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(Hypertension. 1997;29:770-775.)
© 1997 American Heart Association, Inc.
Articles |
Aortic Changes in Experimental Renal Failure
Hyperplasia or Hypertrophy of Smooth Muscle Cells?
the Departments of Pathology Heidelberg (K.A., B.W., C.N., J.T., U.S.) and Darmstadt (G.M.), and Department of Internal Medicine (M.Z., E.R.), Ruperto Carola University Heidelberg (Germany).
Correspondence to Dr Kerstin Amann, MD, Department of Pathology, Im Neuenheimer Feld 220, D-69120 Heidelberg, FRG.
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Abstract |
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Cardiovascular complications are a well-known feature of chronic renal failure. Increased wall thickness of intramyocardial arterioles and elastic (aorta) and peripheral (mesenteric) arteries is seen even after normalization of blood pressure. It is currently unknown whether such increases result from hyperplasia of vascular smooth muscle cells, hypertrophy, or a combination of both or from an increase in aortic extracellular matrix. Using a recently developed unbiased stereological technique (the dissector), we investigated the aortas of subtotally nephrectomized rats and sham-operated controls after perfusion fixation. We determined aortic wall thickness, cross-sectional area of aortic media, total number of vascular smooth muscle cells per unit aortic length (1 mm), mean cell and nuclear volumes, volume density of elastic fibers, extracellular matrix, vascular smooth muscle cells, and total volumes of these structures per unit of aortic length (1 mm). Blood pressure was not significantly increased in subtotally nephrectomized rats. In contrast, wall thickness, cross-sectional media, total number of aortic vascular smooth muscle cells, and volume of extracellular matrix including collagen were significantly increased after subtotal nephrectomy, whereas cellular hypertrophy was only modest and an increase in elastic fibers did not occur. In conclusion, increased aortic wall thickness in experimental renal failure results primarily from an increase in aortic extracellular matrix. In addition, however, proliferation of aortic vascular smooth muscle cells resulting in cell hyperplasia also contributed to aortic wall thickening to a minor degree. It appears that aortic wall thickening is caused by secretory stimulation of the proliferating vascular smooth muscle cells, resulting in increased matrix production. The nature of the underlying stimulus requires further investigation.
Key Words: kidney failure • aorta • hyperplasia • extracellular matrix • muscle, smooth, vascular
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Introduction |
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Patients with renal failure are characterized by abnormal elasticity of the large arteries.1 2 3 4 These changes lead to increased pulse-wave velocity and reduced elasticity module. It has been argued that reduced aortic elasticity has deleterious consequences for stroke work and diastolic coronary perfusion1 2 and that reduced arterial compliance can greatly affect cardiovascular function, ie, plays an important role in the genesis of left ventricular hypertrophy in renal failure.3 4 These findings are of note in view of the extremely elevated cardiovascular mortality of uremic patients.5 6 7
The observations of London et al8 9 argue for functional abnormalities of the aorta, ie, disturbances of aortic compliance, in patients with renal failure, but whether these have a structural basis as well has not yet been properly documented. In particular, the relative contribution of increased cell versus extracellular matrix content and the potential roles of hyperplasia versus hypertrophy of aortic smooth muscle cells have not been investigated.
In this context, observations on experimental models of hypertension in which vessel wall elasticity is also reduced are of interest.10 Using direct measurements of cell number and DNA measurements, Owens and Schwartz11 12 examined the aorta of spontaneously hypertensive rats and rats with renovascular hypertension and found evidence for cellular hypertrophy and hyperploidy of nuclei. In addition, Olivetti et al13 14 performed morphometric analyses in the aorta of postnatal spontaneously hypertensive rats and normotensive Wistar-Kyoto rats and found hypertrophy as well as hyperplasia.
This whole field has been advanced by the introduction of unbiased stereological techniques15 16 17 18 19 that yield reliable three-dimensional estimates based on two-dimensional histological analysis. Using the dissector method, Mulvany et al18 found hyperplasia of vascular smooth muscle cells in the mesenteric arteries of spontaneously hypertensive rats. This increase in mesenteric cell number was documented even in the prehypertensive phase. Unfortunately, similar measurements for the aorta are not available for hypertensive animals.
Because of the clinically important functional repercussions of aortic changes in uremia, we investigated the aortas of subtotally nephrectomized (SNX) rats and their sham-operated controls using the dissector method.
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Methods |
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Animals
Male Sprague-Dawley rats (300 g, Ivanovas Co) were housed in single cages at a constant temperature (20°C) and humidity (25%). The rats were fed a high protein, low salt diet containing 40% protein and 0.6% NaCl (Altromin C 1002/C 1036, Altromin Co). After 3 days of adaptation, the rats were randomly allocated to SNX or sham operation. SNX was performed as follows. First, the right kidney was removed with rats under ketamine/diazepam anesthesia (100 mg/kg or 2.5 µg/kg, respectively). Seven days later, the left kidney was subtotally resected by removal of three quarters of the weight of the resected right kidney from its cortex. Control rats were sham operated by decapsulation of the kidney. Special care was taken not to affect the adrenals.
Blood pressure was measured with rats under light ether anesthesia by tail plethysmography every 2 weeks. Eight weeks after the second operation, the experiment was terminated by perfusion fixation.
Tissue Preparation
At the end of the experiment, the abdominal aorta was catheterized with rats under 10% chloralhydrate anesthesia (7 mL/kg body wt IP), blood samples were taken, and the viscera were fixed by retrograde vascular perfusion at a controlled pressure of 110 mm Hg. Before fixation, the vascular system was rinsed with a 10% dextran solution containing 0.5 g/L procaine-HCl for 2 minutes. Ten seconds after aortic perfusion was started, the vena cava was incised to drain the blood. After dextran infusion, the vascular system was perfused with 0.2 mol/L phosphate buffer containing 3% glutaraldehyde for 12 minutes. After perfusion, the aorta was carefully taken out and cut into several 1-mm-thick pieces perpendicular to the longitudinal axis. At a defined distance from the aortic arch (1 cm), a 1-mm-thick tissue sample was taken and embedded in Epon-Araldite (Serva Co). Per aortic tissue block, eight semithin serial sections (0.5 µm) at a distance of 1 µm were prepared and stained with methylene blue and basic fuchsin.20 Semithin sections were investigated according to the dissector method18 using light microscopy, oil immersion, and phase contrast at a magnification of 1000:1. In addition, several ultrathin sections (0.08 µm) per rat were prepared and stained with uranyl acetate and lead citrate as described in detail elsewhere.20
Quantitative Stereology
Stereological analysis was performed on eight semithin serial sections per aorta with the dissector method as first described by Mulvany et al.18 For preparation of the set of eight parallel sections, some conditions had to be met.
The distance of two subsequent sections had to be large enough to detect visible changes in organ structure but small enough to permit comparison of serial sections. For this reason, a distance between two serial sections was selected that was smaller than the minimal nuclear diameter in any direction so that small nuclei were not missed.
The media thickness of the aortic wall was determined by planimetry with an automatic image-analysis system (IBAS II, Kontron Co) at a magnification of 400:1 on semithin sections. The contours of the aortic profiles were outlined manually with a cursor. The maximal and minimal diameters as well as the wall and lumen areas were then calculated automatically.
Volume densities (VV) of aortic smooth muscle cell cytoplasm and nuclei, elastic fibers, and extracellular matrix (including collagen) were determined on eight systematically subsampled grids per aortic section at a magnification of 1000:1 using a 100-point eyepiece (Carl Zeiss Co), oil immersion, and phase contrast according to basic stereological formulas,21 22 ie, PP=VV. In addition, the number of aortic smooth muscle cells per millimeter squared (NA) was counted at a magnification of 1000:1 using a 100-point Zeiss eyepiece with a definite area, oil immersion, and phase contrast.
The number of aortic smooth muscle cells per volume (NV) was derived from eight semithin serial sections using the dissector method according to Mulvany et al,18 with NV=Q-/V, where Q- is the number of cells on the first section (na) of the tissue sample minus the remaining number of cells on the last section of the sample (nv): Q-=na-nv. V is the volume of the investigated tissue sample calculated according to V=axh, where "a" is the area of the aorta investigated and "h" is the vertical dimension of the tissue sample, which is the number of serial sections minus 1 times the section thickness.
The mean cell number per aortic segment (n) was derived from the aortic volume (VA=Wall Area [mm2]x1 mm) and the cell number per volume (NV) according to n=VAxNV. Mean cell volume (v) was calculated according to Mulvany et al18 with the formula v=VV/NV. The total volume of aortic cells (VC) was then calculated according to VC=VVxVA.
For practical measurements, one has to choose an isotropic uniform random section plane, the so-called look-up plane. Subsequently, a serial section plane, the so-called measure or reference plane (ie, a second section at a distance from the first one), was chosen and compared with the look-up plane. The comparison of the serial sections was performed with a set of two microscopes and a video camera for permanent visualization of the look-up plane and measurements on the reference plane.
Ultrastructural Analysis
Qualitative ultrastructural investigations were performed at various magnifications with a Zeiss EM 10 microscope and several ultrathin sections per rat.
Statistics
Data are given as mean±SD. The arithmetic means of the absolute biological and stereological parameters were compared by Student's t test.23 The results were considered significant at a value of P<.05.
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Results |
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Description of the Model
Table 1
shows descriptive data for SNX and sham-operated rats. After 8 weeks of renal failure, plasma urea and creatinine concentrations were significantly higher in SNX than sham-operated rats. The rats were not anemic. Body weight was slightly but not significantly lower in SNX rats fed ad libitum than in sham-operated controls. The ratio of left ventricular weight to body weight was significantly higher in SNX rats. The left subtotally resected kidney underwent compensatory hypertrophy. Thus, the ratio of left kidney weight to body weight was significantly elevated after SNX.
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Morphometric Measurements of the Descending Thoracic Aorta
Mean Cell Number and Mean Volume of Aortic Smooth Muscle Cells
Aortic lumen area was significantly greater in SNX than sham-operated rats (Table 2). In parallel, absolute wall thickness and media area were also significantly increased after SNX (Table 2, Figs 1A and 2A).
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The absolute number of aortic smooth muscle cells per unit aortic volume and especially per aortic segment was significantly increased after SNX (+67.3%). In parallel, mean cell volume was slightly but significantly increased (+14.3%), and nuclear volume was not altered (Table 3).
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Volume Density and Total Volume of Aortic Smooth Muscle Cells
Aortic vascular smooth muscle cells accounted for only 4% to 6% of total aortic wall volume (Table 4). Volume density and total volume of aortic smooth muscle cells per aortic segment were significantly higher in untreated SNX rats than sham-operated controls (Table 4).
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Volume Density of Elastic Fibers and Extracellular Matrix
Volume density of elastic fibers was significantly decreased after SNX, but the total volume of elastic fibers was not altered after SNX (Table 4
). In contrast, volume density and the total volume of aortic extracellular matrix (excluding elastic fibers) were increased in experimental renal failure (Table 4).
Ultrastructural Findings
Aortic media showed marked structural alterations after SNX: In uremic rats, the nuclei and cytoplasm of smooth muscle cells of the media tended to be enlarged (Fig 2A and 2B). In control rats, cells with fusiform shape were arranged along a preferential direction that was nearly perpendicular to the longitudinal axis of the aorta (Fig 1B). In contrast, in SNX rats, the shape of cells was more rounded off, and they were more isotropically distributed (Fig 2B and 2C). These cellular changes were accompanied by a marked relative and absolute increase in extracellular matrix, including diffuse deposition of collagen fibers, with marked focal accentuation. Elastic fibers were no longer regularly sandwiched between cell layers (Figs 1A and 2A) but were more randomly distributed throughout the vessel wall. Calcification of elastic fibers was not seen. In SNX rats, the relative contribution of elastic fibers to the aortic wall was less than in nonuremic rats. Collagen fiber bundles were more abundant and occupied a larger proportion of the aortic wall (Fig 2B and 2C). The bundles were more irregularly distributed and no longer respected preferential axial orientation as in control rats.
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Discussion |
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The salient feature of the present study is the demonstration that in SNX rats, the aortic wall contains significantly more extracellular matrix and a higher absolute number of vascular smooth muscle cells. Such cells have significantly higher mean cell volume and slightly increased nuclear volume, pointing toward some kind of cell activation that is also suggested by ultrastructural analysis (ie, expansion of the Golgi apparatus and the ergastoplasm with increased vesicle content) as well as toward modulation of phenotype into a more secretory module. Thus, proliferation of aortic smooth muscle cells after SNX is associated with increased secretory activity resulting in increased aortic collagen content and thickening of the aortic wall. It is of note that the extracellular matrix components are not only quantitatively abnormal but also exhibit alterations in the spatial orientation of matrix components (ie, focal deposition of collagen bundles).
In contrast, synthesis of elastic fibers is not stimulated after SNX, resulting in a significant reduction of aortic elastic fiber content at least relative to aortic collagen content. The functional effect of (relatively) diminished elastic fiber content may be even greater than is reflected by the fractional decrease in elastic fiber volume, because the elasticity module also depends on the three-dimensional architecture of the elastic fiber web. Thus, the relative decrease of aortic elastic fiber content may be responsible for increased aortic stiffness and impaired aortic compliance, as documented in patients with renal failure.1 2 9 10
Although we did not carry out further studies to clarify the mechanism or mechanisms involved, increased aortic extracellular matrix and reduced relative content of elastic fibers in a normotensive model of renal failure (at least by casual blood pressure measurements) would argue for an effect of uremia per se that is unrelated to elevated blood pressure. However, we would like to emphasize that we could not formally exclude a minor role of blood pressure per se in the development of the above-mentioned structural vascular changes in our model of renal failure.
We wish to draw attention to some methodological points. Since the aorta is an extremely anisotropic structure, laborious methods are required to obtain unbiased three-dimensional estimates of the number of particular structures, ie, cells or cell nuclei. The dissector technique has the advantage of providing such possibilities but the disadvantage of values that are not directly comparable with the two-dimensional data in the literature. For the interpretation of the study, it is of note that vascular smooth muscle cells are the only cell type in the aortic wall, accounting for roughly 5% of aortic wall volume.
One problem in the design of the study was blood pressure control. It has recently become apparent on the basis of telemetric studies that single (casual) blood pressure measurements are not a reliable reflection of the circadian blood pressure profile, since intermittent elevation of blood pressure in SNX animals and disturbances of the circadian sleep pattern in renal failure have been demonstrated.24 25 Therefore, we could not formally exclude the possibility that SNX rats had slightly higher mean circadian blood pressures than their sham-operated controls. It has been shown, however, that experimental uremia induces myocardial hypertrophy and structural alterations of the myocardium (ie, wall thickening of intramyocardial arterioles) even under normotensive conditions.26 27 In addition, it has been demonstrated that thickening of the aorta in experimental renal failure could not be prevented by nonspecific antihypertensive treatment.28 Thus, it is likely that aortic structural changes in our normotensive model of renal failure are at least in part independent of blood pressure and are a consequence of uremia per se. It is of note, however, that the rats did not have severe anemia. This is of interest because anemia of renal failure is known to induce a hypercirculatory state.29
We have to acknowledge further that these SNX rats were not in advanced terminal uremia. The presence of cardiovascular abnormalities even at a stage of only modest elevation of plasma urea is of interest in view of past observations that the frequency of cardiac events is increased even in early renal failure.30
One major finding of the present study was that the number of aortic smooth muscle cells increased (+67.3%) after SNX, suggesting hyperplasia, with only a slight increase in cell volume (+14.3%), suggesting moderate cellular hypertrophy. The nature of the mitogenic signal is unknown, but increased sympathetic activity31 and growth induction by angiotensin II32 33 via platelet-derived growth factor-AA and transforming growth factor-ß1 may play an important role. However, we would like to emphasize that we can only speculate on the underlying mechanisms because we did not investigate them in detail in the present study.
In the past we found that some of the effects of renal failure on vascular and cardiac structures depended on the permissive action of parathyroid hormone.34 35 This hormone is obviously one possible candidate for inducing aortic changes in renal failure although we did not investigate this in detail. Another interesting possibility is the involvement of advanced glycosylation end product (AGE), although there is only indirect evidence so far. As a result of accumulation of AGE-transformed protein breakdown products, AGEs accumulate in renal failure.19 20 36 37 These compounds directly activate matrix production of cells, eg, mesangial cells, via platelet-derived growth factor.38 In this context, it is of note that a striking increase of the expression of the receptor for AGE (RAGE) was noted in endothelial cells of uremic patients.39 However, it remains unresolved whether the putative agent in uremia acts directly on vascular smooth muscle cells or indirectly via endothelial cells and cell-to-cell cross talk. At least as far as morphological observations are concerned, in an earlier study we noted prominent endothelial cells with enlarged cytoplasm and signs of cell activation, ie, an increased number of intracellular vesicles and actin filaments and expansion of the Golgi apparatus.28
It is of interest to point out that in renal failure, activation of mesenchymal cells and increased deposition of matrix are noted not only in the aorta but also in the cardiac interstitium independent of elevated blood pressure27 34 ; however, the increase in connective tissue is not generalized because in past studies, we failed to demonstrate fibrosis in the liver or pancreas.27 40 41
From studies in genetic and renovascular hypertension, it is known that shear stress stimulates collagen deposition. The abnormality in the total amount of matrix but also in the matrix texture in normotensive SNX animals suggests that factors independent of blood pressure are at least partly involved. This finding is again similar to what is observed in the heart, where interstitial expansion with fibrosis occurs early in uremic animals even when antihypertensive treatment is administered.27 On the basis of some indirect evidence, it has been argued that calcification of elastic arteries occurs in renal failure. In our experiment involving rats with renal failure of limited duration, no calcification was seen by light or electron microscopy.
In summary, the above results document that the microscopic structure of the aorta is altered in renal failure because of proliferation of aortic vascular smooth muscle cells and increased extracellular matrix production, resulting in a decrease of relative elastic fiber content. The quantitative structural data indicate that uremia-specific changes of aortic wall structure occur that are at least in part independent of casual blood pressure in the present model of moderate experimental uremia. The above findings are of interest in view of the well-known functional abnormalities (ie, increased stiffness with reduced aortic compliance) of the aorta in patients with renal failure; however, for several reasons, it is difficult to determine to what extent these experimental data can be extrapolated to humans.
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Acknowledgments |
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This study was performed with grants from the Deutsche Forschungsgemeinschaft (Am 93/2-1), the Faculty of Medicine Heidelberg, and Baxter Healthcare Co, USA. J. Tornig and Ute Schwarz were recipients of a scholarship of the Deutsche Forschungsgemeinschaft (Graduiertenkolleg Nephrologie Heidelberg). The skillful technical assistance of Zlata Antoni, Gudrun Gorsberg, Diana Lutz, and Peter Rieger is gratefully acknowledged. The authors especially thank Harald Derks for excellent phototechnical support.
Received July 15, 1996;
first decision August 22, 1996;
first decision September 12, 1996;
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K. Amann and E. Ritz Microvascular disease--the Cinderella of uraemic heart disease Nephrol. Dial. Transplant., October 1, 2000; 15(10): 1493 - 1503. [Abstract] [Full Text] [PDF]
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U. Schwarz, M. Buzello, E. Ritz, G. Stein, G. Raabe, G. Wiest, G. Mall, and K. Amann Morphology of coronary atherosclerotic lesions in patients with end-stage renal failure Nephrol. Dial. Transplant., February 1, 2000; 15(2): 218 - 223. [Abstract] [Full Text] [PDF]
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 J. Kalliovalkama, P. Jolma, J.-P. Tolvanen, M. Kahonen, N. Hutri-Kahonen, H. Saha, S. Tuorila, E. Moilanen, and I. Porsti Potassium channel-mediated vasorelaxation is impaired in experimental renal failure Am J Physiol Heart Circ Physiol, October 1, 1999; 277(4): H1622 - H1629. [Abstract] [Full Text] [PDF]
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J. TÖRNIG, M.-L. GROSS, A. SIMONAVICIENE, G. MALL, E. RITZ, and K. AMANN Hypertrophy of Intramyocardial Arteriolar Smooth Muscle Cells in Experimental Renal Failure J. Am. Soc. Nephrol., January 1, 1999; 10(1): 77 - 83. [Abstract] [Full Text]
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 J. Blacher, K. Demuth, A. P. Guerin, M. E. Safar, N. Moatti, and G. M. London Influence of Biochemical Alterations on Arterial Stiffness in Patients With End-stage Renal Disease Arterioscler Thromb Vasc Biol, April 1, 1998; 18(4): 535 - 541. [Abstract] [Full Text] [PDF]
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J.-J. Mourad, X. Girerd, P. Boutouyrie, S. Laurent, M. Safar, and G. London Increased Stiffness of Radial Artery Wall Material in End-Stage Renal Disease Hypertension, December 1, 1997; 30(6): 1425 - 1430. [Abstract] [Full Text]
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