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(Hypertension. 1997;30:1284-1288.)
© 1997 American Heart Association, Inc.
Articles |
Increased Expression of Parathyroid Hormone–Related Peptide Gene in Blood Vessels of Spontaneously Hypertensive Rats
From the Departments of Cardiovascular Biology (M.N., Y.T.) and Internal Medicine (M.N., T.K., K.K.), Faculty of Medicine, University of Tokyo (Japan).
Correspondence to Yoh Takuwa, MD, Department of Car- diovascular Biology, University of Tokyo Faculty of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail yohtakwa{at}m.u-tokyo.ac.jp
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Abstract |
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Abstract We have shown recently that mechanical stretch of cultured rat aortic smooth muscle cells induces a marked increase in gene expression of the vasorelaxant parathyroid hormone–related peptide. In the present study, we investigated whether mechanical force affected the in vivo parathyroid hormone–related peptide gene expression in blood vessels. Northern blot analysis revealed that stretch of isolated rat aortic strips increased the expression level of parathyroid hormone–related peptide mRNA. The parathyroid hormone–related peptide transcript level in aorta and mesenteric vessels from 18-week-old spontaneously hypertensive rats (SHR) was 2.5- and 2.2-fold higher, respectively, compared with age-matched Wistar-Kyoto (WKY) controls, whereas the parathyroid hormone–related peptide mRNA level in aorta from normotensive 4-week-old SHR was similar to that of age-matched WKY controls. The aortic parathyroid hormone–related peptide content was higher in 18-week-old SHR than in age-matched WKY controls. Moreover, treatment of mature SHR with an angiotensin II type 1 receptor antagonist or hydralazine caused a concomitant decrease in the parathyroid hormone–related peptide transcript level in aorta with lowering of blood pressure. These results suggest that the in vivo parathyroid hormone–related peptide gene expression in blood vessels is under the control of mechanical force, pointing to a role of parathyroid hormone–related peptide in the regulation of vascular tone.
Key Words: rats, inbred SHR • mechanical force • peptides • parathyroid hormone
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Parathyroid hormone–related peptide was originally identified as a causative factor in malignancy-associated hypercalcemia.1 2 PTHrP shows N-terminal homology with PTH and shares its receptor with PTH.3 It has been reported that unlike PTH, PTHrP and its receptor genes are widely expressed in normal tissues, including vascular smooth muscle, where PTHrP exerts a vasorelaxant activity.4 5 6 7 8 9 10 These data suggested that PTHrP might be an endogenous vasoactive molecule that acts to serve as an autocrine and paracrine regulator of vascular smooth muscle tone.3 7 8
It was reported that various vasoconstrictors, including angiotensin II, endothelin, and thrombin, induced PTHrP gene expression in rat vascular smooth muscle cells.10 11 12 More noteworthy were the recent reports showing that PTHrP gene expression in the nonvascular smooth muscle tissues, including rat urinary bladder and uterus, was stimulated by mechanical stretch.13 14 These observations prompted us to test the possibility that stretch also regulates PTHrP gene expression in rat vascular smooth muscle cells.15 We found that application of repetitive cyclic stretch dramatically increased PTHrP gene expression in cultured vascular smooth muscle cells.16 17 Pirola et al18 recently reported that rocking of cultured vascular smooth muscle cells grown on dishes induced an increase in PTHrP mRNA, suggesting that mechanical force might regulate PTHrP gene expression. However, the exact physiological role of PTHrP and the regulation of its production or gene expression in blood vessels have yet to be established.
In the present study, we tried to extend our in vitro observation15 into the in vivo situation by examining whether mechanical force regulates PTHrP gene expression in blood vessels. To this end, we first studied the effect of stretching isolated rat aorta on PTHrP gene expression. Second, we investigated the effect of transmural pressure on PTHrP gene expression in blood vessels by comparing PTHrP mRNA levels in aorta and mesenteric vessels of SHR and age-matched normotensive WKY controls and by examining the effect of a decrease in blood pressure with antihypertensive treatment on vascular PTHrP gene expression in SHR.
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Methods |
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Preparation of Aortic Strips
Male Wistar rats weighing 400 to 500 g were purchased from Charles River Breeding Laboratories (Shizuoka, Japan). The thoracic aorta was removed from rats anesthetized with diethyl ether and cleared of surrounding connective tissues. Helical strips of isolated aorta were mounted on tissue holders in water-jacketed organ baths containing 10 mL of Krebs-Henseleit bicarbonate buffer of the following composition (mmol/L): NaCl 120, KCL 3.5, MgSO4 1.5, KH2PO4 1.2, CaCl2 1.25, NaHCO3 24.4, glucose 10. The organ baths were kept at 37°C, and the buffer in organ baths was gassed continuously with 95% O2/5% CO2. In these experiments, vascular endothelium was disrupted mechanically. Strips were allowed to equilibrate for 1 hour without stretch and then were subjected to stretch. In preliminary experiments, PTHrP mRNA levels were determined in aortic strips subjected to stretch to 120%, 140%, and 160% of the resting length for 2 hours. The results indicated that stretch of strips to 140% of the resting length caused a maximal increase in PTHrP mRNA level. Therefore, 140% stretch was chosen in the following experiment. Control strips were not stretched throughout the incubation in organ baths.
Animal Experiments
Male 4-, 18-, and 24-week-old SHR and WKY rats were purchased
from Charles River Breeding Laboratories. Antihypertensive drugs, the
angiotensin II type 1 receptor antagonist
TCV-116 (candesartan cilexetil;
(±)-1-(cyclohexyloxycarbon-yloxy)ethyl-2-ethoxy-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}benzimidazole-7-carboxylate)
(10 mg/kg),19 or hydralazine (10
mg/kg) was emulsified into a gum arabic solution and
administered daily into three 24-week-old rats per drug with an
intragastric catheter for 2 weeks. Three control rats received a
vehicle, a gum arabic solution. Systolic blood pressure was
measured 5 hours after drug administration the day before the
experiment by the tail-cuff method.
Northern Blot Analysis
Helical aortic strips incubated as described above and aorta and
mesentery freshly isolated from anesthetized SHR and WKY rats
were rapidly frozen and stored in liquid nitrogen until total RNA
extraction was performed. Total RNA was extracted by the acid
guanidinium isothiocyanate/phenol/chloroform
method.20 RNA extracted from each aorta and mesentery of
18- and 26-week old rats was used as one sample for analysis of
PTHrP mRNA. Because a sufficient amount of total RNA could not be
extracted from one aorta of 4-week old rats due to the small size of
the aorta, RNA from two aortas were combined and used as one sample.
Total RNA was separated by formaldehyde/1.0% agarose gel
electrophoresis and transferred onto a nylon membrane (Hybond N,
Amersham). The polymerase chain reaction–amplified 463-bp rat PTHrP
cDNA encoding most of the coding region and the 5'-untranslated region
was labeled to a specific activity of 5 to 9x108 cpm/µg
DNA with [
-32P]dCTP (Dupont-NEN) by the random priming
method.16 Hybridization was performed at 42°C in a
solution containing 0.87 mol/L NaCl, 50% formamide, 0.5% SDS,
and 167 µg/mL salmon sperm DNA. The membrane was washed in
0.1xSSC and 0.1% SDS at 50°C and autoradiographed. After we
stripped radioactive probes of a membrane, we rehybridized a membrane
with 32P-labeled GAPDH cDNA probe. The radioactivity of
corresponding bands was quantified by a Fuji BAS 2000 Bio-Image
Analyzer (Fuji Film Co Ltd). The PTHrP mRNA level was corrected
for GAPDH mRNA level by calculating the ratio of PTHrP/GAPDH mRNA
radioactivity for each sample. The mean values in nonstretched control
vessels (Fig 1
), control WKY vessels
(Figs 2, 3, and 4),
and vessels from SHR without antihypertensive treatment (Fig 6) were
expressed as 1.0, and the values of other groups in each figure were
expressed as a ratio over the mean value of control groups. The size
(in kilobases) of detected mRNAs was calculated on the basis of the 18s
and 28s ribosomal RNA migration.
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Measurement of PTHrP Contents in Aorta
Thoracic aorta removed from rats was immediately boiled at
100°C for 5 minutes and quickly frozen by immersing in liquid
nitrogen. Frozen tissues were ground into powders and
homogenized in a buffer comprising 1 mol/L acetic
acid, 20 mmol/L HCl, 146 µmol/L pepstatin,
216 µmol/L leupeptin, and 1 mmol/L PMSF using
a Polytron homogenizer. An aliquot of the
homogenate was taken for determination of protein content.
The homogenate was cleared by
centrifugation at 9000g for 30 minutes. The
supernatant was extracted with diethylether and lyophilized. The
lyophilysates were dissolved in 0.1% trifluoroacetic acid and applied
to a Sep-Pak plus short-body cartridge (Waters). The fraction that
eluted at 60% acetonitrile concentration was assayed for PTHrP using a
specific immunoradiometric assay 16 This assay detects
intact (1-141) PTHrP. The PTHrP content was expressed as picomoles per
gram protein.
Statistics
Within-groups comparisons were carried out using unpaired
Student's t test, whereas intergroup multiple comparisons
were made with two-way ANOVA. Differences were considered significant
at P<.05. Values are presented as
mean±SE.
Materials
TCV-116, a nonpeptidic AII type I receptor–selective
antagonist, was a gift from Takeda Chemical Industries LTD
(Osaka, Japan). Hydralazine was purchased from Sigma
Chemical Co. All other chemicals were of reagent-grade purity. The
PTHrP assay kit was obtained from Mitsubishiyuka Medical Sciences.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We first examined whether direct mechanical stretch of isolated rat aortic strips alters PTHrP mRNA expression level. Shown in Fig 1A
is a Northern blot analysis of total RNA extracted from
stretched and nonstretched aortic strips. Northern analysis
detected a single band of 1.4 kb in aortic strips, which is in
agreement with the size of the PTHrP transcript in cultured rat aortic
smooth muscle cells that we and others have described
previously.4 11 12 14 16 Exposure of aorta to stretch
increased the expression level of PTHrP mRNA, but it did not change
GAPDH gene expression. Quantitation of the results revealed a
significant (P<.05) 40% increase in PTHrP mRNA levels in
stretched aorta compared with nonstretched aorta (Fig 1B).
We next sought to reveal the effect of transmural pressure on PTHrP
gene expression in blood vessels in vivo. For this purpose, we compared
expression levels of PTHrP mRNA in aorta from hypertensive SHR and
age-matched WKY controls. Mature 18-week-old SHR had elevated
systolic blood pressure (219±9 mm Hg, n=8,
P<.01) compared with age-matched WKY rats (153±12
mm Hg, n=8). SHR of this age had higher expression levels of PTHrP
mRNA in aorta than age-matched WKY rats (Fig 2A). In contrast, the
expression level of GAPDH was similar between both groups.
Quantitatively, the PTHrP mRNA level of hypertensive SHR aorta was
2.5-fold greater than that of WKY rat aorta (Fig 2B). The PTHrP mRNA
level in mesenteric blood vessels of hypertensive SHR was also higher
(2.2-fold) than that of age-matched WKY controls, whereas the GAPDH
mRNA level was similar between SHR and WKY rats (Fig 3A and 3B). On the
other hand, the expression level of PTHrP mRNA and GAPDH mRNA in aorta
of young 4-week-old SHR at the prehypertensive stage (systolic
blood pressure 116±4 mm Hg, n=8) was similar to that of
age-matched WKY controls (systolic blood pressure 114±4
mm Hg, n=8) (Fig 4A and 4B).
To examine whether expression of the PTHrP peptide in aorta is
increased in 18-week-old SHR compared with age-matched WKY controls, we
determined the PTHrP content in aorta from SHR and WKY rats. As shown
in Fig 5, the PTHrP content in aorta from
18-week-old SHR was 2.3-fold higher than that in age-matched WKY
rats.
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We investigated further the influence of transmural pressure on PTHrP
gene expression in aorta by examining the effect of treatment of mature
hypertensive SHR with antihypertensives on aortic PTHrP mRNA expression
levels. Administration into SHR of the angiotensin II type
1 receptor antagonist TCV-116 and hydralazine for 2
weeks decreased blood pressure (systolic blood pressure:
205±1 mm Hg [n=3] in untreated SHR, 142±2 mm Hg [n=3]
in SHR treated with TCV-116 [P<.01 compared with untreated
SHR], and 146±1 mm Hg [n=3] in SHR treated with
hydralazine [P<.01 compared with untreated SHR]).
SHR treated with either of the antihypertensive drugs had significantly
lower (by 21% and 35%, respectively) levels of PTHrP mRNA in aorta
compared with untreated SHR (Fig 6A and 6B). GAPDH mRNA levels were not altered
by treatment with the antihypertensives.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The vascular wall is constantly exposed to mechanical forces of hemodynamic origin, ie, shear stress and transmural pressure.22 23 Shear stress is sensed by the vascular endothelial cells. Transmural pressure is transmitted to the wall and acts as a tensile stress on the wall constituents, the smooth muscle cells and the endothelial cells. We recently found that exposure of cultured rat vascular smooth muscle cells to stretch induces PTHrP gene expression.16 17 The present study demonstrates that stretch of isolated rat aortic strips induces an increase in PTHrP mRNA level (Fig 1
). This finding
extends our previous in vitro observation16 17 and
suggests the possibility that mechanical force is an important factor
in regulating in vivo PTHrP gene expression in blood vessels. To
examine how transmural pressure influences in vivo PTHrP gene
expression in blood vessels, we compared PTHrP mRNA levels in aorta and
mesenteric vessels between hypertensive SHR and WKY controls. We have
found that PTHrP gene expression in aorta is increased in hypertensive
SHR but not in young SHR at the prehypertensive stage, compared with
age-matched WKY controls (Figs 2 and 4). In SHR at the hypertensive
stage, PTHrP gene expression was also increased in mesenteric vessels,
including smaller resistance arteries, compared with age-matched WKY
controls (Fig 3). We also found that PTHrP peptide content is increased
in aorta of SHR compared with that of age-matched WKY controls (Fig 5).
These results suggest that the increased PTHrP gene expression
accompanied by the increased PTHrP peptide contents in blood vessels of
SHR is caused by elevated blood pressure, but not by the genetic factor
pertinent to SHR. The finding in the present study that treatment
of SHR with either of two types of pharmacologically different
antihypertensive drugs, the angiotensin II type 1 receptor
antagonist TCV-116 and
hydralazine,24 25 causes a concomitant decease in
aortic PTHrP mRNA with a decrease in blood pressure (Fig 6) further
supports this notion. All of these data suggest that transmural
pressure is an important factor in regulating PTHrP gene expression in
the vessel wall and that this pressure acts to stimulate PTHrP gene
expression. An increase in PTHrP mRNA in blood vessels of SHR could be caused by an increase in the transcription rate of the PTHrP gene, a decrease in the degradation rate of the PTHrP mRNA, or both. For example, stimulation of PTHrP gene expression by prostaglandin E1 in HTLV-1–infected T cells was shown previously to be caused primarily by transcriptional activation of the PTHrP gene,26 whereas a serum-induced increase in PTHrP mRNA in osteosarcoma cells was associated with both transcriptional activation of the PTHrP gene and increased stability of PTHrP mRNA.27 In the present study, these different possibilities could not be tested because of technical difficulties associated with animal tissues as a sample source. However, our previous in vitro experiments16 showed that the stretch-induced increase in PTHrP mRNA in vascular smooth muscle cells was not accompanied by a change in the half-life of PTHrP mRNA, suggesting that transcriptional activation was involved in the stretch-induced increase in PTHrP mRNA.
Several groups recently reported that distention of nonvascular smooth muscle organs, including uterus, bladder, and stomach, causes an increase in PTHrP mRNA.13 14 15 These findings, together with the present study, indicate that PTHrP gene expression in different smooth muscle tissues is generally under the control of mechanical force. It is likely that there exists a common mechanism operative for the regulation of PTHrP gene expression by mechanical force in a variety of smooth muscle tissues. Previous studies demonstrated that stretching of cells leads to activation of Ca2+ channels, adenylyl cyclase, and phospholipase C in various cell types.22 23 However, we have shown in the previous study that the [Ca2+]i, protein kinase C, or adenylyl cyclase does not seem to mediate PTHrP gene expression induced by stretch itself in vascular smooth muscle cells.16 17 It remains to be elucidated how smooth muscle cells sense mechanical stimuli and convert it into intracellular signals for regulating PTHrP gene expression.
Arterial smooth muscle in various vascular beds changes its tone in response to alteration in blood pressure so that blood flow is maintained at a relatively constant level despite changes in the local perfusion pressure.22 23 This phenomenon, called autoregulation, involves the intrinsic contractile response of vascular smooth muscle to stretch (the myogenic response). The pressure-induced distention is believed to be the primary stimulus responsible for the myogenic response.23 Current evidence shows that the imposition of stretch on vascular smooth muscle cells causes an increase in [Ca2+]i via activation of both stretch-activated cation channel and voltage-dependent Ca2+ channels, resulting in vascular smooth muscle contraction.23 The increase in [Ca2+]i is also known to open Ca2+-activated K+ channels, which acts to limit membrane depolarization during the response to stretch.23 The PTHrP that has been induced in response to stretch may act as a vasorelaxant to mediate the negative-feedback regulation of the myogenic response to oppose the contractile response caused by stretch. Thus, vascular smooth muscle may finely tune the myogenic response to mechanical strain through regulating the activities of the plasma membrane ionic channels and the gene expression of the vasorelaxant peptide.
In conclusion, the present findings indicate that PTHrP expression in blood vessels is stimulated in response to stretch or intravascular pressure increase. These results suggest that PTHrP may be involved in the local regulation of vascular tone.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grants from the Ministry of Education, Science, and Culture of Japan, by funds for cardiovascular research from Tsumura Co, and by funds from the Japan Heart Foundation and Japan Research Foundation for Clinical Pharmacology. We thank Dr Yumiko Shibouta (Takeda Chemical Industry) for her cooperation in rat experiments with antihypertensive treatment. We are grateful to Fumie Iwase and Rieko Suzuki for technical and secretarial assistance.
Received March 4, 1997; first decision April 18, 1997; accepted April 18, 1997.
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