© 1996 American Heart Association, Inc.
Articles |
Developmental Remodeling of the Internal Elastic Lamina of Rabbit Arteries
Effect of Blood Flow
From the Department of Pathology, University of Toronto (Canada) and The Toronto Hospital.
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Abstract |
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Abstract We examined remodeling of the internal elastic lamina (IEL) of rabbit arteries from 3 to 23 weeks of age. The IELs were fenestrated at all ages; however, the sizes of the fenestrae increased dramatically during postnatal development. Mean areas occupied by the individual fenestrae of the carotid artery IEL increased from 11.3±0.7 µm2 in 3-week-old rabbits to 61.2±5.5 µm2 in adult rabbits. The estimated number of fenestrae per vessel also increased greatly, from 2.68x105 to 9.27x105; however, the increased number of fenestrae did not keep pace with growth of the artery, since fenestrae per square millimeter decreased by 26%. Large increases in the size of fenestrae were also observed in the renal and iliac arteries, although greater decreases in fenestrae per square millimeter occurred with age (70% in iliac arteries). Morphological assessments suggested that enlarging fenestrae frequently fuse with neighbors. By contrast with other arteries, the IEL of the abdominal aorta was not a continuous fenestrated sheet in young animals, perhaps reflecting the extensive remodeling that this vessel undergoes in the postnatal period. We decreased common carotid blood flow by 70% in 5 rabbits at 10 weeks of age by ligating the ipsilateral external carotid artery, and we approximately doubled blood flow in 5 others at the same age, by contralateral common carotid ligation. At 15 weeks of age, fenestrae in the artery carrying increased flow were 39% larger than fenestrae in the control artery, whereas fenestrae were 53.5% smaller after 70% decreases in flow (P<.05). We conclude that flow-dependent enlargement of fenestrae contributes to developmental remodeling of the IEL. Remodeling of the IEL may also have important implications for transport of materials and cell-cell communication between the intima and media.
Key Words: arterial growth • elastin • shear stress • fenestrae • arterial remodeling
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Introduction |
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The arterial system is remodeled throughout development to accommodate the continuously changing demands for blood flow in the peripheral tissues and the changing blood pressures that are required to drive these flows.1 2 Coordination of arterial remodeling with physiological demands is achieved, at least in part, by a direct sensitivity of the arterial wall to hemodynamic stresses. Thus, experimental manipulations of blood pressure modulate the growth of thickness of the arterial media,3 whereas changes in blood flow rates modulate the growth of vessel diameters.1 It follows from these observations that the cells of the arterial wall can deliver newly synthesized arterial tissues, eg, elastin, connective tissues, and daughter cells after mitosis, preferentially in the radial or circumferential directions.1
Elastin is particularly important in the remodeling of large elastic arteries, because it bears much of the wall tension in these vessels4 and thus largely determines resting vessel dimensions. Elastin in large arteries is organized into fenestrated cylindrical lamellae that are separated from neighboring lamellae by single layers of smooth muscle cells.5 The number of these lamellar units is largely determined prenatally,6 7 and postnatal changes in thickness or circumference of the media are accompanied by parallel changes in thickness and circumference of the elastic lamellae, regardless of whether they are spontaneous8 or are induced by experimental changes in hemodynamics.9 10
The mechanisms by which the growth of thickness and diameter of elastic lamellae are coordinated with developmental changes in blood pressure and blood flow are not known. To gain insights into the remodeling of lamellae, we used laser scanning confocal microscopy to examine the internal elastic lamina (IEL) of rabbit arteries during postnatal development. This powerful tool permitted examination of the IEL in whole-mount preparations of arteries that had been fixed at physiological distension. In addition, we assessed how experimental changes in blood flow rates affected developmental remodeling of the IEL. We report that formation and enlargement of fenestrae contribute greatly to changes in IEL dimensions during development and that this process is sensitive to developmental changes in blood flow. We also suggest that tensile stress concentration near fenestrae greatly amplifies their growth.
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Materials and Methods |
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Tissue Preparation for Confocal Microscopy
Five rabbits each at 3, 6, 10, 15 , and 23 (adult) weeks of age were killed 1 minute after infusing 1000 U (1 mL) of heparin by intravenous injection of 1.0 mL of the euthanasia solution, T-61 (Hoechst Canada, Inc), containing 200 mg/mL N-[2-m-methoxyphenyl-2 ethylbutyl-(1)]-2 hydroxybutyramide, 50 mg/mL 4,4'-methylene-bis(cyclohexyltrimethylammonium iodide), and 5 mg/mL tetracaine HCl. A rapid bilateral thoracotomy was followed by retrograde cannulation of the descending thoracic aorta. After briefly flushing the blood from the aorta and carotid arteries with PBS, the left subclavian artery was cannulated, and the cannula was connected to a manometer. Both carotid arteries were fixed by perfusion with 3% paraformaldehyde in 0.1 mol/L phosphate buffer, 1 mmol/L MgCl2, and 0.1 mmol/L CaCl2 (pH 7.4) for 30 minutes at a pressure of 100 mm Hg, which approximates systolic pressure in these animals. The right common carotid artery was exposed along its length and excised from the origin of the right subclavian artery to the carotid bifurcation. The excised vessel was stripped of adventitia, opened longitudinally, and cut transversely into three pieces. Routinely, only the middle third was mounted, with the lumen side facing up, under coverslips with glycerol/PBS (1:9) for en face morphological examination by confocal microscopy (see below).
In additional rabbits, casts of the carotid arteries of 3-week-old (n=10), 6-week-old (n=7), 10-week-old (n=5), and 15-week-old (n=5) rabbits and 23-week-old adult rabbits (n=7) were prepared by infusing Batson's No. 17 anatomic corrosion compound (Polysciences) into the vessels at a pressure of 100 mm Hg and allowing the casting compound to set at this pressure.10 The casts were stripped of tissue, and luminal diameters were measured from the casts using a stereomicroscope with eyepiece graticule. Lengths of right carotid arteries, from the origin of the right subclavian artery to the bifurcation of the common carotid into the internal and external carotid arteries, were also measured from the casts. Vessel diameters were combined with vessel lengths to calculate the luminal surface area of the carotid arteries.
Additional animals at 3 weeks (n=6) and 23 weeks (n=5) of age were killed, and their arteries were fixed by perfusion as described above, except that the thoracic aorta was cannulated anterogradely to allow fixation of the descending aorta and its branches. Segments of renal and iliac arteries and of the abdominal aorta were prepared for examination by laser scanning confocal microscopy, as described above.
To assess the effects of collagen autofluorescence, some carotid arteries were treated for 15 minutes (five arteries), 1 hour (one artery), or 2 hours (one artery) with 640 U/mL of purified bacterial (Clostridium) collagenase before fixation and confocal microscopy. Other arteries were placed in 0.1N NaOH at 70°C for 1 hour, which degrades tissues other than elastin.
Confocal Microscopy and Morphometry
Tissue was examined using a Bio-Rad laser scanning confocal
microscope (model MRC-600) equipped with a krypton/argon laser.
Fluorescence was excited at 488 nm, and emission was detected
using the 522 DF 32 band-pass filter of the Bio-Rad K2 filter block
(transmitted wavelengths were 
500 to 560 nm). The optical sectioning
properties of the confocal microscope were used to examine the
structure of the IEL, which was visible without staining because of the
autofluorescent properties of elastin.11 12 In
each field, the complete thickness of the IEL was imaged by capturing a
series of images at different positions, separated by 1 µm, along the
optical axis of the microscope (z direction). A
projection of the complete IEL was prepared by superimposing these
images using software provided with the confocal microscope (COMOS,
version 6.01). Projections were composites of 4 to 15 images.
We determined experimentally the z-axis resolution of the
microscope using a procedure recommended by the manufacturer. Briefly,
a mirror was placed in the object plane at an angle to the z
axis (20°). Only a narrow portion of the mirror is within the
confocal depth of field of the microscope; therefore, the imaged
reflection of the illuminating beam forms a band on the screen. The
width of the band defines z resolution. Under conditions
used in the present study, z resolution was 0.4 to 1.4
µm, depending on detector apertures, which were adjusted to provide
the best compromise between signal detection and z
resolution. This level of resolution indicates that negligible
information was lost by capturing images separated by 1 µm in the
z direction.
Usually, five fields per sample were examined using a x60 oil immersion objective (Nikon PlanApo 60 with numerical aperture of 1.4). With this objective, fields were 0.024 mm2. The fields were equally spaced and distributed along the complete length of the tissue specimens; however, no fields were within 1 mm of the cut margins of the tissue. To avoid bias in selection of fields, their locations were defined before high-power examination of the tissue using the micrometer drives of the microscope stage. Typically, fields were in the centerline of the tissue samples and were separated by 2 mm.
An image analysis system (C · Imaging, model 640, Compix) was used for morphometry of the IEL. The software computed the area and the density of the fenestrae, ie, the number of fenestrae per square millimeter of luminal surface area. The mean density of fenestrae, calculated by averaging the fenestrae per square millimeter for each rabbit, was multiplied by the mean luminal surface area of the carotid arteries to estimate the total number of fenestrae of the carotid artery in each group.
As stated above, only the middle third of the artery was subjected to routine analysis. This segment contained no branches except the small thyroid artery, which was avoided since branch sites could be sources of variations in fenestral size.13 Preliminary analysis showed that there was no systematic variation in properties of fenestrae along the sample, nor were these properties different from those in immediately adjacent segments of the artery.
Experimental Alterations in Blood Flow
Full surgical anesthesia was induced in
10-week-old New Zealand White rabbits by an intramuscular injection
of 0.04 mL xylazine (20 mg/mL) and 0.18 mL ketamine
hydrochloride (100 mg/mL); anesthesia was then maintained
with a continuous intravenous infusion of the
xylazine/ketamine mixture (1:9, 0.015 mL/min). A midline
cervical incision was made caudal to the thyroid cartilage to expose
the left common carotid artery. In 5 rabbits, the left common carotid
artery was ligated proximal to the origin of the thyroid branch using
3.0 silk sutures (high-flow group). We have shown that this
procedure causes an approximate doubling of flow through the right
common carotid artery.14 In 5 other rabbits, the left
external carotid artery was ligated to reduce blood flow in the left
common carotid artery by 70% (low-flow group).10 15
The incisions were closed in layers with 3.0 Ethilon suture (nylon
monofilament), and the animals were allowed to recover. For sham
experiments, 3.0 silk was passed around the left common carotid artery
or the left external carotid and then removed before closing the
incision (n=5 rabbits per group).
The rabbits were killed at 15 weeks of age and prepared for examination of the IEL by confocal microscopy, as described above.
Statistical Analysis
The data concerning carotid arterial dimensions and
IEL remodeling during normal development were analyzed using a
one-way ANOVA followed by Fisher's least significant difference
test to establish the difference between the groups. The data
concerning experimental blood flow changes were compared using an
unpaired Student's t test. A value of P<.05 was
considered significant in all analyses (n=5 to 10 rabbits for
all groups). All data in the text and figures are presented as
mean±SEM.
All animals used in these experiments were cared for in accordance with the Guide to the Care and Use of Experimental Animals (Canadian Council on Animal Care) and were approved by the Animal Care Committee of The Toronto Hospital.
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Results |
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The body weights of rabbits increased eightfold between 3 and 23 weeks of age, from 0.48±0.12 to 3.90±0.39 kg. As expected, large changes in carotid arterial dimensions accompanied this growth (Table
). Thus, the vessel diameter increased
by 67% and length increased by 140% between these ages. Length
increased throughout the period of study, but significant changes in
diameter were not detected after 10 weeks of age. However, data scatter
for diameter was large at 10 and 15 weeks, so this latter observation
must be interpreted cautiously. As a result of growth in both diameter
and length, total luminal surface area (
xdiameterxlength)
increased fourfold over the ages studied (see Fig 3).
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Changes in the Carotid IEL With Development
The IEL formed a continuous fenestrated layer in carotid arteries
from rabbits at all the ages studied (Fig 1).
Circumferentially oriented arrays of brightly fluorescent
tissue were superimposed on relatively uniform lamellar
fluorescence that was broken only by the fenestrae. Optical
sectioning indicated that these brighter tracks were located at the
abluminal limit of the IEL. These features of fluorescence from
the IEL survived digestion with hot NaOH and collagenase
treatment (not shown). NaOH treatment degrades all other
arterial constituents; therefore, we inferred that the
fluorescent structures we detected were elastin.
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The fenestrae in the IEL were ellipsoidal and generally were oriented
with the long axis of the artery (Fig 1
). The size of the fenestrae in
carotid arteries increased from 3 weeks of age (Fig 1, top) to adult
(Fig 1, bottom), with the cross-sectional areas of the fenestrae
increasing about sixfold over the period of study (from 11.3±0.7
mm2 in 3-week-old rabbits to 61.2±5.5 mm2
in adult rabbits; Fig 2, top). Increases in size of the
fenestrae were greatest up to 10 weeks of age; after which, they
enlarged more slowly. However, growth of the artery showed a strong
correlation with enlargement of the fenestrae (Fig 3).
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The density of the fenestrae in the IEL (fenestrae per square
millimeter of surface area) did not change significantly between 3
weeks and 6 weeks of age (3020±240 fenestrae per square millimeter at
6 weeks), but it decreased significantly (P<.001) by 10
weeks of age (1740±180 fenestrae per square millimeter) before rising
again between 15 and 23 weeks to 2240±170 fenestrae per square
millimeter. The transient decrease in density did not represent
loss of fenestrae; instead, it was due to increased separation of
fenestrae as the vessel grew. Thus, the estimated total number of
fenestrae in the IEL (densityxtotal vessel surface area) increased
rapidly between 3 and 10 weeks of age and then plateaued between 10 and
15 weeks of age (Fig 2, bottom). Surprisingly, there was a sharp
increase in the number of fenestrae in late development, with the total
number of fenestrae increasing by almost 50%.
IEL of Other Developing Arteries
Fenestrae in the IEL of the renal artery of young rabbits were
small and widely separated (Fig 4, top), but the
enlarged fenestrae of mature renal arteries often were in clusters and
appeared to be fusing with neighboring fenestrae (Fig 4, middle). This
inference cannot be tested with methods used in the present study,
but it received some support from morphometry; ie, fenestrae enlarged
more during development in the renal artery than in the carotid artery,
whereas the number of fenestrae per square millimeter decreased to a
greater extent. Thus, the area of fenestrae increased ninefold during
renal artery development (Fig 5, top) versus sixfold
during carotid artery development, whereas the fenestrae per square
millimeter decreased by 70% in the renal artery compared with 26% in
the carotid artery (Fig 5, bottom).
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We also examined the IEL of iliac arteries of 3-week-old and adult rabbits, which resembled the IEL of renal arteries at both ages. Although measurements were not made, it was evident that fenestral size increased dramatically during development and that the fenestrae per square millimeter decreased dramatically, as in the renal artery.
The IEL of the abdominal aorta of three-week-old animals was
different from that of other arteries. At many sites, it did not form a
continuous fenestrated sheet; instead, it appeared to be fibrous,
frayed, or disrupted and sometimes multilayered (Fig 4, bottom). These
special features largely resolved by maturity when the IEL more closely
resembled those of other arteries.
Effects of Changes in Blood Flow
Ligation of the left carotid artery in animals from 10 to 15 weeks
of age, which approximately doubles flow rate through the right
carotid, resulted in obvious enlargement of fenestrae of the IEL of the
right carotid artery when compared with fenestrae of 15-week-old
sham-operated control animals. A 70% reduction in blood flow in
arteries over the same period produced much smaller fenestrae compared
with the 15-week-old sham-operated control arteries. Neither
sham procedure significantly affected the fenestrae.
These qualitative findings were confirmed by morphometry. The
areas of fenestrae in experimental arteries under high-flow
conditions were 39.0% larger (P<.05) than the areas of
fenestrae in sham-operated control arteries (Fig 6),
whereas fenestrae of arteries subjected to low flow were 53.5% smaller
than those of sham-operated arteries. Neither sham procedure
significantly affected the fenestrae.
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The density of the fenestrae (fenestrae per square millimeter) was unaffected by either flow manipulation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present study provides the first in situ visualization of fenestrae in elastic lamellae of arteries that were fixed at physiological distension. Such visualization was possible using laser scanning confocal microscopy, which, when operated in the fluorescence mode, yielded excellent images of the IEL in whole-mount preparations. Staining of elastin was unnecessary, since this protein autofluoresces.11 Collagen also autofluoresces,16 but much more weakly than does elastin, and it did not present detectable background in our investigations of elastin. Thus, fluorescent structures within the IEL conformed with descriptions of arterial elastin morphology.13 17 Furthermore, all structures seen in intact arteries were observed after treatments with collagenase or hot NaOH (see below), although deformation of structure was observed after NaOH. We inferred from these observations that collagen autofluorescence was below detection levels at the neutral density filter settings used to visualize elastin in the present study.
Previous methods for examining elastin morphology have used vigorous elastin purification treatments, including digestion with hot concentrated NaOH. This method has been used, with slight modifications, by many investigators.13 18 19 Other purification methods include repeated autoclaving,20 formic acid digestion,21 22 and enzyme treatments.23 24 All of these methods are based on the resistance of elastin to digestion. Although they risk damage to elastin, some very good preservation of elastic structures has been achieved. For arterial studies, their primary drawbacks are that the elastic lamellae are not fixed at physiological dimensions and the relationships and interactions with other wall constituents are lost, whereas laser scanning confocal microscopy preserves the three-dimensional architecture of pressure-fixed arteries at physiological dimensions.
Our experiments showed that formation and enlargement of
fenestrae contribute substantially to remodeling of elastic lamellae
during postnatal growth. If the total area within the carotid IEL
occupied by fenestrae is estimated by multiplying the mean area of
individual fenestrae (Fig 2, top) by the number of fenestrae per vessel
(Fig 2, bottom), then an increase of 20-fold is observed between 3
weeks of age and maturity. Over this time, total luminal surface area
of the vessel increased fourfold (see Fig 3). Dramatic growth of
fenestrae occurred despite very large net accumulations of elastin
during postnatal development25 26 and despite recent
evidence that newly synthesized elastin accumulates preferentially at
fenestrae.27
The growth of fenestrae appeared to be a general feature of maturation of large arteries, since fenestrae became much larger in the IEL of carotid, renal, and iliac arteries. Morphological and morphometric assessments suggested that some fenestrae fuse with neighbors as they enlarge and that this process is more significant in renal and iliac arteries.
The abdominal aorta was exceptional in that its IEL did not form a consistent well-defined structure in young animals. A frayed, multilayered, and incomplete IEL may be a feature of the massive remodeling that this vessel undergoes postpartum, as it accommodates very dramatic decreases in blood flow (95% in sheep28 ) associated with loss of the placental circulation.29 30
In contrast to our findings in rabbit arteries, Dunmore et al31 observed no difference in the size of fenestrae of IEL of thoracic aortas in 6- to 8-week-old and 6- to 9-month-old pigs. Inconsistency between the two studies may be attributable to species differences, vessel differences, or differing techniques for preparing tissues.
We infer from our observations that at least two processes remodel elastic lamellae during development: synthesis and deposition of new elastin, and formation and enlargement of fenestrae. The growth of fenestrae contributes to increases in lamellar circumference and length, whereas the deposition of new elastin probably produces growth in all directions. The latter inference is based on the observation, by transmission electron microscopy and autoradiography, that incorporation of tritiated valine into mouse elastic lamellae in vivo is generally random,32 except for increased accumulation near fenestrae.27
Experimental changes in blood flow rates during development cause
corresponding modulation of circumferential growth,10 33
and the present data indicate that effects of blood flow on
fenestrae in elastic lamellae contribute to this growth modulation (see
Fig 3). We believe that this is an important mechanism for controlling
growth of vessel diameter, given the importance of elastin in
determining resting arterial dimensions. The very strong
correlation between the mean area of fenestrae and total luminal
surface area during normal development of the vessel supports this
inference.
The mechanism underlying the growth of fenestrae is not known. Their enlargement is not due to passive stretch, because mature arteries usually are under less longitudinal and circumferential stretch than are young arteries.9 34 Formation of discrete fenestrae could result from localized production of an elastase by a subpopulation of vascular cells; alternatively, ubiquitous production of enzyme might induce their formation at random sites of weakness or defects in the lamellae.
If formation and growth of fenestrae are caused by elastolysis, then not all elastin at the sites of fenestrae need be degraded. This is because holes in structures under tension concentrate stresses in the immediately adjacent tissue and cause it to stretch much more than tissue far from the defect.35 Thus, once fenestrae are formed, they are predisposed to immediately enlarge under wall tension. Stress concentration has the potential to minimize the net turnover of elastin that is required to remodel lamellae at a time when elastin secretion and accumulation are maximal.25 26 The potential importance of stress concentration in arterial remodeling was made forcefully by Campbell and Roach13 in their considerations of the implications of lamellar fenestrae in the pathogenesis of berry aneurysms in cerebral arteries.
The present study focused on the importance of lamellar fenestrae in developmental remodeling of the arterial wall; however, our findings have implications for other aspects of vessel wall function. First, the IEL presents a barrier to transport from the blood and intima to the arterial media, and fenestrae very likely reduce this barrier. Penn et al36 measured flux of horseradish peroxidase from circulating blood to the intima and media of the mature rat thoracic aorta and found that the barrier presented by the IEL was one third as large as that of the endothelium. The IEL barrier is sufficient, for example, to exclude from the media luminally administered antibodies37 and oligonucleotides38 that have ready access to neointimal cells after arterial injury. Endothelial permeability is elevated at sites of endothelial cell replication39 ; thus, endothelial permeability is expected to be high during development, when the cells are replicating very rapidly.40 The very small fenestrae in the immature IEL probably offset, to some extent, high endothelial permeability and reduce developmental changes in the transport of materials from the plasma to the vessel media, although their accumulation in the intima may result.
In addition, endothelial cells communicate with smooth muscle cells across the IEL, and communication via soluble mediators may pass preferentially through the fenestrae. These mediators include vasoactive agents that regulate acute physiological responses of the vessel wall41 and possibly mitogens that regulate arterial growth.42 Endothelial and smooth muscle cells also communicate via direct cell-cell contacts. For example, endothelial cells are growth-arrested, at least in vitro, by contact with smooth muscle cells (or pericytes),43 which leads to activation of transforming growth factor-ß, an endothelial growth inhibitor that is constitutively released in a latent form.44 Increased opportunities for such direct contact, as fenestrae enlarge during development, may contribute to growth arrest and stabilization of the mature circulation.
Dye-coupling studies45 provide evidence that endothelial and smooth muscle cells can communicate at sites of contact via gap junctions. Further evidence indicates that gap junctions are important mediators of propagated vasomotion in the microcirculation.46 47 Gap junctions also occur across fenestrae in the IEL of large arteries,48 and although their function in these vessels is not known, direct electrical coupling between endothelium and smooth muscle has been demonstrated.49 If the growth of fenestrae results in the formation of more gap junctions, then endothelium–smooth muscle cell communication via this pathway may increase with age.
In summary, we have shown that formation and growth of fenestrae contribute to growth of the IEL and presumably of other elastic lamellae. We also provide evidence that these processes contribute to the effects of developmental blood flow changes on the growth of arterial diameter. We hypothesize that the growth of fenestrae and deposition of new elastin are coordinately regulated to independently adjust lamellar thickness and circumference, thus allowing the lamellae to remodel appropriately in response to developmental changes in hemodynamics.
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Acknowledgments |
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This study was supported by the Medical Research Council of Canada and the Heart and Stroke Foundation of Ontario. Dr Langille is a Career Investigator of the Heart and Stroke Foundation of Ontario. We are grateful to Donna Koopmans and Doreen LeBlanc for technical assistance.
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Footnotes |
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Reprint requests to Dr B.L. Langille, The Toronto Hospital Research Institute, CCRW 1-836, The Toronto Hospital, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4.
Received September 20, 1995; accepted January 16, 1996.
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