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Am J Physiol Heart Circ Physiol 287: H2346-H2351, 2004. First published June 3, 2004; doi:10.1152/ajpheart.00066.2004
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Role of vasa vasorum in transendothelial solute transport in the coronary vessel wall: a study with cryostatic micro-CT

Mario Gössl, Patricia E. Beighley, Nasser M. Malyar, and Erik L. Ritman

Physiological Imaging Research Laboratory, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905

Submitted 4 February 2004 ; accepted in final form 17 May 2004


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Using cryostatic microscopic computed tomography (micro-CT), we sought to determine the role of coronary vasa vasorum (VV) in transendothelial solute transport in arteries with normal and increased permeability due to high plasma cholesterol levels. In 6-mo-old pigs on a normal (n = 23) and 2% high cholesterol (HC) diet (n = 8), 2-cm segments of the proximal left anterior descending coronary arteries were removed in vivo after a selective injection of X-ray contrast solution. Harvesting of the specimens occurred at 0, 15, 25, 35, or 45 s after completion of the contrast injection. Specimens were snap frozen and scanned in our cryostatic micro-CT. The spatial distribution of contrast in the coronary artery wall was quantified using the CT images. Right coronary arteries were infused with Microfil to determine VV density (VV/mm2) and the cumulative lumen surface area (mm2/mm3). Transendothelial diffusion of contrast into the coronary vessel wall is a dynamic process starting at both the subintima and the adventitia. The subintimal opacification moves as a wave toward the adventitia, whereas the adventitial wave resolves. The coronary vessel wall in animals on a HC diet shows higher opacification than in normal coronary arteries without an increase of VV total luminal surface area. The loss of endothelial integrity in hypercholesterolemia significantly alters VV solute washin to, and washout from, the coronary artery wall.

hypercholesterolemia; coronary artery wall perfusion; permeability; endothelium; microscopic computed tomography

CORONARY ARTERY WALL PERFUSION and transendothelial transport are poorly understood. It has been shown that both luminal and abluminal sources (vasa vasorum) supply the arterial vessel wall and that a decrease of vasa vasorum supply can play a role in atherogenesis (1, 10, 28). In addition, we recently showed in porcine coronary arteries that in addition to vasa vasorum of arterial origin, there are also vasa vasorum that drain into the concomitant vein (8), suggesting that these "venous" vasa vasorum likely play a role in the drainage of the coronary artery wall.

Current imaging modalities do not allow in vivo visualization of the dynamic spatial distribution of transendothelial diffusion within the coronary vessel wall. However, this information is needed to describe the interplay of solute supply to, and drainage from, the arterial wall and thereby the role of the different types of vasa vasorum in normal and disease conditions.

Hypercholesterolemia has been demonstrated to alter the integrity of the vascular endothelium (4) and lead to an increased endothelial permeability (15, 19). For this reason, we use this condition to examine the role of endothelial permeability in vasa vasorum and in the main lumen. There are no in vivo data available that show directly how endothelial changes affect coronary arterial wall solute transport.

Because intravascular contrast agents are known to diffuse across the arterial endothelium, we used these agents to evaluate endothelial permeability (22, 23) in combination with cryostatic microscopic computed tomography (micro-CT), which enables us to image snap-frozen tissue samples (12, 13). Thus, when arterial segments are harvested and snap frozen at different time intervals after the intracoronary injection of a bolus of contrast agent, the contrast agent that traverses the endothelium of the main lumen and of the vasa vasorum is thereby prevented from continuing to diffuse within the vessel wall. Micro-CT scanning of these frozen specimens now allows us to visualize the spatial distribution of the transendothelial transported contrast medium, literally "frozen in time." Therefore, we used cryostatic micro-CT to investigate the dynamic distribution of contrast diffusion within the normal coronary artery wall and how this changes in hypercholesterolemia.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
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Animal Experiments

All animal studies were approved by the Mayo Foundation’s Institutional Animal Care and Use Committee. The study protocol consisted of two experiments.

Experiment 1: distribution and temporal course of coronary vessel wall perfusion. Twenty-three domestic, female, cross-bred swine were fed normal laboratory chow for 6 mo (N group). At the age of 6 mo, all pigs were anesthetized, intubated, and ventilated during the whole procedure as described previously (16). Electrodes on the limbs were used to monitor the electrocardiogram.

The neck was dissected on the left side so that the left carotid and jugular vein could be isolated. An access for the later catheterization was introduced in the left carotid artery and served also for continuous blood pressure measurement. The access for the jugular vein was used for intravenous infusions. To prevent cardiac arrhythmia, pigs received a bolus injection (1 mg/kg) and a continuous drip of lidocaine-HCl (20 µg·kg–1·min–1). We then performed a midline thoracotomy and formed a pericardial cradle to obtain free access to the proximal left anterior descending coronary artery (LAD; Fig. 1). A 2-Fr catheter was advanced through the carotid artery, and its tip was placed in the proximal LAD, monitored by fluoroscopy. Subsequently, 20 ml of radiopaque contrast dye (Iopamidol 76%, ISOVUE Multipack-370, Bracco Diagnostics; Princeton, NJ) were injected over 10 s under constant pressure and flow (monitored by fluoroscopy as well). Lopamidol is a nonionic iodinated contrast agent that distributes between the circulating blood volume and a fraction diffuses through the endothelium into the extravascular space.



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  		Fig. 1. This sketch illustrates the schematic of the experimental design. In open-chest surgery, contrast agent is injected in the left anterior descending coronary artery (LAD) via the intracoronary catheter. After different time intervals after the end of injection of contrast dye, the LAD is clamped proximally and middistally, and a 2-cm LAD segment between the clamps is then cut and immediately immersed into a slurry of acetone and dry ice.

 
After completing the injection of contrast dye, we harvested a 2-cm piece of the proximal LAD either immediately (n = 3) or after waiting 15 (n = 3), 25 (n = 3), 35 (n = 6), or 45 s (n = 3). Three noninfused LADs served as controls. All LADs were clamped proximally and middistally, cut free (with a margin of at least 1 cm on each side well outside the adventitia to protect and preserve all structures of the vessel wall), and immediately dropped into a slurry of acetone and dry ice for rapid freezing (Fig. 1). Simultaneously with the LAD biopsy, the animals were euthanized with a weight-adjusted intravenous injection of Sleepaway (Fort Dodge Laboratories; Fort Dodge, IA). Once frozen, the LAD specimens were stored at –80°C for subsequent scanning with cryostatic micro-CT.

Experiment 2: transendothelial solute transport in hypercholesterolemia. Eight more female pigs were fed a high cholesterol diet (15% lard and 2% cholesterol, TD 93296, Harlan Teklad; Madison, WI) for 3 mo, starting at the age of 3 mo (HC group). At the age of 6 mo, all LADs in this group were harvested 35 s after the end of the injection (as described above). We chose the 35-s time point because the data from experiment 1 demonstrated that at this time the peak of the opacification wave coming from the subintima had reached the adventitia (see below). That way, we were able to evaluate the solute washout function of the coronary vasa vasorum in hypercholesterolemia.

Cryostatic micro-CT Vessel

Cryostatic micro-CT vessels were prepared as described in Refs. 12 and 13.

A double-walled copper vessel, 32, l in volume, was fabricated for scanning the LAD specimens while maintaining them at cryogenic temperatures (in this case, –51°C) via nitrogen gas boiling off liquid nitrogen vented continuously into the top of the chamber during the scanning process. Temperature sensors within the chamber are used to control the rate of inflow of cold nitrogen gas so as to maintain the specimen temperature within ±1°C. The specimen is attached to a small platform on top of a vertical stainless steel pin, which is attached to the computer-controlled rotating stage under the vessel. The maximum size of the specimen accommodated by the vessel is 1.3 cm in diameter and 2 cm long.

Three-Dimensional Image Reconstruction and Display

The scans involved digital recording of 360 X-ray images obtained at 1° intervals around 360°. We then perform a modified Feldkamp cone beam tomographic image reconstruction from these projection data. The resulting stack of transaxial tomographic images (on average 580 images/specimen) was displayed and analyzed using image-analysis software (Analyze 6.0, Biomedical Imaging Resource, Mayo Clinic; Rochester, MN). For this study, the cryostatic micro-CT scanner was configured so that the dimension of the cubic voxels was 18 µm (16-bit gray scale).

Analysis of Tomographic Cryostatic micro-CT Images

Within the stack of tomographic images, those with well-defined cross sections of the LADs were identified and used for further analysis (Fig. 2A). Images spaced by at least 0.4 mm were analyzed to insure reasonably representative cross sections within a LAD specimen (on average, 10 slices/specimen).



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  		Fig. 2. A: cryostatic microscopic computed tomography (micro-CT) cross section of a frozen LAD at 35 s after the end of contrast injection. The outer border of the adventitia is defined by the image-contrast difference between the adventitia and the perivascular fat tissue. The entire wall can then subdivided in three (B) or six (C) concentric layers, where the innermost layer represents the subendothelium and the outermost layer represents the outer adventitia. Mean CT values are calculated for each layer in several cross sections of the LAD.

 
With the use of Analyze 6.0, areas were chosen that allowed clear identification of the border of the adventitia (through the image-contrast difference provided by the periarterial fat tissue or air at the epicardial surface). The coronary vessel wall was then subdivided into three concentric, equispaced layers (10, 18), and the mean CT value was calculated for each layer (Fig. 2B). For a more detailed view on the temporal course of vessel wall opacification, we also analyzed the same cross section with subdivision of the vessel wall in six concentric, equispaced layers (Fig. 2C).

Preparation and Analysis of Right Coronary Arteries for Conventional Micro-CT Imaging

Because transendothelial transport is proportional to the product of endothelial permeability and surface area, we needed to measure surface area so that the permeability could be calculated. Hence, the right coronary arteries (RCAs) of all harvested hearts were prepared for conventional micro-CT imaging, and vasa vasorum branching geometry analysis (i.e., segment lengths and diameters) was performed as described in our previous publications (7, 8). Furthermore, because vasa vasorum density in LADs (n = 6) and RCAs (n = 6) of 3-mo-old pigs showed no statistically significant difference (2.81 ± 0.85 vs. 2.83 ± 0.75 vasa vasorum/mm2), we used RCAs from pigs of the present study as surrogates for vasa vasorum density in normal and hypercholesterolemic LADs.

Statistical Analysis

All data are presented as means ± SD for all arteries. Data were analyzed using an unpaired t-test and one-way ANOVA to establish differences among normal and hypercholesterolemic coronary arteries. A value of P < 0.05 was considered significant in all analyses.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
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Lipid Profile, Systemic Characteristics, and Intima-to-Media Ratios

Table 1 summarizes lipid profiles and systemic hemodynamic data in normal and hypercholesterolemic pigs.


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  		Table 1. Hemodynamic characteristics and lipid profiles

 
Intima-to-media thickness ratios did not differ statistically significant between the groups [N group: 0.26 ± 0.1 vs. HC group: 0.33 ± 0.13 (not significant)].

Temporal Course and Distribution of Coronary Vessel Wall Perfusion

The results of experiment 1 are shown in Fig. 3. The aggregate data from 23 pigs describe the dynamic distribution of the extravascular contrast within the vessel wall. Immediately after the end of the intracoronary injection of the contrast bolus (0-s time point), opacification of the vessel wall was maximal (Fig. 3A). The spatial distribution of contrast agent shows that there was a two-peak distribution of opacification at the 0-s time point (Fig. 3B). One peak was in the subintimal region and the other was in the adventitia. Fifteen seconds after the end of contrast injection, there was a significant decrease in overall vessel wall opacification (Fig. 3). Figure 3B shows that the subintimal peak of opacification moved as a wave toward the adventitia, whereas the initial adventitial contrast accumulation progressively resolved. After 25, 35, and 45 s, vessel wall opacification decreased almost toward the control value and the medial wave propagated further outward and then also dissipated.



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  		Fig. 3. A: coronary vessel wall perfusion over time. The graph shows that the maximal opacification occurs immediately after complete injection of contrast medium (0 s). All layers of the coronary vessel wall show a progressive decrease in opacification. B: enhancement of the scale more clearly conveys how the "wave of opacification" moves through the vessel wall from subintima to adventitia.

 
Indicator Accumulation in the Coronary Vessel Wall in Hypercholesterolemia

Figure 4 shows that at 35 s postinjection, all parts of the hypercholesterolemic coronary vessel wall showed significantly higher transient opacification than the normal walls.



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  		Fig. 4. Mean CT values within three layers of the coronary vessel wall of normal (N) and hypercholesterolemic (HC) pigs (both at 35 s after complete contrast dye injection). Hypercholesterolemic pigs show significantly increased transient opacification in all three layers compared with normal arteries. *P < 0.001.

 
Cumulative Lumen Surface Area in RCAs of Analyzed Animals

With the use of the histological delineation of the coronary artery’s adventitia, transferred to the corresponding micro-CT image, there was no statistically significant difference in vasa vasorum density between hypercholesterolemic and normal pigs (Table 2). In addition, there was no statistically significant difference between the endothelial surface area of vasa vasorum trees [determined by analysis of the branching geometry of the vasa vasorum tree (8) in normal (n = 8) and high cholesterol arteries (n = 9, 13.81 ± 10.88 vs. 6.18 ± 5.84 mm2, respectively)].


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  		Table 2. Quantitative data from cross sections of normal and hypercholesterolemic RCAs

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The results of our first experiment imply that arterial and venous vasa vasorum play a role in the solute washin to (adventitial peak) and washout (from adventitial and subintimal regions) from the normal coronary vessel wall. Immediately after the end of injection of the contrast dye, the coronary vessel wall showed the highest opacification (Fig. 3A). As demonstrated in Fig. 3B, there are two maxima of this initial time point: one is in the inner media and the other one in the adventitia. The first maximum is likely due to the diffusion of contrast dye across the coronary artery’s endothelium. The second maximum (at the adventitia) is most readily explainable by the contribution of arterial vasa vasorum that supply the outer two-thirds of the vessel wall (10). At the next time point (15 s after the end of injection of the contrast dye), we observed a significant decrease in vessel wall opacification (Fig. 3A). Figure 3B shows that as the medial wave moved toward the outer vessel wall, the outer "maximum" resolved locally. These data suggest the effectiveness of the drainage function of the venous vasa vasorum. X-ray contrast medium does not accumulate in the adventitia, although there is continuing transport from the coronary’s subintimal region toward the outer vessel wall. Data from the next time point showed continuation of the described processes, i.e., the wave of opacification moved further toward the outer parts of the vessel wall, where drainage through venous vasa vasorum occurred and the opacification values progressively declined toward those of the normal, nonopacified vessel walls.

The arbitrary subdivision of the vessel wall in three and six concentric layers, respectively, as published elsewhere (10, 18), was chosen as an approximation, because the true anatomic borders cannot be identified directly in the cryostatic micro-CT image.

Our results derived from the porcine coronary artery wall are consistent with earlier findings derived from the canine aortic vessel wall showing that both luminal and abluminal sources are important for nutrition of the vessel wall. The inner third of the vessel wall is nourished mainly by diffusion of nutrients from the main lumen and both the middle and outer thirds receive additional supply by vasa vasorum (10, 28). In addition, we showed that besides the solute supply through arterial vasa vasorum, venous vasa vasorum play a significant role in the drainage of the arterial wall. It would appear from the progressive decrement of peak opacification from subintima to adventitia that drainage toward the coronary main lumen does not occur, and this directionality is likely due to primarily the transmural pressure gradient [Darcey’s law (2)]. In addition, the luminal third of the vessel wall is avascular (9). Hence, venous vasa vasorum in the outer two-thirds of the vessel wall have to drain material that accumulates there by extravascular diffusion from the main lumen and by delivery via the arterial vasa vasorum. With our present data, we cannot exclude the possibility that the contrast media’s concentration gradient between the vessel wall and the lumen contributes to a back transport from wall to lumen in the seconds after the injection. However, the transmural concentration wave’s transmural progression shows that this effect is likely to be insignificant.

The results of the high cholesterol pigs show that endothelial permeability is increased and that washout from the coronary’s adventitia is decreased. Figure 4 shows a significantly higher opacification in all parts of the vessel wall of hypercholesterolemic coronary arteries. This effect may be explained by the well-described loss of endothelial integrity in hypercholesterolemia (4, 15). The loss of endothelial integrity conceivably leads to an increased permeability of both arterial and venous vasa vasorum endothelium, which leads to increased leakage/diffusion in the former and a decreased drainage capacity in the latter. In addition, because there is also increased diffusion across the coronary artery’s main lumen endothelium, even more material, which diffuses toward the adventitia, has to be removed from the adventitia by venous vasa vasorum.

Although we cannot present direct evidence that the radiopaque indicator we used mimics the kinetics of other plasma solutes, it seems plausible that proinflammatory molecules would enter more easily and remain longer in all parts of the coronary vessel wall (Fig. 4). It has been reported that the accumulation of those substances promotes the atherosclerotic process (3, 20, 26) supported by the observation that NF-{kappa}B (as a key transcription factor in early inflammation and proliferation in the vessel wall) is more activated in hypercholesterolemic than normal porcine coronary artery walls (25, 29). Hence, our findings may further support the possible role of malfunctioning vasa vasorum in the initiation of coronary atherosclerosis.

Previous studies have found that adventitial and microcirculatory flow is attenuated in hypercholesterolemia (17, 24, 27). Hence, it seems unlikely that the increased vessel wall opacification in hypercholesterolemia in our experiments is simply due to increased vessel wall perfusion. Furthermore, we did not observe an increase in the number of adventitial vasa vasorum in our 6-mo-old hypercholesterolemic animals. We, therefore, can exclude the increased opacification in hypercholesterolemia being due to increased perfusion of the vessel wall through increased vascularity (i.e., surface area). Some published data show an increase in vasa vasorum density in hypercholesterolemia, but this is likely due to the fact that in our approach we strictly counted only those vessels that lie within the adventitia as determined by histology (8), whereas those other authors define the outer "adventitial" surface based on the lumen diameter rather than histology (6, 11, 14). Consequently, contiguous extracoronary microvessels could be counted as vasa vasorum (6, 11). Another possible contributor to the difference might be the older age of our pigs, suggesting a possible maturity phenomenon that deserves further investigation that is beyond the scope of this current study.

Similarly, the measured surface area of vasa vasorum in hypercholesterolemia did not increase. Using the Renkin-Crone equation [PS = –F x ln (1 – E), where PS is the permeability-surface area product, F is the plasma flow through the host coronary artery lumen, and E is the extraction of the indicator to the extravascular space (5, 21)], we can calculate the permeability ratio of high cholesterol and normal vasa vasorum. Assuming equal vasa vasorum flow, the ratio is 2.27 compared with normal vasa vasorum.

We did not find a significant difference in intima-to-media ratios between both groups, which excludes the chance that a simple thickening of the vessel wall influenced our data interpretation.

There was no significant difference in X-ray attenuation between noninjected hypercholesterolemic and noninjected normal coronary artery walls. However, if there was a difference in attenuation of the hypercholesterolemic arterial wall, it would anyway be expected to be less than normal due to the lower attenuation coefficient of the fatty infiltration.

In summary, we showed that the transendothelial transport within the coronary vessel wall is a dynamic process in which both arterial and venous vasa vasorum play a significant role. The increased permeability of vasa vasorum in hypercholesterolemia leads to an increased delivery to, and decreased drainage from, the coronary vessel wall. This may help to further elucidate the mechanisms by which increased endothelial permeability in hypercholesterolemia could contribute to atherogenesis and emphasizes the possible importance of arterial and venous vasa vasorum.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported in part by National Institutes of Health Grants HL-65342 and EB-000305.


   ACKNOWLEDGMENTS
 
We thank Jill L. Allen and Christine J. O’Brien for helping with the animal studies, Denise A. Reyes for the micro-CT image reconstruction, Steven M. Jorgensen and David F. Hansen for the cryostatic micro-CT-scans, and Michael S. Chmelik for programming. We also thank Julie M. Patterson for help with the figures and Delories C. Darling for editing and formatting the manuscript.


   FOOTNOTES
 

Address for reprint requests and other correspondence: E. L. Ritman, Physiological Imaging Research Laboratory, Dept. of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905 (E-mail: elran{at}mayo.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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Topological Determinants and Consequences of Adventitial Responses to Arterial Wall Injury
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Correlation of Vasa Vasorum Neovascularization and Plaque Progression in Aortas of Apolipoprotein E-/-/Low-Density Lipoprotein-/- Double Knockout Mice
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