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(Hypertension. 1995;26:758.)
© 1995 American Heart Association, Inc.
Articles |
Enhanced Vascular Neuropeptide Y– Immunoreactive Innervation in Two Hypertensive Rat Strains
From the Departments of Molecular Physiology and Biophysics (X.-M.F., E.D.H.) and Anatomy and Neurobiology (C.J.F.), University of Vermont College of Medicine, Burlington.
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Abstract |
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Abstract Considerable evidence indicates an enhanced sympathetic innervation of resistance arterial smooth muscle in the spontaneously hypertensive rat (SHR) compared with its normotensive Wistar-Kyoto (WKY) control. In addition to sympathetic hyperinnervation, an increased vascular innervation by neuropeptide Y–containing fibers, which are known to exert a vasoconstrictive and trophic action in vascular smooth muscle, has also been described. In addition to genetic hypertension, the SHR expresses hyperactive behavior and hyperreactivity to stress. To determine whether the enhanced neuropeptide Y–immunoreactive vascular innervation is specifically associated with hypertension and/or these behavioral abnormalities, four genetically related, inbred rat strains were used: SHR, which are hypertensive and hyperactive; WKY rats, which are neither hypertensive nor hyperactive; WKHA, which are hyperactive but normotensive; and WKHT, which are hypertensive but not hyperactive. The present study demonstrated that whereas the hypertensive strains (SHR and WKHT) exhibited smooth muscle hypertrophy in both superior mesenteric and caudal arteries in adulthood (10 months) but not at a prehypertensive age (1 month), both arteries exhibited significantly increased neuropeptide Y–immunoreactive innervation at both ages. It was further observed that the mesenteric artery in WKHA, a normotensive strain, had significant smooth muscle hypertrophy at 10 months; however, neuropeptide Y innervation in this artery was no different from that of WKY controls. The findings indicate that there is a cosegregation of neuropeptide Y hyperinnervation of the vasculature with the hypertensive phenotype, evident as early as 1 month of life in the hypertensive strains, and this should be considered further as a contributory factor in genetic hypertension. Vascular smooth muscle hypertrophy, while evident in adult hypertensive rats, was also observed in the mesenteric artery (but not the caudal artery) of adult WKHA rats, suggesting that other factors besides genetic hypertension, possibly hyperreactivity to stress, are responsible for this specific hypertrophic change in WKHA rats.
Key Words: neuropeptide Y • rats, inbred • WKY • SHR • WKHT • WKHA • mesenteric artery, superior
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Introduction |
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Pathological changes of systemic vasculature, especially increased vessel wall thickness, play an important role in the increase in vascular resistance associated with chronic hypertension.1 Because sympathetic nerve activity has been shown to exert a trophic effect on the development of blood vessels,2 the vascular changes in the SHR may be related to increased sympathetic nerve activity.3 Indeed, substantial evidence indicates an enhanced density of noradrenergic innervation of cerebral,4 caudal,5 and mesenteric arteries6 7 of the SHR compared with the normotensive genetic control, the WKY. Consistent with these findings, catecholamine levels are elevated in extracts of the SHR mesenteric artery relative to WKY.8 9
In addition to noradrenergic innervation, vascular smooth muscle receives a peptidergic innervation by NPY-containing nerve fibers. NPY coexists with and is coreleased with norepinephrine and epinephrine in cardiovascular regulatory pathways in the nervous system.10 NPY exerts a direct vasoconstrictive action and also potentiates vasoconstriction induced by electrical stimulation or application of norepinephrine.11 12 Recently, Shigeri and Fujimoto13 demonstrated that NPY stimulated DNA synthesis in porcine aortic smooth muscle cells in a dose-dependent manner, which suggests that NPY also exerts a trophic effect on vascular smooth muscle. Together with the findings that NPY-containing nerve density is increased in the vasculature, including cerebral,14 mesenteric,15 16 and pancreatic arteries,17 it is likely that NPY is involved in the pathogenesis of hypertension in the SHR.
The SHR is the most commonly used animal model of genetic hypertension; its characteristics resemble those of human essential hypertension.18 However, compared with WKY controls, the SHR differs in many other characteristics besides hypertension; the most prominent of these are hyperactivity in a novel environment and hyperreactivity to stress.19 Hendley and Ohlsson19 succeeded in genetically separating the hypertensive trait from these behavioral abnormalities of the SHR, producing two new inbred strains, each expressing the one trait without the other: from a crossbreeding of SHR with WKY followed by recombinant, selected inbreeding, they developed the inbred WKHT rat strain, which is hypertensive but not hyperactive or hyperreactive, and the inbred WKHA strain, which is hyperactive/hyperreactive to stress but not hypertensive. The longitudinal patterns of hypertension in WKHT and hyperactivity in WKHA paralleled those of the SHR as determined from ages 4 to 6 weeks through 1 year.19 Together with the SHR, which expresses both hypertension and hyperactivity, and the WKY, which expresses neither, these four related, inbred strains are considered to be the most appropriate means available for seeking correlations of biological differences with either hypertension or the most prominent behavioral abnormalities of the SHR.
The primary aim of the present study was to examine quantitatively the NPY-containing innervation of superior mesenteric and caudal arteries from SHR, WKY, WKHA, and WKHT rats to determine whether the enhanced innervation by NPY-immunoreactive fibers in the vascular beds of the SHR is associated with inheritance of either hypertension and/or hyperactivity.
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Methods |
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Animals
Male SHR, WKY, WKHA (F23-26), and WKHT (F20-23) rats were bred and maintained in a closed rat colony in the University of Vermont Animal Care Facility. The colony was maintained at constant temperature (23°C) and humidity (50%) with a 12:12-hour light-dark cycle. Water and food were available ad libitum. Blood pressure and activity measurements were routinely obtained for all animals in the colony at 3 months of age as a means of monitoring the phenotypic expression of the hypertension and hyperactive traits; in some cases, measurements were also made at other ages. Systolic pressure was determined as the average of 8 to 10 measurements in conscious, restrained, naive rats, at 37°C, with an occlusive tail cuff and a pressure transducer (Narco Scientific). The apparatus for determination of spontaneous activity in a novel environment is a square Lucite cage equipped with four sets of light beams and photocell detectors, described previously in detail.19 A digitized display recorded the number of interruptions of light beams made by the movements of the rats when they were placed in the activity cage. The number of light-beam breaks in a 15-minute session was taken as the activity score.
Tissue Preparation
Age-matched male rats from each strain (1 and 10 months old)
were anesthetized with sodium pentobarbital (50 mg/kg IP) and
perfused intracardially with 0.15 mol/L sodium chloride solution,
followed by 4% paraformaldehyde in 0.1 mol/L PB, pH
7.4. Approximately 2 mm of superior mesenteric and caudal arteries,
beginning at their starting point from the descending aorta, were
dissected under a microscope and postfixed for 2 hours in 4%
paraformaldehyde in PB. After being rinsed in PB,
tissues were equilibrated in 30% sucrose in PB at 4°C. Tissues were
then embedded in Tissue-Tek OCT compound (Miles Laboratories) and
frozen rapidly on dry ice. Arteries were sectioned transversely at 20
µm on a cryostat, and every 10th section was thaw-mounted onto
chrome alum–coated slides. Six to 10 sections were obtained from each
animal for immunohistochemical staining.
Immunohistochemistry
After being rinsed in PBS (0.1 mol/L sodium phosphate, 0.15
mol/L sodium chloride, pH 7.4), sections were preincubated for 20
minutes in 10% normal goat serum containing 0.3% Triton X-100 and
then incubated in rabbit anti-NPY (JH3)20 diluted 1:5000
in PBS at 4°C overnight. JH3 anti-NPY was generously provided by Dr
Richard Mains (Department of Neuroscience, The Johns Hopkins University
School of Medicine, Baltimore, Md). After PB rinses, the sections were
incubated in 1:100 biotinylated goat anti-rabbit IgG (Vector
Laboratories) for 60 minutes, rinsed, and incubated with 1:200
avidin-biotinylated horseradish peroxidase complex (Vector
Laboratories). Finally, sections were incubated in PB containing 0.05%
diaminobenzidine for 20 minutes, followed by addition of 0.01%
hydrogen peroxide and incubation for another 20 minutes. After being
rinsed in PB, slides were dehydrated in ethanol and coverslipped with
DPX mounting medium (BDH, Ltd).
Data Analysis
Sections were viewed via transmitted light microscopy, and
images were televised with a video camera. Images were digitized with
an image processing system and NEUROLUCIDA
software.21 Output images and a mouse-driven cursor
were displayed on a monitor to allow operator selection of an area in
the visual field. The inner and outer surfaces of the vascular muscle
layer were traced to determine the cross-sectional area of the
smooth muscle layer of the artery and its lumen. The
cross-sectional area of the smooth muscle layer was calculated as
the difference between the areas derived from the inner and outer
surfaces of the vascular muscle layer. The cross-sectional area of
the NPY-immunoreactive nerve fiber layer was obtained in a similar
fashion; in this case, the inner and outer perimeters of the
NPY-containing nerve fiber layer were traced, and the difference
between the two cross-sectional areas was taken as the
cross-sectional area of the nerve fiber layer. Measuring the
cross-sectional area of the entire NPY-immunoreactive fiber layer
eliminated a major shortcoming noted when we tried to quantify
innervation by counting the number of the NPY-staining fibers in a
selected longitudinal area: the innervation had a very uneven
distribution both around and along the artery, which made it difficult
to sample equivalent selected longitudinal areas among the four
strains. Instead, we chose to measure the entire area of the layer of
NPY innervation surrounding the circumference of the artery, sampled
equivalently throughout the same 2-mm segment of artery in all four
strains.
Statistics
Data consisting of 6 to 10 measurements from each rat for each
parameter of measurement were pooled, and the mean value
was calculated and used in the final analysis. Thus, each rat
contributed only one value for each parameter. In these and
all other measurements, the four rat strains were compared by ANOVA,
followed by Newman-Keuls multiple comparison test with
significance set at P<.05. Grouping of subjects for ANOVAs
was by strain and, in a separate analysis, by the
phenotypic traits expressed by these strains: for the hypertensive
trait, the hypertensive strains, SHR and WKHT, were combined and
compared with the combined normotensive strains, WKY and WKHA.
Similarly, for the hyperactivity trait, the hyperactive strains (SHR
and WKHA combined) were compared with the nonhyperactive strains (WKY
and WKHT combined).
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Results |
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Systolic pressure and activity scores were measured in the 10-month-old rats that had been used in this study when they were 3 months old (Table 1A). Systolic pressure was significantly higher in the hypertensive strains, SHR and WKHT, than in the normotensive strains, WKY and WKHA. Activity testing at 3 months indicated that WKHA and SHR were significantly more active than WKY and WKHT rats; the scores in WKHA rats exceeded even those of the SHR. The results of these determinations confirmed previous findings in the history of these homozygous strains: that SHR and WKHT are hypertensive; SHR and WKHA are hyperactive; and WKHA males, although normotensive, exhibit significant elevations in systolic pressure compared with WKY controls.19 This elevation in pressure has previously been linked to hyperreactivity of WKHA rats to the stress (restraint and heating) associated with blood pressure measurement by tail plethysmography. We showed this in a previous study in which WKHA rats had higher systolic pressures than WKY rats when tested by tail plethysmography; however, when blood pressure was tested several weeks later in these same rats after they were fitted with an indwelling catheter in the tail artery, WKHA rats when undisturbed had systolic pressures no different from those of the WKY controls.22
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Table 1B shows systolic pressures by tail plethysmography and activity scores in 4-week-old rats tested previously in our colony of homozygous strains; thus, these measurements were not obtained specifically from the 4-week-old rats of the present study. Systolic pressure did not differ significantly among the four strains at this age, as also reported by others using tail plethysmography in SHR and WKY.3 23 Nor was there any significant difference in pressures when the rats were grouped for the hypertensive trait (P=.17). In contrast, activity scores did show a significant main effect of strain (P<.01) at this young age and a highly significant effect of the hyperactivity trait (P=.0008).
In superior mesenteric and caudal arteries, no differences were
observed among the strains in cross-sectional area of the lumen at
either 1 month or 10 months of age (Tables 2 and 3). In all strains, the luminal area increased by
40% in superior mesenteric arteries and 25% in caudal arteries
between 1 and 10 months.
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In the superior mesenteric artery, the cross-sectional area of
smooth muscle in all four strains was 6x104
µm2 at 1 month (Table 2 and Figure). In
each strain, the smooth muscle layer increased significantly in
thickness from 1 to 10 months of age; however, the increase was greater
in the SHR, WKHT, and WKHA compared with the WKY (Table 2 and Figure).
Thus, in the WKY, the cross-sectional area of the smooth muscle
layer at 10 months was 150% of that at 1 month, whereas in the SHR,
WKHT, and WKHA, the cross-sectional area at 10 months was 250% of
that at 1 month (Table 2). There was no significant
difference in cross-sectional area of the superior mesenteric
artery smooth muscle layer among SHR, WKHT, and WKHA at 10 months of
age (Table 2).
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In the caudal artery, there was no significant main effect of strain on thickness of smooth muscle at either 1 or 10 months of age (Table 3). At 10 months, however, the hypertensive rats (SHR and WKHT combined) showed a significant hypertrophy of the caudal arterial smooth muscle layer (P=.014). One-month-old hypertensive rats did not show this hypertrophy; furthermore, there was no significant influence of the hyperactivity trait on smooth muscle layer thickness (P>.05 in each case).
In contrast to the similarity of luminal and smooth muscle layer areas, significant differences in NPY-immunoreactive innervation were observed: in superior mesenteric arteries at 1 month of age, both SHR and WKHT exhibited hypertrophied NPY-immunoreactive innervation relative to either WKY or WKHA (Table 2 and Figure). The cross-sectional area of the NPY-immunoreactive nerve layer surrounding the superior mesenteric artery increased fivefold to sevenfold in each strain from 1 to 10 months of age. Thus, at 10 months of age, the NPY innervation to the superior mesenteric artery remained significantly hypertrophied in the SHR and WKHT relative to either WKY or WKHA (Table 2 and Figure). In caudal arteries, a similarly enhanced innervation by NPY-containing nerves was observed in the hypertensive strains at both ages (P<.05 for the hypertensive trait at 1 and 10 months, Table 3).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the present study using four genetically related rat strains that express hypertension and hyperactivity in all possible combinations, we found that the NPY-immunoreactive nerve fiber layer surrounding the superior mesenteric artery was hypertrophied in SHR and WKHT relative to WKHA and WKY normotensive rats in both young and adult rats. This enhanced NPY-immunoreactive innervation of the vascular bed had apparently cosegregated with the hypertensive trait among the four strains. In contrast, vascular hypertrophy was observed in the superior mesenteric artery in both hypertensive and hyperactive strains at 10 months of age. In the caudal artery, the NPY-immunoreactive innervation was also significantly increased at both 1 and 10 months in hypertension (SHR and WKHT combined compared with WKHA and WKY normotensive strains combined); however, the extent of the increase was less than in the superior mesenteric vascular bed. Thus, different vascular beds in the four strains may show different patterns of NPY-immunoreactive innervation in hypertension, as has been reported for the SHR by others.3 15
Increased vascular resistance is the basic hemodynamic abnormality in chronic, stable, essential hypertension. Enhanced sympathetic activity may lead to a sustained increase in vascular resistance through a variety of physiological and adaptive mechanisms, one of which is that the released sympathetic transmitters, including norepinephrine and NPY, can cause sustained arterial vessel constriction as well as vascular hypertrophy. The trophic effect of adrenergic nerves on systemic vasculature has been confirmed by denervation experiments, in which it has been observed that vascular smooth muscle cell proliferation and wall-to-lumen ratio are attenuated and decreased, respectively, by ganglionectomy.2 NPY, which is coreleased with catecholamines in peripheral and central cardiovascular regulatory pathways, has a potentiating action on catecholaminergic vasoconstriction as well as a trophic effect on vascular smooth muscle, confirmed by the recent report that NPY exerted a direct stimulation of mRNA synthesis in vascular smooth muscle cells.13 Our findings that the NPY-immunoreactive innervation in the peripheral arteries was enhanced in hypertensive rat strains suggest that abnormal disposition of NPY, like norepinephrine, might contribute to the development and maintenance of hypertension.
In the present study, we found that the increase in the cross-sectional area of the superior mesenteric vascular smooth muscle in SHR, WKHT, and WKHA relative to WKY was not present at 1 month of age but was significant at 10 months. In contrast to the mesenteric vessels, significant hypertrophy of the caudal arterial muscle layer correlated only with the hypertensive trait. As found for the superior mesenteric artery, no hypertrophy of the caudal artery was present at 1 month. In addition, Peruzzi et al24 reported that in the large conductive blood vessels, aorta and carotid artery, adult SHR and WKHT exhibited vascular hypertrophy, whereas WKHA vessels did not.
Our findings that vascular wall hypertrophy is not present in 4-week-old hypertensive rat strains are consistent with those of Lee,3 who found similar results in SHR compared with WKY. When WKHA and WKHT rats were added as additional genetic controls, it was surprising to note that WKHA rats, whose systolic pressures are not hypertensive but are nevertheless significantly higher than in WKY when measured by tail plethysmography, had increased medial wall thickness in the mesenteric vascular bed. The hypertrophic changes reported here in adult WKHA mesenteric artery (but not caudal artery) have not as yet been explored further; however, they are likely to be related to the hyperreactivity trait of WKHA rats, particularly their increased sympathetic–adrenal medullary responsiveness to stress22 and hyperreactivity of blood pressure, heart rate, and peripheral resistance increase in response to stress.25 Thus, although the WKHA has resting blood pressure not different from that of the WKY,22 repetitive stress responses may have increased the lifetime average pressure such that a secondary hypertrophy is present in the mesenteric arterial bed. The lack of an enhanced innervation in response to this hypertrophy is striking, because increases in target size are generally associated with a concomitant increase in innervation.26 27 28
It is generally believed that the growth of sympathetic nerves is regulated by NGF, which is supplied to neurons via their terminals, after its production and release by cells within target effector tissues. NGF levels were increased in the spleen and mesenteric vascular bed of the SHR compared with the WKY in both young and adult rats29 30 ; NGF may be involved in the early enhanced sympathetic innervation in the blood vessels of SHR. This hypothesis was further confirmed by recent findings that tissues with enhanced sympathetic innervation, including renal and mesenteric vasculature in SHR, were associated with an increased expression of NGF mRNA.31 Since the enhanced NPY innervation cosegregated with the hypertensive phenotype in the two new strains, it will be important to show whether this increase in the expression of NGF mRNA also cosegregates with hypertension.
In the present study, we found that the enhanced innervation of NPY-containing nerves in the superior mesenteric arteries of SHR was specifically associated with the inheritance of the hypertensive trait. This NPY-immunoreactive hyperinnervation in hypertensive rats was present in weanlings (1 month) when no hypertrophy of vascular muscle layer was found, whereas both hypertrophy and hyperinnervation of NPY-containing nerves were apparent in the adult (10 months). Thus, enhanced NPY innervation of the vasculature may be a contributing factor in the development of hypertension.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by NIH grant NS 26390 to Dr Hendley and American Heart Association grant 92011300 to Dr Forehand. We thank Drs Victor May and Karen M. Braas for their helpful discussion and comments.
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Footnotes |
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Reprint requests to Dr Cynthia J. Forehand, Department of Anatomy and Neurobiology, College of Medicine, University of Vermont, Burlington, VT 05405.
Received March 13, 1995; first decision April 27, 1995; accepted August 3, 1995.
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