and 10 mmol/L
ß-mercaptoethanol at 55°C, and 0.5x SSC. Finally, the vessel
sections were dehydrated in graded alcohols and air dried.
Results were quantified by densitometric analysis of the slides with a Molecular Dynamics PhosphorImager SF. Slides were exposed on the phosphorimager screen for 5 to 7 days before analysis. Using a volume integration function, the total density minus background was determined for each vessel cross section. The mean value in arbitrary units was calculated to obtain a single value for each vessel. For c-myc, any values for sense were subtracted from antisense to obtain specific binding.
Materials
The cDNA for c-myc was a 1.4-kb fragment of exons 2
and 3 obtained from Michael Cole (Princeton University). Human
18S rRNA and ß-actin templates were obtained from Ambion Inc.
Radiolabeled CTP was obtained from Du Pont. All other chemicals or
biochemicals were obtained from Sigma Chemical Co, Fisher Scientific,
Gibco BRL, or Promega.
Statistics
Data are presented as mean±SEM. Statistical
analysis was performed by ANOVA and linear regression
analysis with rejection of the null hypothesis at a value
of P<.05.
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Results |
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Diameters and Wall Stresses
Fig 1
shows the group data for
internal diameter of the arteries throughout the experiment. As the
pressure was raised stepwise to 70 mm Hg, the diameter
increased in all groups. After that, the mean diameter was maintained
in the 90 and 140 mm Hg groups and decreased in the 165
mm Hg group because of myogenic constriction. Four of the 10
arteries in the control group constricted to increasing pressure,
whereas 12 of 20 arteries in the 140 mm Hg group and 7 of the
10 arteries in the 165 mm Hg group showed myogenic tone.
Myogenic tone was greatest in the latter group but tended to decrease
during the 3-hour period of elevated pressure. The myogenic
constrictions of the vessels varied such that the ranges of wall
stresses for each of the groups were from 1.76 to 2.63, 1.60 to 4.44,
and 2.52 to 3.62x106 dynes/cm2 for control
(90 mm Hg), 140 mm Hg, and 165 mm Hg,
respectively.
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There were no significant differences in the responses of any of the different groups to treatment with norepinephrine (2 µmol/L) or acetylcholine (2 µmol/L), showing that vessels without tone were equally viable and capable of constricting. The response to acetylcholine indicates the presence of a functional endothelium and provided a measurement of relaxed diameter that did not differ between the groups.
Expression of c-myc mRNA
Quantitation of in situ hybridization by phosphorimager is an
unusual application that is suitable in this case, as previously
shown,23 because expression of proto-oncogenes and 18S
rRNA is uniform across the vessel media, there are no adjoining tissues
in the samples, and the density measurements correlate with
quantitation by autoradiography using grain
counting.
Fig 2 shows the expression of
c-myc plotted as a function of pressure groups (A), mean
wall stress throughout the experiment (B), and the experimental
diameter (C), shown as a percentage of the relaxed diameter at 90
mm Hg. The group comparisons show a highly significant increase in
c-myc expression in the 140 mm Hg group but not in
the 165 mm Hg group, possibly because of the greater myogenic
tone in that group. There was a direct correlation between wall stress
and c-myc expression in these vessels, with a correlation
coefficient of .616 (Fig 2B). As can be seen in this figure, most of
the arteries with high wall stress are from the 140 mm Hg
group.
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The correlation of c-myc expression with experimental
diameter (Fig 2C
) is not statistically significant. Experimental
diameter shown as a percentage of relaxed diameter at 90 mm
Hg is an indicator of cell length rather than vessel size. Thus, if
cell stretch were the important parameter, a strong
correlation should be present in this graph.
Expression of 18S rRNA
The group data for 18S rRNA expression (Fig 3A) show significant elevations in both
of the high-pressure groups, but raising the pressure to 165
mm Hg did not increase expression above that of the 140
mm Hg group. The significant correlation with wall stress (Fig 3B)
again suggests that this is the important parameter for a
pressure increase to activate a growth response. The lack of
any correlation with experimental diameter (Fig 3C) suggests once again
that cell stretch is not required for this response to occur.
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Expression of ß-Actin mRNA
Fig 4 shows expression of ß-actin
mRNA again as a function of pressure group (A), wall stress (B), and
experimental diameter (C). There were no differences in ß-actin
expression among the three pressure groups and no correlation between
ß-actin expression and wall stress or experimental diameter. This
suggests that the increases in c-myc and 18S rRNA seen with
increased wall stress represent a specific pattern of gene
expression rather than a generalized upregulation of all genes.
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Discussion |
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In hypertension, many mechanisms may contribute to hypertrophy of the vascular wall. In all cases, however, there is an increase in intraluminal pressure that in itself may play an important role in hypertrophy. Interventions that lower blood pressure in the SHR, either by drug treatment3 4 or use of a ligature to protect a part of the vascular system,5 normalize arterial structure, suggesting that pressure itself may be one of the dominant factors influencing vessel-wall hypertrophy. The use of in vivo models, however, is confounded by the presence of hormonal as well as mechanical effects. Mechanical effects can be studied separately by use of in vitro approaches to the problem. Studies using cultured VSMC subjected to stretch have produced considerable amounts of information,9 10 11 12 13 14 15 but because of possible phenotypic changes,24 25 some caution must be used when interpreting these results. Stretching cells 10% to 20%, either cyclically or statically, has been shown to result in an increase in phosphoinositide turnover,13 an increase in adenylate cyclase activity,11 and proto-oncogene induction.12 13 These early signaling events are followed by increases in protein9 10 and DNA12 14 15 synthesis. The autocrine release of PDGF-AA has been implicated in this model, since antibodies to PDGF-AA significantly blocked the mitogenic effects of stretch.14 In this model, it has also been demonstrated that stretch is sensed through specific matrix/integrin interactions because treatment with RGD peptide or antibodies to ß3 or
vß5 integrins also abolished the
mitogenic effects of stretch.15 Another
approach taken to investigate the effects of stretch was the use of
stretched whole-vessel preparations, which have the advantage over
isolated cell cultures in that cell-cell and cell-matrix interactions
are maintained. Stretched vessels showed increased phospholipase C
activity19 and DNA16 18 20 and
protein17 18 synthesis, showing that stretch is also a
stimulus for growth in whole vessels. The stimulus used in these whole vessels and cultured smooth muscle cells (ie, cell stretch) may not be the same as the stimulus occurring in hypertension. In vivo, vessels maintain tone and the VSMC are embedded in an extracellular matrix where they are unlikely to experience an increase in cell length with developing hypertension. Both cultured cells and cells in situ, however, are anchored through their integrins, making it possible that the mechanotransduction pathway has similar features whether the cell is stretched or responds to an increase in pressure, since both will experience an increase in stress conducted through the adhesion molecules.26 Indeed, in isolated arteries, an increase in intraluminal pressure results in the production of second messengers inositol 1,4,5-trisphosphate and 1,2-diacylglycerol21 and also protein synthesis.27 We have shown previously that in mesenteric arteries subjected to high pressures, proto-oncogene and 18S rRNA expression are specifically increased,23 demonstrating that these vessels are able to sense the increase in pressure and elicit the signaling pathways that immediately precede a growth response.28 Those vessels were largely passive, thereby subjecting the high-pressure vessels to a small degree of circumferential stretch (<3%). This amount is much smaller than is typically applied in cell culture (10% to 20%), but it may have contributed to signal transduction. In addition to this increase in cell stretch, there was also a significant increase in wall stress (60% to 80%) in the high-pressure vessels,23 which may been the stimulus for growth.
The present study was an attempt to differentiate between cell
stretch and wall stress more completely in the same isolated
pressurized mesenteric artery preparation. In these experiments, many
of the vessels showed some degree of myogenic constriction as the
pressure was increased, resulting in a decrease in vessel diameter. At
high pressures (140 or 165 mm Hg), vessels showed a range of
myogenic constriction such that the resulting wall stresses ranged from
equal to approximately double those seen in controls (90 mm
Hg). On the basis of results of our earlier study,23 we
selected the 3-hour time point at which increased expression of both
c-myc and the very abundant 18S rRNA could be detected.
Phosphorimages showed that gene expression was uniform throughout the
media of the arteries, and this was confirmed by
autoradiography,23 but detection with the
phosphorimager does not rule out the possibility that expression also
occurs in endothelial cells, adventitia, or any neural
tissue in the vascular wall. In the present experiments, the
induction of c-myc and 18S rRNA was attenuated in mesenteric
arteries showing myogenic responses in which vessel wall stresses were
normalized (Figs 2B and 3B). The stimulus for proto-oncogene and rRNA
expression was therefore most likely the increase in wall stress, since
this correlated significantly with gene expression. Cell stretch would
not appear to be important in this model because there was no
correlation between normalized vessel diameter, ie, cell stretch, and
gene expression (Fig 2C and 3C). Increased gene expression was observed
in constricted vessels where the cells were shorter than those in
control vessels, but wall stress was elevated by an increase in the
pressure. This also shows that the myogenic response did not directly
reduce gene expression through a signaling pathway but only by virtue
of the reduced wall stress.
These results therefore suggest that wall stress and not cell stretch may be the important factor sensed by the vasculature during hypertensive disease. The finding that vessels with myogenic responses and normalized wall stresses do not show increased gene expression may explain why the small arterioles in the hypertensive vasculature respond differently than the arteries. Large arteries in the hypertensive vasculature undergo hypertrophy, leading to an increased media to lumen ratio.3 29 In contrast, the arterioles (<100 µm) that show the largest myogenic constrictions are therefore the most likely to normalize wall stress by lumen reduction during hypertension. This is accomplished first by active vasoconstriction followed by structural changes, ie, inward eutrophic remodeling.6 7 In between are the small arteries (100 to 300 µm) that develop some tone and undergo a combination of hypertrophy and lumen reduction.2 30 These findings suggest that arteries regulate wall stress through a gradient of responses, with hypertrophy decreasing from large arteries to the smallest and lumen reduction varying in the reverse direction. The hypertrophic response varies inversely with the myogenic ability of the vessel. In the terminal arterioles, where pressure has been normalized by upstream resistance, there appears to be little difference between hypertensive and normotensive vessels.6 7 31 32
Although constriction of an artery may inhibit the growth response as measured by expression of early response genes, it is possible that maintained constriction initiates another signaling pathway with different end points. An isolated VSMC constricts in a corkscrewlike fashion33 because of the arrangement of the actin filaments and focal adhesion sites. In the vascular wall, such a constriction reduces circumferential wall stress, but it may result in tangential shearing stress between focal adhesion sites and the matrix. Focal adhesion sites on endothelial cells undergo continuous remodeling, which becomes directed in the line of flow when the cells are exposed to a shear stress.34 A similar realignment of adhesion sites on VSMC may be part of the remodeling process of the arteriolar wall whereby the lumen becomes structurally reduced without hypertrophy.
The isolated mesenteric vessel preparation therefore appears to be an advantageous model for investigating early mechanotransduction events. This model may complement cell stretch experiments because both cell stretch and increased wall stress, with and without cell stretch, most likely result in an increase in stress in the cytoskeleton and focal adhesions. The integrins and associated molecules, particularly protein kinases and mediators of phospholipid metabolism,35 may therefore play an important initial role in mechanotransduction events, as has been suggested by Wilson et al.15
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by National Institutes of Health grants HL-36551 and HL-54810 and the Thomas F. Jeffress and Kate Miller Jeffress Memorial Trust. Dr Allen is the recipient of a Fellowship from the American Heart Association, Virginia Affiliate.
Received June 21, 1996; first decision July 18, 1996; accepted January 21, 1997.
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P. Fridez, A. Rachev, J.-J. Meister, K. Hayashi, and N. Stergiopulos Model of geometrical and smooth muscle tone adaptation of carotid artery subject to step change in pressure Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2752 - H2760. [Abstract] [Full Text] [PDF]
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C. M. Spofford and W. M. Chilian The elastin-laminin receptor functions as a mechanotransducer in vascular smooth muscle Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1354 - H1360. [Abstract] [Full Text] [PDF]
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J. P. M. Wesselman, A. D. Dobrian, S. D. Schriver, and R. L. Prewitt Src Tyrosine Kinases and Extracellular Signal-Regulated Kinase 1/2 Mitogen-Activated Protein Kinases Mediate Pressure-Induced C-Fos Expression in Cannulated Rat Mesenteric Small Arteries Hypertension, March 1, 2001; 37(3): 955 - 960. [Abstract] [Full Text] [PDF]
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A. D. Dobrian, M. J. Davies, R. L. Prewitt, and T. J. Lauterio Development of Hypertension in a Rat Model of Diet-Induced Obesity Hypertension, April 1, 2000; 35(4): 1009 - 1015. [Abstract] [Full Text] [PDF]
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S. B. Parker, A. D. Dobrian, S. S. Wade, and R. L. Prewitt AT1 receptor inhibition does not reduce arterial wall hypertrophy or PDGF-A expression in renal hypertension Am J Physiol Heart Circ Physiol, February 1, 2000; 278(2): H613 - H622. [Abstract] [Full Text] [PDF]
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V. A. Miriel, S. P. Allen, S. D. Schriver, and R. L. Prewitt Genistein Inhibits Pressure-Induced Expression of c-fos in Isolated Mesenteric Arteries Hypertension, July 1, 1999; 34(1): 132 - 137. [Abstract] [Full Text] [PDF]
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 M. J. Davis and M. A. Hill Signaling Mechanisms Underlying the Vascular Myogenic Response Physiol Rev, April 1, 1999; 79(2): 387 - 423. [Abstract] [Full Text] [PDF]
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F. C. Luft, E. Mervaala, D. N. Muller, V. Gross, F. Schmidt, J. K. Park, C. Schmitz, A. Lippoldt, V. Breu, R. Dechend, et al. Hypertension-Induced End-Organ Damage : A New Transgenic Approach to an Old Problem Hypertension, January 1, 1999; 33(1): 212 - 218. [Abstract] [Full Text] [PDF]
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