(Hypertension. 1997;29:1296-1302.)
© 1997 American Heart Association, Inc.
Articles |
Shear Stress Augments Expression of C-Type Natriuretic Peptide and Adrenomedullin
From the Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine (T.-H.C., H.I., Y.O., N.T., K.T., T.I., J.Y., K.D., M.I., K.M., K.N.), and Department of Cardiovascular Biomechanics, Faculty of Medicine, University of Tokyo (R.K., J.A.) (Japan).
Correspondence to Hiroshi Itoh, MD, PhD, Department of Medicine and Clinical Science, Kyoto University School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606 Japan. E-mail hiito{at}kuhp.kyoto-u.ac.jp
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Abstract |
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Abstract Shear stress is known to dilate blood vessels and exert antiproliferative effects on vascular walls; these effects have been ascribed to shear stress–induced upregulation of endothelium-derived vasoactive substances, mainly nitric oxide and prostacyclin. We have demonstrated the significance of C-type natriuretic peptide (CNP) as a novel endothelium-derived relaxing peptide (EDRP) that shares a cGMP pathway with nitric oxide. Adrenomedullin is a recently isolated EDRP that elevates intracellular cAMP as prostacyclin does. To elucidate the possible role of these EDRPs under shear stress, we examined the effect of physiological shear stress on CNP mRNA expression in endothelial cells derived from the human umbilical vein (HUVECs), bovine aorta (BAECs), and murine lymph nodes (MLECs) as well as adrenomedullin mRNA expression in HUVECs. CNP mRNA was stimulated prominently in HUVECs under shear stress of 15 dyne/cm2 in a time-dependent manner (4 hours, sixfold increase compared with that in the static condition; 24 hours, 30-fold increase). Similar results were obtained in BAECs (4 hours, twofold increase; 24 hours, threefold increase) and MLECs (4 hours, threefold increase; 24 hours, 10-fold increase). Augmentation of CNP mRNA expression that was dependent on shear stress intensity was also observed (5 dyne/cm2, 2.5-fold increase of static; 15 dyne/cm2, 4.5-fold increase). Increased CNP secretion was also confirmed by the specific radioimmunoassay for CNP. Adrenomedullin mRNA expression in HUVECs increased under shear stress of 15 dyne/cm2 in a time-dependent manner (4 hours, 1.2-fold increase of static; 24 hours, threefold increase) and shear stress intensity–dependent manner (15 dyne/cm2, threefold increase compared with that at 5 dyne/cm2). These results suggest that the coordinated augmentation of mRNA expression of these novel EDRPs may constitute shear stress–dependent vasodilator and antiproliferative effects.
Key Words: atrial natriuretic factor • adrenomedullin • endothelium • nitric oxide • prostacyclin
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Hemodynamics plays a crucial role in the physiology and pathophysiology of the cardiovascular system. One of the primary hemodynamic forces, shear stress, is now under intense investigation as a key factor in endothelium-dependent regulation of vascular tone and structure. Vascular endothelial cells sense shear stress and transduce the signal into transcriptional regulation of several sets of vasoactive substances, growth factors, and adhesion molecules.1 For example, the production of endothelium-derived vasorelaxing factors, ie, NO2 and prostacyclin,3 is known to increase in cultured endothelial cells under physiological shear stress. In contrast, the expression of ET-1, a potent endothelium-derived vasoconstricting peptide, has been reported to decrease.4 The coordinated endothelial gene regulation in endothelial cells in response to hemodynamic change is considered to be an adaptive response to keep vascular tone within a limited range and protect vascular walls from atherosclerotic change.
The natriuretic peptide family, which exerts potent natriuresis/diuresis and vasorelaxation, consists of three peptides: ANP, BNP, and CNP. Natriuretic peptides activate the cGMP cascade through the two particulate guanylate cyclases, ANP-A and ANP-B receptors.5 Although ANP and BNP show high affinity for the ANP-A receptor, CNP selectively binds to the ANP-B receptor.6 Our group has demonstrated that CNP is produced and secreted from vascular endothelial cells,7 whereas ANP and BNP are mainly secreted by the atrium and ventricle, respectively.5 We have further demonstrated gene expression of CNP and ANP-B receptor in in vivo vascular walls8 and also have reported the detection of CNP in human plasma.9 In addition, we and others have established the inhibitory effect of CNP on VSMC proliferation through the activation of the intracellular cGMP cascade.10 11 Furthermore, our recent immunohistological study has shown attenuated expression of CNP in the endothelium of atherosclerotic lesions,12 which supports the possible involvement of CNP in vascular remodeling. Thus, we have characterized CNP as a novel EDRP that acts on vascular walls and exhibits vasodilator and antiproliferative effects.
The novel peptide AM has been isolated from pheochromocytoma tissues and shown to be a substance that increases intracellular cAMP in platelets.13 Recently, AM has also been recognized as an EDRP that potently decreases vascular tone,14 possibly through activation of the cAMP cascade of VSMCs.15 Furthermore, cAMP accumulation in endothelial cells by AM has also been reported.16 Increased plasma levels of AM have been confirmed in individuals with essential hypertension, congestive heart failure, and renal failure.17 Thus, the significance of AM in the vascular system as an autocrine and paracrine EDRP is an emerging subject of interest.
To further illustrate the involvement of these novel EDRPs in the regulation of vascular tone and structure in vivo and their relevance to the pathophysiology of hypertension and atherosclerosis, we examined the effect of physiological shear stress on CNP and AM expressions in cultured mammalian endothelial cells.
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Methods |
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Cell Culture
Primary HUVECs,18 BAECs,7 and MLECs (C57BL/6 strain)19 20 were isolated as previously reported. HUVECs were grown in medium-199 (Dainippon Pharmaceutical Co, Ltd) supplemented with 15% fetal bovine serum (Cell Culture Laboratories), 2 mmol/L L-glutamine, 100 U penicillin/mL, and 100 µg heparin/mL. BAECs were cultured in medium-199 containing 15% fetal bovine serum, 100 U penicillin/mL, and 100 µg streptomycin/mL. MLECs were cultured in Dulbecco's modified Eagle's medium (Life Technologies Inc) containing 20% fetal bovine serum, 10 mmol/L HEPES, 2 mmol/L L-glutamine, 1 mmol/L sodium pyruvate, 100 µmol/L 2-mercaptoethanol, 1% (vol/vol) 100x nonessential amino acids (Flow Laboratories), 100 U penicillin/mL, and 100 µg streptomycin/mL.
Flow-Loading Apparatus
To apply well-defined laminar flow, we used a parallel
plate-type flow chamber as previously reported.20 Briefly,
endothelial cells grown on glass plates were subjected
to constant laminar flow in a flow path
5.5x10-2 m wide,
8.5x10-2 m long, and
0.02x10-2 m tall. Shear stress intensity
(
, dyne/cm2=10-1xPa
[N/m2]) was calculated by the formula =6
µQ/ab2, where µ is the
viscosity of the medium (0.0094 P=.00094 Pa·s at 37°C in this
experiment), Q is flow volume (milliliters per second),
a is the width of the flow path
(5.5x10-2 m), and b is the height
(0.02x10-2 m). Flow-loading experiments were
performed at 37°C and 5% CO2 in a humidified
incubator.
Semiquantification of mRNA Levels of CNP, AM, ET-1, and GAPDH by
RT-PCR Southern Blot Analysis
Total cellular RNA was isolated from endothelial
cells immediately after cessation of flow loading by the acid
guanidinium thiocyanate/phenol/chloroform extraction
method21 and treated with RQ-1 RNase-free DNAse (Promega).
RT into cDNA was carried out for 2 µg total RNA in 20 µL reaction
volume with 0.5 µg Oligo(dT)15 Primer (Promega) and 200 U SuperScript
II RNaseH reverse transcriptase (Life Technologies Inc) following the
manufacturer's protocol. PCR was carried out for 2 µL cDNA in 100
µL reaction volume containing 10 mmol/L Tris-Cl (pH 8.3),
50 mmol/L KCl, 4 mmol/L MgCl2, 100 µmol/L
primers, 200 µmol/L dNTP mix, and 0.5 U Taq DNA
polymerase (Takara Shuzo Co, Ltd). Sense and antisense primers for
human, bovine, and mouse CNP22 23 24 ; human
AM25 ; and human ET-126 (Table
)
were synthesized. A pair of common PCR primers was purchased for human,
bovine, and rat GAPDH (Clontech Laboratories, Inc). The temperature for
cycle amplification with a DNA Thermal Cycler (Perkin-Elmer Cetus) was
set at 95°C for 30 seconds, 55°C for 1 minute, and 72°C for 1
minute. After amplification of 15, 20, 25, 30, 35, and 40 cycles, 10
µL of each sample was electrophoresed in 3.0% NuSieve 3:1 agarose
(FMC BioProducts) and transferred to nylon membranes as described
elsewhere. Oligonucleotides corresponding to each PCR
product (Table) were synthesized as internal probes, 5'-end labeled
by [
-32P]dATP (Amersham Corp), and hybridized to the
membranes. The membranes were washed in 0.3x SSC at 55°C and exposed
to an imaging plate (Fuji Photo Film Co, Ltd). The radioactivity of
each band was quantified with a BAS 2000 (Fuji). mRNA levels for CNP
and AM were compared between samples by calculation of their relative
ratios to corresponding GAPDH mRNA levels.
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Radioimmunoassay of Human CNP
Radioimmunoassay for CNP was performed with monoclonal antibody
to mouse CNP, which we developed.27 The sensitivity
threshold was 0.4 fmol/mL. The cross-reactivities with 
-ANP, porcine
BNP, rat BNP, and CNP-53 were 0.2%, 14%, less than 0.001%, and 100%
on a molar basis, respectively. The medias of HUVECs in a static
condition and under shear stress were extracted by Sep-Pak C18
cartridges (Millipore Corp) and measured by the radioimmunoassay for
CNP, as previously reported.27
Statistics
Data are presented as mean±SEM. The significance of
differences in CNP mRNA expression between HUVECs in a static condition
and under shear stress was evaluated by repeated measures ANOVA
followed by Fisher's protected least significant difference test. A
value of P<.05 was considered significant.
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Results |
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CNP mRNA Expression in HUVECs Under Shear Stress
As shown in Fig 1
, RT-PCR/Southern analysis
of CNP and GAPDH mRNA expressions yielded logarithmically amplified
bands from 20 to 30 cycles of amplification. The linearity of PCR
amplification was confirmed also for AM and ET-1 (data not shown). No
PCR product for GAPDH was observed without RT even after 40 cycles
of amplification (data not shown). The application of moderate shear
stress (15 dyne/cm2), which is comparable to that estimated
to be present in arteries, elicited a time-dependent augmentation
of CNP mRNA expression in HUVECs (Fig 1). Compared with CNP mRNA
expression observed in HUVECs cultured in a static condition (without
shear stress) for 24 hours, the message was augmented by sixfold with
shear stress of 15 dyne/cm2 in 4 hours and by 30-fold in 24
hours. CNP mRNA expression in a static condition was confirmed to
be unchanged after 24 hours of incubation (data not shown).
Application of shear stress did not affect GAPDH mRNA expression (Fig 1).
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CNP mRNA Expression in HUVECs, BAECs, and MLECs
To elucidate CNP gene regulation in
endothelial cells obtained from different tissues of
different species, we examined the effect of shear stress on CNP mRNA
expressions in BAECs and MLECs. As shown in Fig 2, basal
CNP mRNA expression without shear stress in BAECs was relatively high
compared with that in HUVECs and MLECs. Moderate shear stress (15
dyne/cm2) elicited a twofold increase of CNP mRNA
expression in 4 hours and threefold increase in 24 hours compared with
that observed in a static condition for 24 hours. Basal CNP mRNA
expression in MLECs was relatively low, but a similar augmentation by
shear stress was observed (threefold increase in 4 hours and 10-fold in
24 hours).
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Effect of Shear Stress Intensity on CNP mRNA Expression in
HUVECs
We conducted two sets of experiments to examine the effect of
various shear stress intensities on CNP mRNA expression. As shown in
Fig 3, with the application of low shear stress (1.5 and
3 dyne/cm2), which is comparable to that present in
veins, CNP mRNA expression in HUVECs was not apparently potentiated in
an intensity-dependent manner. The application of moderately high shear
stress (15 and 25 dyne/cm2) that can be observed in
arteries clearly elicited intensity-dependent augmentation of CNP mRNA
expression (Fig 3). Fig 4 shows the quantification of the effect of
shear stress intensity on CNP mRNA expression in HUVECs.
The average increases of CNP mRNA expression in HUVECs compared with
that in a static condition by shear stress of 5
dyne/cm2 for 6 hours and 15 dyne/cm2 for 6
hours were 2.5-fold and 4.5-fold, respectively.
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Potentiation of CNP Secretion From HUVECs
We examined CNP secretion into the circulating medium from HUVECs
under shear stress by a radioimmunoassay specific for CNP. Without
shear stress, CNP concentration after incubation for 6 hours was below
the sensitivity threshold in all samples examined (<0.4 fmol/mL, n=4).
In the medium of HUVECs under shear stress of 15 dyne/cm2,
CNP concentration was 2.2±0.1 fmol/mL (n=4) after 6 hours of
incubation.
Comparison of CNP, AM, and ET-1 mRNA Expressions by Shear
Stress
We compared the effects of shear stress on mRNA expression of CNP,
AM, and ET-1 in HUVECs. Fig 5 shows the time-dependent
augmentation of CNP mRNA expression by shear stress of 15
dyne/cm2, as described above. AM mRNA expression was also
augmented by the same shear stress. Southern blotting quantification
showed no significant augmentation in 4 hours with application of 15
dyne/cm2 shear stress but demonstrated a threefold increase
in 24 hours. Shear stress lowered ET-1 mRNA expression in a
time-dependent manner, as previously reported.4
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Effect of Shear Stress Intensity on AM mRNA Expression in
HUVECs
Fig 6 shows the effect of shear stress intensity on
AM mRNA expression. HUVECs under shear stress from 1.5 to 15
dyne/cm2 for 6 hours showed intensity-dependent
augmentation of AM mRNA expression (Fig 6). AM mRNA expression in
HUVECs under 15 dyne/cm2 shear stress was threefold that
observed under 1.5 dyne/cm2 shear stress.
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Discussion |
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Shear stress has been reported to affect the gene expression of several endothelium-derived vasoactive substances. Physiological laminar shear stress upregulates endothelial NO synthase mRNA expression and prostacyclin production, whereas it downregulates ET-1 mRNA expression. In the present study, mRNA expression of the two novel EDRPs CNP and AM were augmented in HUVECs upon shear stress loading. Augmentation of CNP mRNA expression by shear stress was also observed in other endothelial cells derived from different tissues of different species (BAECs and MLECs). AM mRNA expression in BAECs and MLECs was not examined in this study, because AM genes for bovine and mouse were not yet clarified. Augmented production of CNP by shear stress was also confirmed by the specific radioimmunoassay for CNP. AM secretion was not examined in this study because the radioimmunoassay for AM had not been developed in our laboratory. Previous study has shown that augmentation of AM mRNA expression by interleukin-1 (IL-1), tumor necrosis factor-
(TNF-), and bacterial lipopolysaccharide (LPS) correlates
well with the potentiation of AM secretion.28 It is
expected that the potentiation of AM secretion by shear stress may
occur concomitantly with augmentation of AM mRNA expression, which
should be confirmed in future studies. It is not well defined how endothelial cells sense shear stress and transduce its signal into transcriptional regulation.1 Intracellular increases of calcium concentration29 and activation of potassium channels30 are considered to constitute primary events in endothelial cells upon shear stress loading. As the cis-element that is responsible for shear stress–responsive transcriptional regulation, Resnick and colleagues31 have reported SSRE (5'-GAGACC-3') in the promoter sequence of platelet-derived growth factor-B chain as a positive regulatory element and confirmed that the sequence is sufficient to confer shear stress responsiveness. This element is also found in the 5' promoter region of other shear stress–inducible genes, such as endothelial NO synthase, tissue plasminogen activator, and transforming growth factor-ß1.32 We have reported the cloning of human22 and mouse24 CNP genes. In mouse CNP gene, SSREs exist in exon 2 and the 3'-untranslated region. The human CNP gene also contains a complementary SSRE (5'-GGTCTC-3'). The bovine CNP gene has not been cloned. In the present study, CNP mRNA expression was augmented by shear stress in all three endothelial cells from human, bovine, and mouse tissues. It should be examined whether SSREs that exist on human and mouse CNP genes at different locations have any effect on the shear stress inducibility of CNP mRNA expression. The human AM gene also contains several copies of SSRE and complementary SSRE in its promoter region and 3'-untranslated region.33 Thus, the significance of SSRE as a common cis-element for the shear stress responsiveness of these two EDRP mRNA expressions should be examined in future studies.
Recently, heterodimeric nuclear factor-
B (NF-B) (p50/p65) has
been identified as the transcriptional factor that binds to the SSRE
sequence.34 NF-B is an inducible pleiotropic
transcriptional factor that regulates a wide variety of cellular and
viral genes. The pathway is activated by various
cytokines and substances, such as IL-1, TNF-, phorbol
esters, and LPS. To date, we and others have published that CNP
secretion from endothelial cells is significantly
upregulated by TNF-, IL-1, phorbol ester, and LPS.7 35
AM expression is also augmented prominently by IL-1, TNF-, and
LPS.28 36 In patients with septic shock, plasma
concentrations of CNP and AM are remarkably elevated, and the extent of
elevation is proportionally correlated with the severity of the
disease.9 37 These previous findings and those of the
present study may support the interpretation that
NF-B–dependent signal transduction is a converged common pathway
for regulation of the endothelial gene expression of
these two EDRPs, CNP and AM, under either
physiological or
pathophysiological conditions.
The change of morphology of endothelial cells and alteration of extracellular matrix composition in response to shear stress are also considered to be possible causes for shear stress–inducible gene regulation.38 Our group has recently reported the augmented production of these EDRPs, CNP and AM, from endothelial cells cultured on laminin- or fibronectin-coated gel.39 These findings suggest the existence of integrin-associated modulation of endothelial gene expression and raise the possibility that the effect of shear stress on CNP and AM mRNA expressions is partly due to endothelial gene regulation through integrin-associated signal transduction.
CNP activates the cGMP cascade in VSMCs, which is shared
by NO. On the other hand, AM shares the cAMP cascade with prostacyclin.
A previous report has described that cGMP production from
HUVECs is augmented by shear stress and the effect of shear stress can
be abrogated almost totally by
N
-methyl-L-arginine, the
competitive antagonist of NO synthase.40 Since
the CNP-selective receptor, the ANP-B receptor, is scarcely expressed
on endothelial cells, as we have
reported,41 CNP may contribute little to cGMP
production in endothelial cells under shear
stress. However, our previous report showed that cGMP
production in the coculture of endothelial
cells and VSMCs, which express abundant ANP-B receptor, can be almost
abolished by treatment with monoclonal antibodies to
CNP.10 This suggests that CNP at the augmented level under
shear stress can act on VSMCs to increase cGMP production. cAMP
production in HUVECs is also known to increase under shear
stress. The cAMP production has been considered to be due to
the autocrine effect of shear stress–induced
prostaglandins. AM is an additional autocrine and paracrine
factor that acts on both endothelial cells and VSMCs
for intracellular cAMP accumulation.42 43 Thus, the
participation of AM in cAMP production in
endothelial cells by shear stress is expected.
CNP and AM exert potent effects on vascular tone through cGMP and cAMP cascades, respectively. CNP dilates resistant arteries, which has been proven by the blood pressure–lowering effects observed after systemic intravenous administration of CNP into human volunteers,44 and the increase of forearm blood flow after intra-arterial local administration.45 AM also significantly decreases blood pressure46 and increases blood flow to peripheral organs, such as kidneys and mesenteric arteries.47 Therefore, augmented expression of CNP and AM by physiological shear stress can be relevant to the control of blood pressure and regulation of blood flow to peripheral organs.
Impaired endothelial function in essential hypertension48 is an important aspect in considering the causes and consequences of elevated blood pressure. The endothelial dysfunction has been mainly characterized by the reduction of acetylcholine-induced vasodilation, which is due to impaired NO production. Recently, it has been reported that attenuated shear stress–induced vasodilation is observed to exist before the appearance of the reduced acetylcholine effect on vasodilation in skeletal muscle arterioles of the genetically hypertensive rat49 and normotensive rat fed high salt.50 These reports have indicated that the attenuated shear stress–responsive vasodilation is also ascribed to decreased induction of NO production. Further examination of shear stress–induced expression of CNP and AM, as well as the enzymes responsible for NO and prostacyclin synthesis, in endothelial cells of hypertensive and normotensive subjects will clarify the significance of these endothelium-derived relaxing factors in the pathophysiology of essential hypertension.
In conclusion, the sustained augmentation of CNP and AM mRNA expressions in endothelial cells under physiological shear stress demonstrated in this study may further indicate the significance of an EDRP system composed of CNP and AM in the regulation of vascular tone and structure.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported partly by research grants from the Japanese Ministry of Education, Science, and Culture, the Japanese Ministry of Health and Welfare; Disorders of Adrenal Hormone Research Committee; the Molecular Approach for the Pathogenesis of Immunological Disorders Research Committee; the Smoking Research Foundation; the Yamanouchi Foundation for Research on Metabolic Disorders; the Salt Science Research Foundation; the Uehara Memorial Foundation; and the Japanese Society for Cardiovascular Diseases. We thank Hisayo Kitoh for her secretarial work and appreciate the technical assistance of Yuko Mori.
Received August 19, 1996; first decision October 15, 1996; accepted November 25, 1996.
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