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(Hypertension. 1999;34:415-422.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Elastic Properties and Composition of the Aortic Wall in Old Spontaneously Hypertensive Rats

Valérie Marque; Pascal Kieffer; Jeffrey Atkinson; Isabelle Lartaud-Idjouadiene

From the Laboratoire de Pharmacologie Cardiovasculaire, Faculté de Pharmacie, Université Henri Poincaré-Nancy 1, Nancy, France.

Correspondence to Jeffrey Atkinson, Laboratoire de Pharmacologie Cardiovasculaire, Faculté de Pharmacie, Université Henri Poincaré-Nancy 1, 5 rue Albert Lebrun, 54000 Nancy, France. E-mail atkinson{at}pharma.u-nancy.fr

	Abstract

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Abstract—We hypothesized that age-linked changes in the composition and elastic properties of the arterial wall occur earlier in hypertensive than in normotensive rats. We evaluated the consequences of hypertension and aging on aortic mechanics, geometry, and composition in 3-, 9-, and 15-month-old awake Wistar-Kyoto rats (WKY) (normotensive) and spontaneously hypertensive rats (SHR) (hypertensive). The elastic modulus of the thoracic aorta, calculated from aortic pulse wave velocity and geometry, was higher in young and adult SHR than in age-matched WKY, as was wall stress; however, isobaric pulse wave velocity and pulse wave velocity–pressure curves were similar. Elastic modulus, isobaric pulse wave velocity, and the slope of the pulse wave velocity–pressure curve dramatically increased in old SHR compared with age-matched WKY; there was no further elevation of blood pressure or wall thickness. Fibrosis did not develop with age in SHR, and the ratio of elastin to collagen decreased in a similar fashion with aging in both strains. In conclusion, although elastic properties of the aortic wall are not intrinsically modified in young and adult SHR in comparison to age-matched WKY, aging is associated with a dramatic stiffening of the aortic wall in old SHR but not in WKY. Changes in blood pressure, aortic wall geometry, or scleroprotein composition do not appear to explain this age-linked aortic stiffening in SHR, suggesting that other mechanisms of disorganization of the media may be involved.

Key Words: elastin • collagen • elasticity • stress • aging • hypertension, experimental

	Introduction

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Aging produces many vascular changes, one of the most important being a progressive rise in arterial stiffness.^{1 2} The thickness of the media increases with age because of smooth muscle cell hypertrophy and fibrosis. The elastic fiber network develops longitudinal fissures, transverse breaks, and fragmentation. Such structural modifications (fibrosis and degradation of elastin) lead to a decrease in elasticity.³ Hypertension also may produce an increase in large-artery stiffness,^{4 5} at least when elastic properties are measured at a hypertensive level.^{6 7 8 9}

However, previous experiments on the effects of hypertension were performed mainly in young or adult subjects,^{6 7 8 9} and the consequences of a combination of hypertension and aging on the elastic properties of the aortic wall remain unexplored.^{10 11} The first objective of the present study was to evaluate the elastic properties of the aorta of 3-, 9-, and 15-month-old normotensive Wistar-Kyoto rats (WKY) and hypertensive spontaneously hypertensive rats (SHR). This was done by analyzing in awake animals the relationships between (1) pulse wave velocity and central mean aortic blood pressure under a wide range of pressure and (2) elastic modulus and circumferential wall stress. We hypothesized that age-linked mechanical alterations of the arterial wall will occur earlier in SHR than in normotensive rats. Our second objective was to study possible links between elastic properties and the geometry and scleroprotein composition of the vessel wall.

	Methods

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Animals
Two-month-old normotensive WKY (n=30) and SHR (n=30) were purchased from Iffa Credo (L'Arbresle, France), kept under standard conditions (21±1C°, lights on 6 AM to 6 PM), and given a standard rodent diet (UAR) and water ad libitum until 3, 9, or 15 months of age. Experiments were performed in accordance with the guidelines of the European Union and the French Ministry of Agriculture.

Aortic Pulse Wave Velocity in Awake Rats
Procedures have been described in detail elsewhere.^{12 13} Briefly, polyethylene cannulas (0.96/0.58 mm OD/ID) were chronically implanted under halothane (2%)/oxygen anesthesia into the descending thoracic aorta, the abdominal aorta, and the abdominal vena cava. There were no deaths during the period of recovery from surgery (24 hours), and weight loss was 5±1% in both SHR and WKY.

Twenty-four hours later, the aortic cannulas of nonanesthetized, unrestrained rats were connected to the pressure recording system, for which the dynamic frequency response is flat with a phase lag <-6° up to 30 Hz and then slightly underdamped.¹³ The pressure signals were converted into digital form and recorded online at a sampling rate of 256 Hz. After a 30-minute habituation period, baseline parameters were determined beat to beat and averaged over periods of 4 seconds every 30 seconds for 30 minutes. An algorithm detected the maximal and minimal values of each pressure signal, calculated mean aortic blood pressure (mm Hg) from the waveform area, pulse pressure as the diastolic-systolic difference, and heart rate (bpm) by counting the entire number of cycles over the 4-second period.

Pulse wave velocity (cm/s) was calculated as the distance between the 2 cannula tips (measured in situ after postmortem fixation by placing a damp cotton thread onto the aorta) divided by the transit time. Transit times (ms) were measured online by an algorithm that systematically shifted in time the peripheral pressure waveform with respect to the central pressure waveform and determined the value of the time shift giving the highest correlation.^{12 13} The accuracy of transit time determination was improved by performing the calculation for the entire waveform, with the use of least squares analysis of the differences in amplitude between the central and peripheral signals, and by increasing the number of sampling points by creating intermediate points for the peripheral signal by linear interpolation. Because the sampling rate was 1/3.9 ms and 10 intermediate points were created, the theoretical resolution of the calculated transit time was 0.39 ms, which gives a ±3.9% error for the lowest value of transit time observed in the present study for 15-month-old SHR (9.9 ms).

Pulse Wave Velocity–Pressure Curves During Pharmacological Hypotension in Awake Rats
After baseline hemodynamic measurements, central mean aortic blood pressure was reduced in a stepwise fashion (10 mm Hg per step) to half its initial value by progressively increasing the infusion rate of a sodium nitroprusside solution (Sigma Chemical Company; 2.3 mmol/L in phosphate buffer 10 mmol/L, pH 7.4, at 25°C).¹² At each stabilized pressure step, 15 measurements of aortic blood pressure and transit time were performed and averaged. At the end of infusion, animals had received a volume <4% of their total blood volume; mean dose of sodium nitroprusside was 140±14 nmol/kg per minute in 3-month-old rats (P_Age<0.05) versus 100±18 nmol/kg per minute in 9-month-old rats and 95±9 nmol/kg per minute in 15-month-old rats (P_Strain=0.2121, P_AgexStrain=0.2864; 2-way ANOVA). For each rat, pulse wave velocity was expressed as a function of central mean aortic blood pressure with the use of an exponential model¹⁴ [pulse wave velocity=b · e^{a(central mean aortic blood pressure)}]. Slopes (a) and intercepts (b) were treated as independent, parametric variables and averaged. Because heart rate, via a change in the harmonic composition of the pressure pulse, influences pulse wave velocity,¹⁵ and baroreflex function may be different between groups, we also studied the "heart rate–corrected" pulse wave velocity–pressure curves by dividing pulse wave velocity by heart rate recorded simultaneously at each pressure step.

Descending Thoracic Aorta Geometry, Wall Stress, and Elastic Modulus
At the end of the hemodynamic measurements, rats were killed with a sodium pentobarbital overdose and perfused for 30 minutes at their baseline central mean aortic blood pressure with 10% formol containing phosphate-buffered saline. A 0.5-cm sample of the proximal descending thoracic aorta was excised, immersed in 10% formol, then dehydrated in graded ethanol solutions and embedded in paraffin. Three 20-µm-thick sections were stained with hematoxylin-eosin for measurement of internal diameter and medial thickness (Saisam, Microvision Instruments). The coefficient of variation for 3 repeated measurements of medial thickness/internal diameter performed by one observer was <4.5%; the interobserver coefficient of variation for the same measurements was <3.5%.

Elastic modulus and wall stress (10⁶ dyne/cm²) were calculated from the Moens-Korteweg or Lamé equations: elastic modulus=(PWV² · D_i · )/h and wall stress=(CMABP · D_i)/2h, where PWV is baseline pulse wave velocity in awake rats (cm/s), D_i is internal diameter (cm), h is medial thickness (cm), is blood density (1.05 g/cm³), and CMABP is baseline central mean aortic blood pressure in awake rat (dyne/cm²). For each group, elastic modulus was plotted against wall stress with an exponential model [elastic modulus=b · e^{a(wall stress)}].

Descending Thoracic Aortic Wall Composition
A second 0.5-cm sample of the thoracic aorta was hydrolyzed in hydrochloric acid (6 mol/L, 24 hours, at 105°C). Protein content was determined by the dinitrofluorobenzene reaction,¹⁶ with 92 used for the molecular weight of an amino acid.¹⁷ Collagen content was determined by the chloramine T and paradimethylaminobenzaldehyde reaction as (hydroxyproline contentx7.46/protein content)x100.¹⁷ Desmosine and isodesmosine contents (cross-linking amino acids specific to elastin) were determined by capillary zone electrophoresis,¹⁸ and elastin content was calculated as (desmosine plus isodesmosinex200/protein content)x100.^{19 20} The ratio of elastin to collagen was also calculated.

A third 1-cm sample of the thoracic aorta was excised, and the wall calcium content was determined by atomic absorption spectrophotometry (AA10, Varian Ltd) after mineralization and nitric acid digestion.²¹

Statistical Analysis
Values are given as mean±SEM. Differences between groups (P<0.05) were evaluated with 2-way ANOVA (factors: age and strain) plus the Bonferroni test. In the cases in which this analysis revealed a significant interaction between the age and strain sources of variation, the effect of age was evaluated with a 1-way ANOVA performed for each strain separately.

	Results

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Body Weight, Central Aortic Blood Pressure, and Heart Rate in Awake Rats
There were no significant differences in body weight between WKY and SHR at 3, 9, and 15 months of age (Table 1). In both strains, there was rapid growth during maturation followed by slower growth with aging. Central diastolic, mean, pulse, and systolic aortic blood pressures were higher in SHR than in age-matched WKY. Maturation and aging were associated with a slight decrease in central diastolic and mean aortic blood pressures, which were similar in both strains. The decrease in systolic and pulse pressures during maturation and aging was higher in SHR than in WKY. Heart rate was slightly higher in SHR than in age-matched WKY and rose slightly with maturation and aging in both strains.

View this table: [in this window] [in a new window]   Table 1. Body Weight, Baseline Central Aortic Blood Pressures, Heart Rate, and Pulse Wave Velocity in Awake 3-, 9-, and 15-Month-Old Hypertensive and Normotensive Rats

Baseline Pulse Wave Velocity and Pulse Wave Velocity–Pressure Curves in Awake Rats
Baseline pulse wave velocity was higher in SHR than in age-matched WKY (Table 1). Effects of maturation and aging were different in the 2 strains. Pulse wave velocity decreased slightly with maturation in SHR, then rose to a very high level in 15-month-old SHR. There were no changes in baseline pulse wave velocity with maturation or aging in WKY.

At 3 and 9 months of age, the pulse wave velocity–pressure curves of SHR were similar to those of WKY (Figure 1a), indicating that aortic elasticity was similar in both strains at a given level of aortic blood pressure. However, at 15 months of age, the pulse wave velocity–pressure curve was steeper in SHR than in WKY. After correction of pulse wave velocity by heart rate, similar results were obtained, with a steeper curve in 15-month-old SHR (Figure 1b).

View larger version (24K): [in this window] [in a new window]   Figure 1. Pulse wave velocity–pressure curves (a) and heart rate–corrected pulse wave velocity–pressure curves (b) (average of the individual exponential relationships y=b · ea · x obtained during sodium nitroprusside infusion) in 3-, 9-, and 15-month-old WKY () and SHR (). *P<0.05 vs age-matched WKY. Slopes, intercepts, and probability values are shown.

Thoracic Descending Aorta Geometry, Wall Stress, and Elastic Modulus
Internal thoracic aorta diameter and medial thickness were higher in SHR than in age-matched WKY (Table 2). Geometry did not significantly change with maturation, but internal diameter and medial thickness increased with aging in both SHR and WKY. Thickening of the aortic wall was directly related to age-associated dilation as medial thickness/internal diameter remained constant with age in both strains, with a higher value in SHR than in age-matched WKY. The linear relationship between medial thickness and internal diameter was similar in WKY and SHR at all 3 ages (intercept=0.028±0.007 mm, slope=0.024±0.005, n=30, P=0.0001 in 3-, 9-, and 15-month-old WKY; intercept=0.040±0.014 mm, slope=0.028±0.008, n=30, P=0.0022 in 3-, 9-, and 15-month-old SHR).

View this table: [in this window] [in a new window]   Table 2. Thoracic Aortic Wall Geometry, Wall Stress, and Elastic Modulus in 3-, 9-, and 15-Month-Old Hypertensive and Normotensive Rats

Wall stress was higher in 3- and 9-month-old SHR than in age-matched WKY (Table 2). As medial thickness/internal diameter remained constant but central mean aortic pressure decreased with aging in both strains, wall stress decreased with aging in both SHR and WKY. At 15 months of age, wall stress was similar in SHR and WKY.

Elastic modulus was higher in SHR than in age-matched WKY (Table 2). It did not significantly change with maturation but dramatically increased with aging in SHR. There were no changes in elastic modulus with maturation or aging in WKY. Elastic modulus was significantly related to wall stress in all groups (Figure 2). The ratio of elastic modulus to wall stress was clearly higher in 15-month-old SHR than in younger groups, whereas there was no difference between SHR and WKY rats at 3 and 9 months of age (Table 2).

View larger version (16K): [in this window] [in a new window]   Figure 2. Elastic modulus (EM) as a function of wall stress (WS) (y=b · ea · x) in 3-, 9-, and 15-month-old WKY () and SHR (). Slopes, intercepts, and probability values are shown.

Thoracic Descending Aorta Composition
Globally, the evolution with age of the composition of the aortic wall was similar in both strains, because the "agexstrain" interaction was not significant for any of the components (Table 3). Protein as well as elastin contents were similar in SHR and in age-matched WKY and decreased in a similar fashion with maturation and aging in both strains. The collagen content was lower in SHR than in age-matched WKY and did not change markedly with age. Consequently, the ratio of elastin to collagen, which was higher in SHR than in age-matched WKY, decreased in a similar fashion with maturation and aging in both strains. Finally, the evolution of total calcium content with maturation and aging was similar in both groups.

View this table: [in this window] [in a new window]   Table 3. Thoracic Aortic Wall Contents of Total Protein, Collagen, Elastin, and Calcium in 3-, 9-, and 15-Month-Old Hypertensive and Normotensive Rats

	Discussion

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The aims of the present study were to determine whether aortic stiffening occurs earlier in SHR than in WKY during aging and to analyze the relationship between aortic wall structure and mechanics at different ages. The main findings are that aortic stiffness is not increased in young and adult SHR compared with age-matched WKY when determined under isobaric conditions, but stiffness is dramatically increased with aging in SHR despite no substantial increase in blood pressure or changes in aortic geometry and scleroprotein composition.

The aortic wall is stiffer in young and adult SHR than in their normotensive counterparts when determined at their individual blood pressures. This increase in aortic stiffness is directly related to the higher pressure and wall stress levels, with elastic modulus strongly correlated to wall stress in SHR (and WKY) at 3 and 9 months of age and the ratio of elastic modulus to wall stress similar in both strains. Furthermore, when measured at a given level of blood pressure, pulse wave velocities of 3- and 9-month-old SHR are similar to those of age-matched WKY: pulse wave velocity–pressure curves obtained in SHR overlap those of WKY at both ages. This indicates that aortic stiffness is not intrinsically increased in 3- and 9-month-old SHR, confirming previous studies on large-artery distensibility performed in young or adult hypertensive subjects and SHR.^{3 4 5 6 22} The later study²² reported similar aortic distensibility in SHR and WKY after ultrasonic measurements, a method that allows dynamic evaluation of the aortic elastic properties. Interestingly, dynamic distensibility and compliance may be maintained in hypertensive rats because enlargement of the artery compensates for a stiffer wall (with stiffening measured under static conditions and enlargement measured under unstressed conditions, ie, at a low pressure value).²³ In the present study, elasticity has been evaluated under static conditions by stepwise decreases in aortic mean blood pressure and pulse wave velocity. Pulse wave velocity and the Moens-Korteweg elastic modulus reflect directly the elastic properties of the arterial wall material. All these observations lead to the conclusion that elastic properties of the aortic wall may be maintained in young and adult SHR not only under dynamic²² but also under static (present results) conditions of measurement. This conclusion should be tempered, however, by the fact that unstressed volume was not evaluated in the present study, and elastic modulus was calculated from both in vivo and in vitro measurements.

In contrast to the results in young rats, pulse wave velocity and elastic modulus are dramatically increased in old SHR compared with age-matched WKY. Furthermore, the pulse wave velocity–pressure curve is shifted upward with a steeper slope, and the ratio of elastic modulus to wall stress is markedly higher in old SHR. This indicates that aging intrinsically modifies the aortic elastic properties in SHR, earlier than in normotensive WKY. In another normotensive rat model, aging increases passive circumferential and longitudinal stiffness from 23 months of age, with different modulation of the biaxial stiffness by smooth muscle activation.²⁴ In the present study, circumferential and longitudinal stiffness cannot be distinguished because pulse wave velocity measurement reflects both of these components; the latter, as well as the lack of unstressed volume measurement (see above), tempers our interpretations. Whatever these limitations, the strong increase in ratio of elastic modulus to wall stress clearly reflects an age-related stiffening of the aortic wall in SHR. This aortic stiffening cannot be related to wall thickening because the medial thickness/internal diameter ratio remained constant with age in both strains.

Therefore, other determinants of the aortic wall elastic properties (eg, relative proportion and/or interaction between smooth muscle cells and extracellular matrix) may change during aging in hypertensive rats. The increase in medial thickness with aging, with no parallel changes in protein, collagen, or elastin contents, suggests a greater proportion of smooth muscle cells in the aortic wall of SHR, but this would tend to maintain aortic elastic properties at a low level, as it does in young and adult SHR.⁵ Concerning the extracellular matrix components, changes in collagen content are not involved in the age-linked aortic stiffening in SHR, because fibrosis does not develop with aging in SHR (or in WKY). Second, even though the elastin content slightly decreases with age, it does not decrease faster in SHR than in WKY, and the ratio of elastin to collagen decreases in a similar fashion with aging in both strains. Therefore, our results exclude the possibility that changes in blood pressure, aortic wall thickening, or modifications in scleroprotein content play a major role in age-linked aortic stiffening observed in SHR. One explanation may be that, despite the lack of change in scleroprotein content, the degree of recruitment of stiff collagen fibers is higher in old SHR because of the higher internal diameter and wall stress. However, such a hypothesis is weakened by the observation that age-induced enlargement of the aorta is proportionally similar in both SHR and WKY (+11% between young and old rats).

Another possibility is that structural disorganization of the media leads to mechanical alteration of the aortic wall in old SHR. It has been shown recently that the elastin network plays a major role in the maintenance of aortic elastic properties in adult SHR, not through variations of its total amount but through increases of the extent of its anchorage to the smooth muscle cells.^{5 6} Similarly, an increase in the fibronectin and integrin contents, through changes in cell-matrix interactions, may participate in the mechanical adaptation of the arterial wall to the higher level of circumferential wall stress.²² It could be hypothesized that aging either amplifies such mechanical adaptation in SHR—a further increase in the number of cell-matrix attachments leading finally to an increase in the passive stiffness of the wall material—or reverses it. It would be therefore interesting to repeat the type of experiment of Bezie et al^{6 22} in old SHR.

Other hypotheses can also be advanced to explain the age-linked aortic stiffening in SHR: a more rapid increase with age in the ratio of collagen type I to III,²⁵ an accelerated accumulation of advanced glycation end products on both elastin and collagen fibers,²⁶ or a change in the elastic properties of the elastic lamellae themselves after fragmentation induced by the cumulative fatiguing cyclic stress.²⁷ Finally, the fact that doses of sodium nitroprusside required to modify pulse wave velocity decrease with age, suggesting an increase in sensitivity of the soluble guanylate cyclase, may be an indirect indication of a loss of the endothelium-dependent reduction in vasomotor tone. This could account for the increased arterial stiffness with age, because vascular smooth muscle tone modulates arterial wall anisotropy differently with aging.²⁴ However, the latter conclusion was drawn on the basis of experiments on the carotid artery, a more muscular artery than the thoracic aorta; in the latter, changes in local smooth muscle tone do not seem to modify markedly aortic wall elasticity.^{12 28}

Surprisingly, despite the dramatic age-linked aortic stiffening of the aortic wall, central systolic and pulse aortic pressures are not increased but significantly decreased in old SHR compared with other groups. This suggests that stroke volume falls with aging in SHR. Old SHR have been described as a good model of cardiac failure with reduced ejection fraction,²⁹ and the dramatic age-dependent aortic stiffening observed in this strain may account for such a cardiac dysfunction.

In conclusion, aortic stiffness is not intrinsically increased in young or adult SHR, confirming previous studies of large-artery distensibility. However, aging in SHR is associated with a dramatic stiffening of the aortic wall, which cannot be explained by further increase in blood pressure or substantial age-linked aortic wall thickening, fibrosis, or elastocalcinosis. This suggests that some other structural disorganization of the media (which occurs earlier in hypertensive than in normotensive rats, eg, changes in the number of muscle to elastic lamellae connections, an increase in the ratio of collagen type I to III, or an accumulation of the advanced glycation end products) leads to mechanical alteration of the aortic wall in old SHR.

	Acknowledgments

 
This study was supported by grants from the French Education and Research Ministry (Paris, France); the Regional Development Committee (Metz, France); the Greater Nancy Urban Council (Nancy, France); and Rhône Poulenc-Rorer (Paris, France). The authors thank Drs René Peslin, Claude Duvivier, and Philippe Giummelly (Institut National de la Santé et de la Recherche Médicale U14 and Laboratoire de Pharmacologie Cardiovasculaire, Faculté de Pharmacie, Nancy, France) for help with signal analysis and Dr Nathalie Dartois (Rhône Poulenc-Rorer, Paris, France) for her intellectual, material, and moral support.

Received December 8, 1998; first decision December 18, 1998; accepted May 17, 1999.

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