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Proceedings of the Society for Experimental Biology and Medicine 224:166-171 (2000)
© 2000 Society for Experimental Biology and Medicine

Original Article

Effects of Cholesterol Diets on Vascular Function and Atherogenesis in Rabbits

Yi-Ping Sun*,1, Nancy C. Lu{dagger}, William W. Parmley* and Clarie B. Hollenbeck{dagger}


* Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California 94143; and
{dagger} Department of Nutrition and Food Science, San Jose State University, San Jose, California 95192


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Vascular endothelial dysfunction is an important early event in atherogenesis. To evaluate the effects of different levels of cholesterol-containing diets on vascular function and atherogenesis, 17 New Zealand White male rabbits were randomized into four groups: Control with noncholesterol, 10-week 0.5% (0.5C-10) or 1% cholesterol (1C-10), and 14-week 0.5% cholesterol (0.5C-14) feedings. After 10 or 14 weeks, the aortas were harvested for studies of vascular endothelial function and percentage surface lipid lesions. The 0.5% and 1% cholesterol feedings resulted in the same degree of hypercholesterolemia independent of the level and period of cholesterol feeding. There was a decreased trend in vascular endothelial-dependent relaxation to acetylcholine in cholesterol-fed rabbits. Fourteen-week cholesterol feeding induced the least vascular dilation at a concentration of 10-7 M acetylcholine (–38 ± 3%, –23 ± 4%, –23 ± 2%, and –15 ± 5% in control, 0.5C-10, 1C-10, and 0.5C-14 groups, respectively, P = 0.003). More cumulative exposure of arterial walls to cholesterol induced more surface lipid lesions in the aorta (r = 0.877, P < 0.001). There was a negative relationship between aortic lesions and vasodilation (r = –0.557, P = 0.020 for calcium ionophore; r = –0.463, P = 0.062 for acetylcholine). We conclude that the 0.5% and 1% cholesterol feedings induce similar degrees of hypercholesterolemia. However, aortic lipid lesions and vascular reactivity are dependent on cumulative exposure to cholesterol rather than serum cholesterol level only. Furthermore, decreased vascular endothelial relaxation in cholesterol-fed rabbits was related to lipid plaques in the aorta.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Atherosclerotic disease including coronary artery disease is still the leading killer in industrial countries. The development of coronary artery disease is a lifelong process. Hypercholesterolemia is one of the major risk factors for coronary artery disease (1). Epidemiological and experimental data have indicated that a high cholesterol–containing diet is highly related to the development of hypercholesterolemia. Rabbits develop hypercholesterolemia rapidly after excessive cholesterol feeding (2-4). Atherosclerosis, a basic pathological lesion of coronary artery disease, can be induced by injury or pathophysiological changes in the vascular endothelium. Hypercholesterolemia impairs vascular endothelial function by reducing an endothelium-derived relaxing factor (EDRF), now identified as nitric oxide (NO) (5, 6), even before atherogenesis. Endothelial dysfunction is an important early event in atherogenesis. NO preserves the integrity of the endothelium and may prevent atherosclerosis. The present study was designed to evaluate the effects of different cholesterol-containing diets on vascular endothelial function and atherogenesis in a rabbit model.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusions
 References
 
Protocol.
The study protocol was approved by the Committee for Animal Research of the University of California San Francisco and was in accordance with Public Health Service Policy and Animal Welfare Regulations.

The study was designed to minimize the number of animals used. Seventeen New Zealand White male rabbits (11–13 weeks old, average body weight 3.3 ± 0.1 kg) were housed individually with free access to water. The rabbits were assigned randomly into four groups: Non-cholesterol feeding for 10 weeks (control, Purina Mills, Inc., St. Louis, MO), 10-week 0.5% (0.5C-10) or 1% (1C-10) cholesterol plus 3% soybean oil by weight (Ziegler Brothers, Inc., Gardners, PA) feedings and 14-week 0.5% cholesterol plus 3% soybean oil feeding (0.5C-14). There were four rabbits in each group except five in the control group.

Body weight and food intake were measured and recorded. The loss of appetite and body weight were used to monitor possible pain or discomfort. The end point of the study was 10- or 14-week completion of the control or cholesterol-diet feedings. All rabbits were euthanized at the end of the study with an injection of 130 mg/kg pentobarbitol via the marginal ear vein in accordance with University of California San Francisco institutional guidelines. Aortic rings were harvested for studies of vascular reactivity. Surface lipid lesions in the aorta were quantitated by planimetry.

Biochemical Studies.
Total serum cholesterol and triglyceride levels were measured by quantitative enzymatic assays (Sigma Diagnostics, St. Louis, MO) (7, 8). The comparison of values yielded a correlation coefficient of 0.99, and the regression equations were y = 0.97x + 6.3 and y = 0.98x – 3.5. As a measurement of cumulative exposure of arterial walls to cholesterol by week, the area under the cholesterol-time curve was calculated in cholesterol- weeks (mg/dl x weeks) (2). HDL-cholesterol (HDL-C) was determined by quantitative measurement with HDL-C reagent after precipitation of other lipoprotein classes with phosphotungstic acid and magnesium chloride (PTA/MgCl2, Sigma Diagnostics) (9, 10). The correlation coefficient was 0.99, and the regression equation was y = 0.95x + 0.2. The serum lipid measurements were done with a spectrophotometer.

The rabbits were held inside a specific restrainer for blood sample collecting. Blood samples were collected via ear venipuncture at the beginning, every 4–5 weeks, and at the end of the study.

Vascular Reactivity In Vitro.
Vascular tension was measured in intact aortic rings suspended in organ chambers (11, 12). After lethal injection with pentobarbitol, aortic segments (5–6 mm in diameter and 4–5 mm in length) were harvested from the thoracic aorta and were carefully dissected free from adjacent tissue to avoid stretching and endothelium damage. All rings were taken from the same position in the aorta from each animal. The vascular rings were suspended in organ chambers and then immediately placed in a bath containing warm (37°C) Kreb's bicarbonate solution bubbled with a gas mixture of 95% O2 and 5% CO2 (13). After being attached to a force transducer, the rings were gradually stretched over a period of 60 min to a preload of 4 g. As a reference, endothelium-dependent relaxation was measured using acetylcholine and the calcium ionophore A23187, and endothelium-independent relaxation was assessed using nitroglycerin. The dose needed to induce a half-maximal contraction (EC50) was determined by increasing the concentration of phenylephrine in half-log increments(10-9 through 10-4 M) until reaching the maximal response (14). To quantitate endothelial relaxation, the vascular rings were exposed to a cumulative increase in concentration of acetylcholine (10-9 through 10-4 M) to relax the phenylephrine-induced contraction. The vasorelaxation response was expressed as a percentage relaxation of the contraction induced by EC50 phenylephrine.

Morphological Studies.
The intimal lipid lesions in the aorta were examined quantitatively by estimation of the percentage of Sudan IV stained regions (lipid infiltration) in photographs of each aorta by planimetry (3, 4, 15). After removal of the aortic ring, the whole aorta was removed from its origin (2 cm distal to the aortic valve) down to the bifurcation of the internal iliac arteries. The vessels including the rings for vascular reactivity study were opened by a linear vertical incision, fixed in a formalin solution for 24 hr, stained with Sudan IV lipophilic dye, and photographed. The intimal lipid lesions were determined quantitatively by estimation of the percentage of sudanophilic stained areas in the total aortic intimal area in photographs by planimetry (16, 17).

Statistical Analysis.
All values are expressed as mean ± SEM. The comparisons of the differences among the groups were done by a general linear model implementation of one-way analysis of variance (ANOVA) with the regression equation for multiple comparisons. The correlative tests were analyzed for the relationships between two variables. All computations were done with MINITAB Release (10.51, Xtra, State College, PA) (18, 19) and KaleidaGraph (Version 2.1.3; KaleidaGraph, Reading, PA). Actual P-values were presented, and a P-value < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusions
 References
 
Two rabbits in the 10-week 1% cholesterol-fed group developed jaundice at the end of the study, but all animals in the study were included for data analysis. There was no significant difference in body weight before cholesterol feeding, but the weight gains during the study were significantly less in the rabbits receiving cholesterol feeding (P < 0.001, Table IGo). The 0.5% or 1% cholesterol feeding, especially 14-week 0.5% cholesterol feeding, inhibited food intake (P < 0.001, Table IGo). The 14-week 0.5% feeding induced less cholesterol intake because advanced liver failure led to less food consumption.


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  		Table I.   Body Weight and Food Intake in the Rabbitsa
 
Biochemical Studies.
Serum cholesterol levels were significantly elevated after the 10- or 14-week cholesterol feedings. The 0.5% and 1% cholesterol feedings induced a similar degree of hypercholesterolemia (Table II)Go. Hypercholesterolemia was independent of the feeding duration in this study, comparing the 0.5C-14 and 0.5C-10 groups. The 14-week cholesterol group had a lower HDL-C when compared with the control group (P < 0.001). A higher cholesterol-weeks in all lipid-fed groups were observed due to high cholesterol feeding. No significant changes were found in serum triglyceride.


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  		Table II.   Serum Lipids Among the Groupsa
 
Vascular Reactivity In Vitro.
There were no significant differences in phenylephrine-induced maximal vasoconstriction (305 ± 20%, 309 ± 40%, 271 ± 9%, and 334 ± 31% in the control, 0.5C-10, 1C-10, and 0.5C-14 groups, respectively). There was a decreased trend in maximal endothelial-dependent vasodilation with acetylcholine and calcium ionophore in the hypercholesterolemic rabbits based on the phenylephrine-induced half-maximal contraction, but these were not statistically significant (to acetylcholine: –72 ± 3%, –70 ± 2%, –71 ± 3%, and –66 ± 4%; to calcium ionophore: –72 ± 3%, –60 ± 4%, –64 ± 4%, and –60 ± 3% in the control, 0.5C-10, 1C-10, and 0.5C-14 groups, respectively). However, cholesterol-fed rabbits showed significantly less vasodilation to acetylcholine at a concentration of 10-7 M (P = 0.003, Fig. 1Go). There were no significant differences in nitroglycerin-induced vasodilation among control, 0.5C-10, and 1C-10 groups.



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  		Figure 1.   Dose response of vasodilation to acetylcholine. Although maximal response to acetylcholine did not differ significantly, cholesterol-fed rabbits showed much less endothelial-dependent vasodilation than control rabbits at 10-7 M acetylcholine (P = 0.003 by one-way ANOVA, all P < 0.05 comparing each lipid-fed group with control individually). Group designations as in Table IGo.

 
Morphological Studies.
Control rabbits on a noncholesterol diet did not develop any lipid lesions during the study. The average percentage lipid lesions in the aorta were 0, 17.7 ± 4.9%, 17.1 ± 3.5%, and 41.7 ± 5.1% in control, 0.5C-10, 1C-10, and 0.5C-14 groups, respectively (Fig. 2)Go. Ten-week 0.5% or 1% cholesterol feeding did not differ in inducing surface lipid lesions in the aorta. Rabbits with the 14-week 0.5% cholesterol feeding had more surface lipid lesions in the aorta probably due to more cumulative exposure of the aortic walls to cholesterol. There was a close relationship between cholesterol-weeks and aortic lipid lesions (r = 0.877, P < 0.001).



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  		Figure 2.   Percentage of surface lipid lesions in the aorta. Control rabbits with noncholesterol feeding did not develop any lipid lesions during the study period. The 0.5% and 1% cholesterol feedings induced significant surface lipid lesions in the aorta. Fourteen-week 0.5% cholesterol feeding induced more severe surface lipid lesions in the aorta with more cumulative exposure of aortic walls to cholesterol (P = 0.001 and P < 0.001 compared with 10-week 0.5% or 1% cholesterol feeding, respectively). Group designations as in Table IGo.

 
There was an inverse relationship between aortic lipid lesions and acetylcholine or calcium ionophore–induced maximal vasodilation (r = –0.463 and r = –0.557 for acetylcholine and calcium ionophore, Fig. 3Go).



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  		Figure 3.   Correlations between vasodilation and aortic lesions. An inverse relationship occurred between aortic lipid lesions and acetylcholine or calcium ionophore–induced maximal vasodilation.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusions
 References
 
In the present study, we investigated the effects of 0.5% and 1% cholesterol diet feedings for 10 and 14 weeks on vascular endothelial function and atherogenesis in rabbits. We also evaluated the relationships among hypercholesterolemia, vascular function, and atherosclerosis. The major findings of the study can be summarized as follows: i) The 0.5% and 1% cholesterol feedings induced a similar degree of hypercholesterolemia; ii) Aortic lipid lesions and vascular reactivity were dependent on cumulative exposure to cholesterol rather than serum cholesterol level only; and iii) Less vasodilation may be caused by lipid plaques in the aorta.

Vascular disease is a very prevalent disorder leading to coronary artery disease and stroke, the most common causes of death in the United States (20). Coronary artery disease can be initiated by hypercholesterolemia induced by cholesterol diet and genetic influences (21). Atherosclerosis results from multiple complex interactions among injurious stimuli and the healing or reparative responses of the arterial wall involving both environmental and genetic factors (22).

Dietary Cholesterol and Hypercholesterolemic Models.
Rabbits, rats, mice, pigeons, pigs, and monkeys have been the subjects of most experimental atherosclerosis research. Among these different animal models and experimental designs, excessive cholesterol feeding to rabbits induces the rapid development of abnormal vessel function and atherogenesis and thus serves as a reasonable model for cardiovascular disease (15-17, 23). Different levels of cholesterol-supplemented diets (from 0.1%–2% cholesterol) are used to induce hypercholesterolemia based on different study periods. The initial lesions in hypercholesterolemic rabbits are fatty streaks with the migration of monocytes through the endothelial layer similar to human atherosclerosis. Over time the lesion develops into a so-called complicated lesion-fibrous plaque. Previous data showed that a 3-week 0.3% cholesterol diet followed by either 0.3% or 0.5% cholesterol feeding for another 10 weeks induced 19.8% ± 5.6% and 32.4% ± 5.5% of aortic lipid lesions in the rabbits, respectively (19). Rabbits fed a 4-week 1% cholesterol diet followed by a 12-week 0.5% cholesterol diet showed impaired endothelium-dependent relaxation in aortic rings ex vivo (24). Significantly impaired endothelium-dependent vasodilation in the carotid artery was also found in rabbits with 8–10 weeks of 1% cholesterol feeding (25). The 0.1% cholesterol-supplemented diet is closer to an adult's diet in the United States. In this study, the cholesterol content of the diet was increased to 0.5% and 1% to shorten the study period to 10 and 14 weeks. Regardless of the feeding duration, the 0.5% and 1% cholesterol-fed rabbits developed similar hypercholesterolemia in this study. Perhaps 0.5% cholesterol feeding induced the maximal cholesterol response in rabbits.

Injury to Vascular Endothelium.
Hypercholesterolemia may induce a subtle form of injury to endothelium (26). The response-to-injury hypothesis of atherogenesis proposes that injury is the initiating event. The injury may cause no morphologic alterations but may be enough to lead to endothelial dysfunction. Hypercholesterolemia impairs vascular endothelium-dependent relaxation and induces atherogenesis in both animal models (25) and humans (27, 28). The earliest alteration to the endothelium after exposure to high cholesterol levels is the loss of EDRF (5, 6) which exerts a variety of physiological actions in addition to its well-known relaxation of vascular smooth muscle, including inhibition of platelet aggregation (29), attenuation of leukocyte adherence to the endothelium (30, 31), and the quenching of superoxide radicals (32). Significant endothelial dysfunction characterized by reduced EDRF release was shown within 2 weeks after initiation of a 0.5% cholesterol diet before any coronary artery plaque occurred (33). This is consistent with other reports of endothelial dysfunction in cholesterol-fed rabbits (34). Hypercholesterolemia is also one of the most important factors that cause endothelial dysfunction in human coronary arteries (35). In agreement with other findings, our hypercholesterolemic rabbits showed impaired vascular relaxation. The rabbits with hypercholesterolemia had significantly reduced vasodilation to 10-7 M acetylcholine (Fig. 1)Go. The impaired endothelium-dependent relaxation found in atherosclerotic arteries may be caused by the following factors: i) decreased synthesis or functional changes of EDRF; ii) impaired transit of EDRF; iii) altered responses of vascular smooth muscle cells to the relaxing factors; or iv) release of endothelium-derived constrictor factors.

The Relationships Among Dietary Cholesterol–Induced Hypercholesterolemia, Vascular Dysfunction, and Atherosclerosis.
The decrease in endothelium-dependent relaxation appears to be related to the amount of cholesterol in the diet, the length of the diet periods, and the severity of atherosclerotic lesions. Many strategies have been used to reverse the endothelial dysfunction induced by evelated levels of cholesterol. Our data showed that a high cholesterol diet induced obvious aortic lipid lesions during the study period with the most severe lesions in the 14-week cholesterol feeding group. There was a significantly positive relationship between cumulative exposure of cholesterol and lipid lesions, consistent with other results (23, 36).

It was also demonstrated that enhancement of vascular NO activity can induce regression of preexisting intimal lesions in the thoracic aorta of hypercholesterolemic rabbits (37). Clinical and experimental observations suggest that atherosclerosis alters vascular reactivity. A negative relationship between aortic lipid lesions and endothelium-dependent vasodilation was found in our study. The possible explanations for the reduced endothelium-dependent relaxation response include functional or mechanical barriers that limit diffusion of NO, inability of the smooth muscle to relax, and competing vasoconstrictive stimuli. In the present study, we have shown that atherosclerotic lesions lead to less vasodilation, but we could not prove the exact time sequence of functional and pathological changes. Although endothelial dysfunction has been demonstrated early in the course of the disease process, it has been difficult to establish a causal relationship (38). Disparities between abnormal endothelium-dependent vasodilation in the microvasculature and the extent of atherosclerosis in the aorta indicate that different mechanisms may be responsible for these two phenomena (39).

Although different animal models and experimental designs have been used to study cholesterol-induced vascular endothelial dysfunction and atherosclerosis, this 10–14 week short-term model with animals incompletely represents the chronic complicated changes of atherosclerosis in humans. The small number of animals in each group is another limitation in the study design. But it is still an appropriate animal model in cardiovascular research to understand better the fundamental biology of early atherosclerosis and to aid in the development and testing of potential therapies.


   Conclusions
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
References
 
We conclude that the 0.5% and 1% cholesterol feedings induced similar degrees of hypercholesterolemia. Vascular dysfunction and aortic lipid lesions caused by cholesterol feeding are dependent on cumulative exposure to cholesterol rather than serum cholesterol level only. Decreased endothelium-dependent vasodilation is associated with surface lipid lesions in the aorta.


   Acknowledgments
 
The authors gratefully thank Dr. Bo-qing Zhu and Ms. Amanda E.M. Browne for their kind laboratory assistance.


   Footnotes
 
This study was supported in part by the George D. Smith Fund. The author would also like to thank the College of Applied Sciences and Arts, San Jose State University, for the funding of College Small Research Grant.

1 To whom requests for reprints should be addressed at 1176-Moffitt Hospital, Box 0124, Division of Cardiology, Department of Medicine, University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143. E-mail: sun{at}medicine.ucsf.edu Back


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 

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Received for publication August 23, 1999. Accepted for publication February 23, 2000.




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