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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:529-533.)
© 1995 American Heart Association, Inc.

Articles

Early Change of Vascular Permeability in Hypercholesterolemic Rabbits

Chau-Chung Wu; Shu-Wen Chang; Muh-Shy Chen; Yuan-Teh Lee

From the Departments of Internal Medicine (Cardiology) and Ophthalmology (S-W.C., M-S.C.), National Taiwan University Hospital, Taipei, Taiwan, ROC.

Correspondence to Dr Yuan-Teh Lee, Department of Internal Medicine (Cardiology), National Taiwan University Hospital, 7 Chung-Shan S Rd, Taipei, Taiwan, ROC, 10016.

	Abstract

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Abstract To study the effect of hyperlipidemia on vascular permeability, serial anterior chamber fluorophotometric examinations were carried out on 33 control rabbits (group 1) and 32 diet-induced hypercholesterolemic (group 2) rabbits. Changes in the blood-aqueous barrier function associated with total serum cholesterol (CHO) and triglyceride (TG) levels were studied at the beginning of the study and every 2 weeks thereafter for up to 16 weeks following 0.5% cholesterol–enriched diet feeding. Concurrently, a slit-lamp biomicroscope was used to examine the iris for evidence of atheromatous plaque. In group 1, the CHO level decreased slightly during the first 6 weeks and remained rather steady thereafter. The status of the blood-aqueous barrier correlated significantly with serum CHO and TG levels (r=.46, P<.001; r=.23, P=.01, respectively). In group 2, CHO and TG levels increased significantly after 2 and 8 weeks of cholesterol-enriched diet feeding, respectively. The blood-aqueous barrier also became more permeable than that in group 1 after 2 weeks' and increased above its baseline level after 6 weeks' feeding. Both CHO and TG levels correlated well with the degree of blood-aqueous barrier breakdown (r=.51, P<.001; r=.25, P<.001, respectively). The first evidence of iridic lipid-streak deposition was noted at 7.6±0.7 weeks, while definite iridic atheromatous plaque appeared 11.2±0.7 weeks after feeding. The change in the blood-aqueous barrier also correlated well with the semiquantitative score of iridic plaque (r=.58, P<.001) and usually preceded visual evidence of plaque formation. Pathological examinations of the eye showed marked foam cell infiltration in the stroma of the ciliary body, the ciliary process, and iris stroma, similar to changes in atheromas of the thoracic aorta after 16 weeks of feeding. In conclusion, anterior segment fluorophotometry is a valuable tool for detecting vascular integrity in vivo. These results suggest that the permeability change correlates well with serum CHO level and occurs in the very early stages of atherogenesis.

Key Words: vascular permeability • fluorophotometer • hyperlipidemia • blood-aqueous barrier • iris

	Introduction

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The vascular endothelium forms a highly selective permeability barrier.^{1 2 3} Endothelial cells normally attach to each other by tight and gap junctions, which may serve as potential sites of increased endothelial transport, particularly when they have been injured in diseases such as atherosclerosis or hypertension. Hypercholesterolemia is closely related to atherosclerosis and is one of the most important coronary risk factors.⁴ Besides smooth muscle cell proliferation and accumulation of connective tissue matrix, changes in endothelial permeability are major common pathogenic mechanisms in atherosclerosis. Several studies have pointed out that hypercholesterolemia enhances vascular endothelial dysfunction,^{5 6} smooth muscle cell proliferation,⁷ blood coagulability, and thrombogenicity.^{8 9} In diet-induced hypercholesterolemic rabbits, a prominent site for the development of xanthomata is the eye, in which the capacity of the iris to accumulate cholesterol is particularly noteworthy.¹⁰ Because vascular lesions in rabbits with experimental atherosclerosis are similar to native atherosclerosis in humans and because there is a high correlation between the severity of iridic and aortic involvement in experimental models,¹⁰ changes in iridic vessels in the eye will be good indicators of the general status of the vascular system.

The blood-aqueous barrier can be evaluated clinically by anterior segment fluorescein angiography,^{11 12 13} the cell-flare meter,¹⁴ and fluorophotometry.^{15 16} Among these, fluorophotometry is the most sensitive method to quantify the breakdown of the blood-aqueous barrier.¹⁷ Because of corneal clarity, the iris vasculature is one of the most easily assessed vessels in the body. This anterior chamber fluorophotometric study on detecting early changes in vascular permeability provides a good "window" for monitoring the pathological or pharmacological effects of various factors on systemic arterioles. In this experiment, we used fluorophotometry to detect the status of the blood-aqueous barrier in hyperlipidemic rabbits.

	Methods

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Animals, Diets, and Examination Schedules
Male New Zealand White rabbits weighing 1.4 to 1.6 kg were randomly divided into two groups. Thirty-three animals fed standard rabbit chow (Purina 5321) for 4 months served as controls (group 1). Another 32 animals (group 2) were fed the same diet enriched with 0.5% cholesterol (Wako Co) and coconut oil (Yeali Co). The lipids made up 40% of the total energy source of the diet. Both the salt and vitamin mixtures met American Institute of Nutrition Standards. All animals were allowed food and water ad libitum during the experiment, except for an overnight fast before blood sampling.

Biochemical Measurements
Blood was sampled at the time of fluorophotometric examination. Serum total cholesterol (CHO) and triglyceride (TG) levels were determined by automated enzymatic methods (Merck 14366 and 14354, respectively).^{18 19}

Fluorophotometry
Anterior chamber fluorophotometry was done at the beginning and then every 2 weeks for up to 16 weeks of the feeding schedule. Anterior chamber fluorophotometry was performed according to a protocol modified from that suggested by Miyake et al²⁰ and Fearnley et al.²¹ The rabbits were anesthetized with an intramuscular injection of a 2:3 (vol/vol) mixture of xylazine (2%, Bayer) and ketamine (50 mg/mL, Parke-Davis Co). Fluorophotometry was performed with the Fluorotron Master II (Coherent Co) fitted with an optical anterior segment adapter. After measurement of the lens and corneal autofluorescence, each rabbit received an intravenous injection of 10% fluorescein sodium (15 mg per 1 kg body weight). Because autofluorescence of the rabbit cornea and lens was small, there was hardly a significant spread between the lens and corneal autofluorescence peaks. Anterior chamber fluorescein concentration 60 minutes after intravenous injection of sodium fluorescein was measured. The mean value of anterior chamber fluorescence along the visual axis over a 2.0-mm band positioned in the anterior chamber was averaged (F60). We used F60 to represent the status of the blood-aqueous barrier.^{16 20} Because it is impossible to distinguish between the various metabolites of fluorescein with the Fluorotron Master, all fluorophotometric results were expressed as total fluorescence in terms of equivalent concentrations of fluorescein sodium.

Morphology
The iridic plaque was initially a yellowish streak-like deposit on the iris. In the advanced stage, the atheroma protruded into the posterior chamber from the posterior aspect of the iris. Two independent observers examined both eyes of each animal for the presence of iridic atheroma during fluorophotometric examinations. When no iridic atheroma was detected by visual inspection, we used a slit-lamp biomicroscope to determine whether there was any lipid streak deposit. The iridic atheromatous plaques (IAPs) were scored as follows: 0, no evidence of atheromatous plaque, even with the slit-lamp biomicroscope; 1, streak-like deposits detected under the slit-lamp biomicroscope but not detectable by visual inspection; and 2, iridic plaque visible by both slit-lamp biomicroscope and visual inspection. The times at which the first evidence of iridic deposition appeared, both with and without biomicroscopic aid, were recorded. All animals were killed by an overdose of intravenous pentobarbital at the end of the 16-week experiment period. Both eyes of each animal were enucleated immediately. They were processed for hematoxylin and eosin (H&E) stain and examined under a light microscope. A segment of the thoracic aorta containing atheromatous plaque was also dissected and processed for H&E stain.

Data Analysis
All values are expressed as mean±SEM. The levels of CHO and TG, the IAP score, and F60 in each group were averaged at different intervals. To avoid overestimation, data for both eyes of each animal were averaged and analyzed. Chronological changes in F60, CHO, TG, and IAP score were examined by one-way ANOVA in both groups. Differences between the two groups at the various experimental intervals were examined by Student's t test. Correlations of CHO, TG, and IAP score to F60 were examined. A probability value of <.05 was considered statistically significant. The time at which IAP appeared, identified with or without biomicroscopic aid, was averaged.

	Results

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The Table summarizes the chronological changes of CHO, F60, and IAP score.

View this table: [in this window] [in a new window]   Table 1. Summary of Serum Total Cholesterol, F60, and Iridic Atheromatous Plaques

Blood Chemistry
In group 2, the CHO level escalated rather rapidly in the first 2 months. This increase was significant after 2 weeks on a cholesterol-enriched diet. However, it became less acute in the third month, even declined from 12 to 14 weeks, and escalated again from 14 to 16 weeks. The TG level also increased significantly after 8 weeks of a cholesterol-enriched diet. In contrast, there was a slight decrease in CHO and TG levels in the first 6 weeks; these levels remained rather steady thereafter in group 1. The CHO correlated significantly with the TG level in both groups (r=.35, P<.001; r=.57, P<.001, respectively).

Fluorophotometry
Fig 1 shows the chronological changes of F60, CHO, and TG in both groups. In group 1, both CHO and TG levels correlated with F60 (r=.46, P<.001; r=.23, P=.01, respectively). The F60 in the first few weeks decreased slightly, in accordance with the slight decrease in CHO, and remained rather steady thereafter. In group 2, there was no initial decrease in F60. Instead, it remained rather stable initially and increased above its baseline level after the first 6 weeks of feeding. It also escalated further up to 16 weeks. However, there was a slight drop of F60 from 10 to 14 weeks, at which time the CHO levels also dropped. The rise in F60 roughly paralleled the rise in CHO and TG (r=.51, P<.001; r=.25, P<.001, respectively). F60 always correlated better with CHO than with TG levels in both groups. There was a significant difference in F60 between groups 1 and 2 after 2 weeks of a cholesterol-enriched diet (group 1: 497.9±15.4 ng/mL; group 2: 608.1±28.1 ng/mL, P<.001).

View larger version (21K): [in this window] [in a new window]   Figure 1. Line graph showing changes of anterior chamber fluorescein concentration 60 minutes after intravenous injection of sodium fluorescein (F60), serum total cholesterol (CHO), and triglyceride (TG) in groups 1 and 2. indicates F60 in group 1; , F60 in group 2; , CHO in group 1; , CHO in group 2; , TG in group 1; and , TG in group 2.

Morphology
With the aid of a slit-lamp biomicroscope, the first trace of iridic streak deposition appeared at 7.6±0.7 weeks, while definite IAP could be identified without biomicroscopic aid at 11.2±0.7 weeks of a cholesterol-enriched diet. The Table also summarizes mean IAP score at different time points in group 2. IAP score increased most significantly in the third and fourth months. Both CHO and F60 correlated significantly with IAP score (r=.45, P=.002; r=.58, P<.001, respectively). Pathological examinations at the end of the 16-week experiment showed there were abundant foam cells in the irides (Fig 2, top), ciliary bodies, ciliary processes (Fig 2, middle), and choroid of group 2 animals but not in those of group 1. The trabecular meshwork was also infiltrated by foam cells in some cases (Fig 2, bottom). These changes were similar to the atheromatous plaques of aortas (Fig 3). The conjunctiva, lens, and retinas seemed little affected by the systemic hypercholesterolemia.

View larger version (89K): [in this window] [in a new window]   Figure 2. Photomicrographs of the eye of a hypercholesterolemic rabbit. Top, Numerous foam cells infiltrated (arrows) the iris stroma. The bulk of iris atheroma plaque (double arrows) projected into the posterior chamber (PC) of the eye (hematoxylin and eosin stain; original magnification, x400). Middle, The ciliary body (CB) and ciliary process (P) were invaded by abundant foam cells (hematoxylin and eosin stain; original magnification, x200). Arrow indicates a foam cell at the root of the ciliary process. Bottom, There were also some foam cells (arrow) in the trabecular meshwork (TM) (hematoxylin and eosin stain; original magnification, x200).

View larger version (149K): [in this window] [in a new window]   Figure 3. Photomicrograph of atherosclerotic lesion from the thoracic aorta of a rabbit fed a cholesterol-enriched diet. Arrows indicate internal elastic lamina (hematoxylin and eosin stain; original magnification, x400).

	Discussion

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Although the posterior fourth of the iris is derived from the neuroectoderm, the anterior three fourths, ie, the vascular stroma, is mesodermal and thus similar to systemic arterioles. The iridic vessels, which frequently appear thick-walled, consist of an endothelial lining and a thick collar of collagen fibrils. This thick adventitia accounts for the remarkably low permeability of iridic vessels in the normal state.²² The capillaries in the iris have no fenestration, and the adjacent endothelial cells attach to each other by junctional complexes.²³ Normally, these intercellular attachments allow little extravascular permeation, even to small molecules such as fluorescein,²⁴ and thus form a blood-aqueous barrier. The aqueous fluid is in part a filtrate of serum. The huge molecular size of low-density (cholesterol-rich) serum lipoprotein probably prevents it from gaining easy access to the aqueous. Therefore, in diet-induced hypercholesterolemic rabbit models, the aqueous fluid might show only a modest increase in cholesterol despite an enormous change in serum cholesterol level.²⁵ However, this small increase in cholesterol in the aqueous does not guarantee an intact blood-aqueous barrier. During the early stages of experimental hyperlipidemia in hamsters, the aortic wall shows increased permeability to albumin.²⁶ In this study, we demonstrated an increase in iridic vessel permeability to sodium fluorescein in the early stage of diet-induced hyperlipidemia, even before visual evidence of iridic atheromatous plaque formation. Furthermore, F60 correlated well with both CHO level and IAP score. Because vascular lesions in rabbits with experimental atherosclerosis are similar to native atherosclerosis in humans, we believe that disruption of the integrity of the iridic vessel wall is a good indicator of incompetence of the systemic vasculature.

In group 1, the initial decrease in F60 may have been due to the concurrent decrease of CHO level or to the age-associated functional change in iridic vascular permeability. F60 became significantly different between groups 1 and 2 only after 2 weeks on a cholesterol-enriched diet because there was no initial decrease in both CHO and F60 levels in group 2. However, while the CHO level rose significantly after 2 weeks, F60 increased above its baseline level only after 6 weeks in group 2. These results demonstrated that although it lagged slightly behind, the trend in F60 roughly paralleled the change in CHO in both groups. We do not know the exact mechanism by which lipid levels modified F60. Nevertheless, a high-fat, high-cholesterol diet may cause endothelial injury⁶ and alter the endothelial barrier. It has been postulated that alterations in permeability of the local vasculature lead to changes in the iridic deposits,^{27 28} which lead to the development of sudanophilic substance accumulation and foam cell formation.^{27 29 30} In the study of Roscoe and Vogel,¹⁰ in which rabbits were fed 1% cholesterol, there was a linear increase in total iridic cholesterol during the first 2 months of cholesterol feeding. Nevertheless, the biggest increase in total iridic cholesterol was in the third month. In our study, the F60 and serum total CHO levels reached a peak in weeks 10 to 12 and a trough in week 14 and then rose again. Roscoe and Vogel did not describe the chronological changes in serum CHO and TG in their results, while we found a rather rapid increase in serum CHO in the first 2 months. F60 increased slightly in the first month and rose more rapidly in the second and third months, in a delayed pattern similar to the increase in serum total CHO level. However, the IAP score increased most notably in the third and fourth months. Although F60 also correlated well with the IAP score, the alteration in F60 usually preceded visual evidence of iridic deposits, which were already visible under a slit-lamp biomicroscope after 7.6±0.7 weeks' feeding of a cholesterol-enriched diet.

After reaching a peak in weeks 10 to 12, both F60 and CHO had a slight drop and a trough in week 14. The fact that the rabbits ate less and their body weights also decreased slightly during this period might partially explain the decrease in both serum total CHO and F60. Another possibility is that thrombosis might have occurred in the iridic arterioles, because hyperlipidemia would alter the platelet surface negative charge³¹ and enhance platelet–vessel wall interactions.³² Both factors might contribute to acute thrombosis formation, which could have resulted in less inflow of fluorescein-rich serum. Therefore, F60 was smaller in some rabbits, although we presumed that there would be a more significant breakdown of the blood-aqueous barrier. At week 16, the more severely broken-down blood-aqueous barrier contributed to an even higher F60, with more advanced hyperlipidemia, despite the possibility of vascular thrombosis.

In this study, we do not know whether breakdown of the blood-aqueous barrier involved the iridic arterioles or capillaries. However, a previous histopathologic examination delineated that the first evidence of an iridic lesion was the presence of lipid droplets in the walls of small blood vessels.³⁰ Lipid droplets or globules then appeared in the adjacent connective tissue. Both conditions preceded the appearance of lipid-filled macrophage or foam cells,³⁰ similar to the atheromas found in systemic atherosclerosis. This might reflect a change in the vascular permeability during the early stages of an increased serum cholesterol level.²⁹ Because the animals were killed after being fed a cholesterol-enriched diet for 16 weeks, histopathologic changes in the early stages were not reproduced. However, we found abundant foam cell infiltration that was similar to advanced atheroma formation reported in the literature.^10,30 The iris connective tissue has little effect on the passage of the fluorescein molecule once it has entered the subendothelial space. Thus, the anterior chamber fluorescein concentration would increase with subtle changes of the blood-aqueous barrier, possibly long before the visually detectable iridic deposition or pathologically detectable sudanophilic substance accumulation.

In summary, using anterior segment fluorophotometry, we evaluated vascular endothelial integrity in vivo. The change in vascular permeability correlated well with serum CHO level and occurred during the very early stages of atherosclerosis. Moreover, this alteration of vascular permeability preceded visual evidence of atheromatous plaque. This method was found to provide a good window into the early detection of endothelial functional change in systemic hypercholesterolemia and possibly atherosclerosis.

	Acknowledgments

 
This work was supported by research grant DOH83-HR-301 from the Department of Health, Executive Yuan of Taiwan, ROC.

Received October 30, 1994; accepted January 20, 1995.

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This Article Abstract Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wu, C.-C. Articles by Lee, Y.-T. Search for Related Content PubMed PubMed Citation Articles by Wu, C.-C. Articles by Lee, Y.-T.