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Departments of Veterinary Biomedical Sciences and Medical Physiology, and Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri 65211
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The purpose of this study was to test the hypothesis that the content of endothelial nitric oxide synthase (eNOS) protein (eNOS protein/g total artery protein) increases with decreasing artery diameter in the coronary arterial tree. Content of eNOS protein was determined in porcine coronary arteries with immunoblot analysis. Arteries were isolated in six size categories from each heart: large arteries [301- to 2,500-µm internal diameter (ID)], small arteries (201- to 300-µm ID), resistance arteries (151- to 200-µm ID), large arterioles (101- to 150-µm ID), intermediate arterioles (51- to 100-µm ID), and small arterioles(<50-µm ID). To obtain sufficient protein for analysis from small- and intermediate-sized arterioles, five to seven arterioles 1-2 mm in length were pooled into one sample for each animal. Results establish that the number of smooth muscle cells per endothelial cell decreases from a number of 10 to 15 in large coronary arteries to 1 in the smallest arterioles. Immunohistochemistry revealed that eNOS is located only in endothelial cells in all sizes of coronary artery and in coronary capillaries. Contrary to our hypothesis, eNOS protein content did not increase with decreasing size of coronary artery. Indeed, the smallest coronary arterioles had less eNOS protein per gram of total protein than the large coronary arteries. These results indicate that eNOS protein content is greater in the endothelial cells of conduit arteries, resistance arteries, and large arterioles than in small coronary arterioles.
arteries; blood flow; coronary disease; endothelium; endothelial-derived factors; capillary endothelium
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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IT IS GENERALLY WELL ACCEPTED that fundamental differences exist among arteries of different tissues. (13). Indeed, there is evidence for inherent diversity of phenotype of vascular smooth muscle (12) and endothelium (1) within and among arteries in the same tissue. Consistent with the notion of variable expression of endothelial nitric oxide synthase (eNOS) in endothelium of different sized arteries, Ando et al. (1) report that eNOS expression and eNOS enzyme activity are greater in cultured aortic endothelial cells than in cultured microvascular endothelial cells. Furthermore, a recent study of the effects of exercise training on eNOS content throughout the coronary arterial tree of pigs revealed that exercise training induced nonuniform increases in eNOS protein content along the coronary tree (10). Therefore, available evidence suggests that eNOS protein content differs among coronary arteries of differing size. The endothelium is a single cell layer throughout the coronary arterial tree (9). If all coronary endothelial cells contain a similar amount of eNOS protein, one would expect the amount of eNOS per gram of artery to decrease as artery size increases because the relative amounts of vascular smooth muscle protein and connective tissue protein increase with increasing diameter of arteries. Therefore, on the basis of the assumptions that the relative amount of total endothelial cell protein decreases with increasing artery diameter and that endothelial cells contain similar amounts of eNOS protein, we formulated the hypothesis that eNOS protein content increases with decreasing artery diameter in the coronary arterial tree. The following study was designed to test this hypothesis.
We examined eNOS expression in six specific sizes of coronary arteries: large coronary arteries [internal diameter (ID) = 301-2,500 µm], small coronary arteries (ID = 201-300 µm), resistance arteries (ID = 151-200 µm), large arterioles (ID = 101-150 µm), intermediate arterioles (ID = 51-100 µm), and small arterioles (ID < 50 µm). We selected these specific sizes of arteries because these size categories encompass the size range of arteries used in previous work showing increased endothelium-mediated dilation (14) and increased eNOS expression in some coronary arteries after exercise training (10). Also, these size categories encompass the size range of coronary arterioles in which differential sensitivity to shear stress was observed in arteries of different size (7). Content of eNOS protein (amount of eNOS protein/g total protein) was measured with standard immunoblot techniques, and the distribution of eNOS in the different cell types of the arteries was assessed with immunohistochemistry.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Experimental animals. Fourteen female Yucatan miniature swine (25-40 kg) were used for these experiments. Animal care and use procedures were approved by the University of Missouri, Animal Care and Use Committee and complied with the Guide for the Care and Use of Laboratory Animals (NIH Publication no. 80-23, Revised 1996).
Isolation of coronary arteries.
Pigs were anesthetized and hearts were removed and maintained at
0-4°C during vessel isolation as described previously
(10). Segments of large coronary artery (ID > 300 µm), small coronary artery (ID = 201-300 µm), and
resistance arteries (ID = 151-200 µm) were carefully
dissected from left ventricular myocardium, fat, and connective tissue.
Arterioles were isolated from myocardium (left ventricular free wall)
by dissecting along the length of 300-µm-ID arteries to the smallest
branches. Single arterioles 1-2 mm in length (or 2-5
arterioles with equal diameters, sufficient to have a total length of
1-2 mm) were isolated, diameters and lengths were recorded, and
anterioles were placed in a microcentrifuge tube (
70°C). This
approach to isolation of arteries resulted in most samples coming from
the epicardium except for the resistance arteries and arterioles, which
were collected from the epicardium and midmyocardium of the left ventricle.
Amount of eNOS protein in arterioles of similar size. To determine whether there is significant variation of eNOS content among arterioles of similar size, we compared eNOS content among arterioles of the same diameter. We completed three experiments in which we compared eNOS content of arterioles of equal size that were isolated from different locations in the left ventricle: at the base of the heart, near the circumflex coronary artery, at the apex of the heart near the terminal branch of the left anterior descending coronary artery, and two or three arterioles from different locations in the left ventricular free wall. Thus we made the following comparisons of eNOS content in 1) five arterioles that had an ID of 85 µm and a length of 1,530 µm, 2) four arterioles that had an ID of 119 µm and a length of 1,700 µm, and 3) four arterioles that had an ID of 170 µm and a length of 1,700 µm. Arterioles with similar lengths and diameters were selected so that samples would contain similar amounts of total arteriolar protein, and eNOS was measured in single arterioles as described (4). Data from the single arteriole experiments are presented as eNOS protein per arteriole in relative densitometric units (Fig. 4).
eNOS protein content. eNOS protein content of arteries was determined from immunoblots by using standard procedures of loading equal amounts of total artery or arteriole protein on different lanes of the same gel allowing comparisons among arteries and arterioles of different sizes on the same gel (10). Total protein was measured with NanoOrange Protein Quantitation kits (Molecular Probes), which allow measurement of total protein in small samples. Because there is not sufficient protein in a single arteriole to allow measurement of protein content and have a sufficient sample to run on an SDS gel, it was necessary to pool samples of five arterioles. In preliminary experiments, we determined that five arterioles of a length of 1-2 mm provided enough protein to measure total protein content and to have a sufficient amount of sample remaining for immunoblot analysis. All samples of arteries and arterioles were solubilized in 20 µl of Laemmli buffer (8), boiled, and sonicated for 2 min and subjected to SDS-PAGE under reducing conditions. Proteins were transferred to polyvinylidene difluoride membranes (Hybond-ECL, Amersham) and blocked (1 h at 25°C) with 5% nonfat milk in Tris-buffered saline-Tween (20 mM Tris · HCl, 137 mM NaCl, and 0.1% Tween 20). Blots were incubated overnight (25°C) with primary antibody against eNOS (1:1,600; Transduction Laboratories) and, in some cases, GAPDH (1:10,000; Chemicon), followed by incubation for 1 h with secondary antibody (1:2,500; horseradish peroxidase-conjugated anti-mouse). Protein content was determined with chemiluminescence (enhanced chemiluminescence, Amersham) and quantified with densitometry by using NIH Image software (National Institutes of Health, Bethesda, MD). To verify that cellular-derived proteins were not underrepresented in some sizes of artery due to contamination with connective tissue, we did immunoblot analysis by using anti-collagen antibodies. This experiment demonstrated that our solubilized samples do not contain measurable amounts of collagen (data not shown), i.e., the solubilization conditions used do not extract extracellular connective tissue. Therefore, the material loaded onto each lane in our gels is representative of cellular-derived proteins.
Vascular histology. In eight hearts, the distal portion of the anterior descending branch of the left coronary artery was cannulated and perfusion fixed as described previously (11). Cardiac and smooth muscle were relaxed with infusion of 10-20 ml of Lock's solution containing 10 ml/100 ml procaine. Without interruption of perfusion, the perfusion solution was switched to neutral buffered formalin fixative. Perfusion pressure was held at 120 mmHg. The myocardium was then stored in fixative until time for processing. The heart was sliced serially at 5-mm intervals from apex toward the base orthogonal to the anterior descending branch of the left coronary artery. Samples of the artery and ~2 cm of the adjacent myocardium were processed routinely to paraffin, sectioned at a thickness of 5 µm, and stained with hematoxylin and eosin. Images of coronary arteries and arterioles in cross section were captured with a Spot Insight digital camera (Diagnostic Instruments, Sterling Heights, MI). Digital images were analyzed with Image Pro Plus (Version 4.1, Media Cybernetics, Silver Spring, MD) to determine external diameter and counts of nuclei within the intima (endothelium) and media (vascular smooth muscle).
To confirm the localization of eNOS to the endothelium, sections from four hearts were floated onto positively charged slides (Fisher, St. Louis, MO). Sections were deparaffinized and steamed in citrate buffer at pH 6.0 (Dako target retrieval solution S1699, Carpintera, CA) for 20 min to achieve antigen retrieval and then cooled for 20 min. The Dako autostainer (Dako DC34000) was used for immunohistochemical staining. Sequential Tris buffer and water wash steps were performed after each step in the automated staining protocol. Sections were incubated with avidin biotin two-step blocking solution (Dako X590) to inhibit background staining and in 3% hydrogen peroxide to inhibit endogenous peroxidase. Nonserum protein block (Dako X909) was applied to inhibit nonspecific protein binding, and slides were incubated in primary mouse monoclonal IgG1 anti-eNOS antibody (Transduction Laboratories N30020) at 1:800 dilution for 60 min. After the appropriate washing steps were completed, slides were incubated with biotinylated anti-mouse link secondary antibody in PBS containing 15 mM sodium azide and peroxidase-labeled streptavidin (Dako LSAB+ kit, peroxidase, K0690). Diaminobenzidine (Dako) applied for 5 min allowed visualization of eNOS antibody staining. Slides were counterstained with Mayer's Hematoxylin stain for 1 min, dehydrated, and coverslipped as described previously (5).Data analysis. All values are means ± SE. Between-group differences were assessed by using repeated-measures ANOVA or Student's t-tests where appropriate. Differences of P < 0.05 were considered significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Smooth muscle content and artery size.
A set of representive photomicrographs used in our examination of the
relationship between coronary artery diameter and number of smooth
muscle cells/endothelial cells in the arterial wall are presented in
Fig. 1 for a large artery (670-µm outer
diameter), a resistance artery (180-µm outer diameter), and two small
arterioles (32- and 42-µm outer diameter). As shown in Fig.
2, our results indicate that the smallest
coronary arterioles consist of one layer of endothelial cells and one
layer of smooth muscle cells, whereas the large coronary arteries have
10-15 smooth muscle cells per endothelial cell (Figs. 1 and 2).
Because our eNOS protein content is examined in coronary artery size
categories, we have also averaged the data presented in Fig. 2 to
reflect the number of smooth muscle cells per endothelial cell in these
size categories (coronary arteries > 301 µm: 5.42 ± 0.68;
201-300 µm: 2.71 ± 0.43; 151-200 µm: 2.5 ± 0.32; 101-150 µm: 2.06 ± 1.58; 51-100 µm: 1.58 ± 0.07; and 50 µm: 0.85 ± 0.04).
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Similar amount of eNOS protein in arterioles of similar size.
Figure 4A presents a sample
immunoblot that compares eNOS protein in arterioles isolated from
different locations in the left ventricle. As can be seen from these
data, arterioles of similar diameter have similar amounts of eNOS
protein. Average results for two different sizes of arteriole are
presented in Fig. 4B. These results indicate that it is
acceptable to pool arterioles of similar size as is done in the next
sets of data on eNOS protein content of small- and intermediate-sized
arterioles.
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Amount of eNOS protein in coronary arteries.
Figure 5 presents two sample immunoblots
for eNOS protein. Note that each gel was loaded with equal amounts of
total protein for arteries of all six sizes. When equal amounts of
total protein for all sizes of interest from one heart are loaded, it
serves to control for variations in background, primary and secondary antibody reactivity, and film processing in the data. This strategy allows comparison of the relative eNOS immunoreactivity (optical density) in arteries of different sizes from the heart of each pig.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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This study was designed to test the hypothesis that eNOS protein content of coronary arteries increases with decreasing artery diameter. The major findings of this study are that 1) the relative amount of vascular smooth muscle decreases with decreasing diameter in the coronary arterial tree from 10 to 15 smooth muscle cells per endothelial cell in large arteries to 1 smooth muscle cell per endothelial cell in small arterioles; 2) coronary arterioles of the same diameter isolated from different regions of the left ventricular free wall have similar eNOS content; 3) the amount of eNOS protein, relative to total arterial protein, is similar across different sized coronary arteries (ID of 1,000 through 51 µm) and arterioles of <50-µm ID have significantly less eNOS protein per gram protein than large coronary arteries; 4) these results indicate that the amount of eNOS in endothelial cells of porcine coronary arteries is not the same throughout the coronary arterial tree. Indeed, endothelial cells of larger coronary arteries appear to contain substantially greater amounts of eNOS than do endothelial cells of coronary arterioles. Differences in eNOS protein content of arteries throughout the coronary arteriolar tree may reflect the prevailing hemodynamic conditions in these arteries (i.e., shear stress, pressure, etc.). On the other hand, the eNOS content of endothelial cells in conduit arteries may be greater than in coronary arterioles to compensate for the extra NO needed to relax the smooth muscle cells in the outer ring of these larger arteries. Additionally, it is possible that the extra NO released into the bloodstream by larger coronary arteries participates in control of structure and/or function of downstream arteries and arterioles so that eNOS protein content is not required to be as great in small coronary arterioles (3, 19).
Ando et al. (1) reported that eNOS expression and eNOS enzyme activity are greater in cultured aortic endothelial cells than in cultured microvascular endothelial cells. It would be reasonable to expect that our conduit coronary artery endothelial cells would be similar to aortic endothelial cells and that our arteriolar endothelial cells would be similar to the "microvascular" endothelial cells studied by Ando et al. (1). If endothelial cells in the smallest coronary arterioles reflect the microvascular endothelial cells of Ando et al., then our results confirm those of Ando et al., indicating that endothelial cells of large conduit arteries have greater eNOS protein content than endothelial cells of microvessels. However, because the microvascular endothelial cells of Ando et al. were likely from various sized coronary arteries, veins, and perhaps capillaries, it is difficult to know whether these cultured cells reflect properties of small coronary arteries, or large or small coronary arterioles. Joyce et al. (6) reported that endothelial cells of the first three branch orders of sheep uterine artery exhibit a decreasing gradient of eNOS protein content during the luteal phase of the ovarian cycle. Our porcine coronary artery tree did not exhibit such a pattern. Although the conduit coronary arteries have greater eNOS content than the smallest diameter arterioles, the eNOS content of the other four sizes of coronary arteries were similar to those of the large coronary arteries (Fig. 7). These results do not support the hypothesis that eNOS protein content of coronary arteries increases with decreasing artery diameter in the coronary tree.
Positive eNOS staining was observed in the endothelium of capillaries (Figs. 1 and 3) of every heart examined. Similarly, Segal et al. (18) observed eNOS immunoreactivity in the capillaries as well as throughout the skeletal muscle vascular beds in hamster retractor and cremaster muscles. Although our study was not designed to examine eNOS expression in coronary veins, we observed positive eNOS staining in the veins contained in our specimens. Thus our results indicate that eNOS protein is present in the endothelial cells throughout the porcine coronary vascular tree. These results are consistent with the report of Andries et al. (2), showing that eNOS staining is present in all coronary endothelial cells of rat heart. Andries et al. (2) also reported that eNOS staining was more intense in coronary arterial endothelium than in venous or capillary endothelial cells. We did not measure eNOS staining intensity in our study, but our results are consistent with the observations of Andries et al., as it can be seen in Fig. 1, B and C, that arterial endothelial cell staining appears darker than in capillaries or veins.
Our hypothesis that eNOS protein content would increase with decreasing coronary artery diameter was based on two assumptions: 1) that endothelial cells lining all coronary arteries contain a similar amount (concentration) of eNOS protein; and 2) that as coronary artery diameter increases, the amount of vascular smooth muscle relative to the amount of endothelium increases because the endothelium is a single cell layer throughout the coronary arterial tree. If the amount of connective tissue and smooth muscle proteins relative to total arterial protein do increase with increasing coronary artery diameter as proposed, then the relative eNOS protein content of coronary arteries would decrease with increasing artery diameter. Present results confirm that the number of smooth muscle cells per the number of endothelial cells across the arterial wall decreases with diameter (Fig. 1). However, our results also indicate that eNOS protein content/total protein content is similar across coronary arteries of differing diameters (Fig. 7). These results do not support our hypothesis. Furthermore, these results indicate that endothelial cells lining coronary arteries do not contain similar amounts of eNOS protein. Indeed, these data suggest that eNOS protein content is greater in endothelial cells of large arteries than in endothelial cells of small coronary arterioles.
In conclusion, the results of this study indicate that eNOS protein content does not increase with decreasing artery diameter in the coronary arterial tree. We conclude from these results that eNOS protein content is not equal among endothelial cells throughout the coronary arterial tree. Indeed, similar eNOS protein content in arteries with increasing smooth muscle cell-to-endothelial cell ratios suggests that eNOS expression per endothelial cell increases with increasing diameter of the artery in the coronary tree.
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ACKNOWLEDGEMENTS |
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The authors thank Pam Thorne, Tammy Strawn, and Denise Holiman for excellent technical contributions to this work.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-52490 (to M. H. Laughlin) and HL-09739 (to C. R. Woodman) and National Aeronautics and Space Association Grant 00-GSRP 045 (to W. G. Schrage).
Address for reprint requests and other correspondence: M. H. Laughlin, E102, Vet. Med. Bldg., Univ. of Missouri, Columbia, MO 65211.
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.
First published December 19, 2002;10.1152/ajpheart.00792.2002
Received 13 September 2002; accepted in final form 10 December 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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