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From the Department of Medicine, Division of Rheumatology, Mayo Clinic and Foundation, Rochester, Minnesota
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and vascular endothelial growth factor but not fibroblast growth
factor-2 as mediators associated with vasa vasorum proliferation. Giant
cells and CD68-positive macrophages at the media-intima junction were
found to be the major cellular sources of vascular endothelial growth
factor. These data demonstrate that formation of new vasa vasorum in
vasculitis is regulated by inflammatory cells and not by arterial wall
cells, raising the possibility that it represents a primary
disease mechanism and not a secondary hypoxia-induced event. Increased
neovascularization in interferon--rich arteries suggests that the
formation of new vasa vasorum is determined by the nature of the immune
response in the arterial wall, possibly resulting from the
generation and functional activity of multinucleated giant
cells.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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.7
IFN--releasing CD4 T
cells have been mapped to the adventitial layer of inflamed arteries,
giving rise to the hypothesis that the site of the immunological injury
in this vasculopathy is the adventitia.8 Inflammation of the arterial wall in GCA is followed by a series of structural changes that are partially the result of tissue-destroying mechanisms. A typical finding in GCA is the degradation of the internal elastic laminae (IEL). Giant cells, which have a tendency to accumulate along the IEL, have been implicated in removing fragments of digested elastic tissue. However, arterial wall destruction with hemorrhage is not a typical manifestation of GCA. Rather, patients are threatened by ischemia resulting from arterial stenosis. Stenotic lesions are due to the concentric growth of the intima with little evidence of thrombosis. The degree of luminal stenosis has been closely correlated with the production of platelet-derived growth factors (PDGF)-AA and -BB.3 Macrophages and giant cells in the media and along the media-intima junction have been identified as the major cellular sources of PDGF. These findings suggest that the growth of the intima, not the destruction of arterial wall layers, is the major factor determining the pathological consequences of GCA.
In addition to the fragmented elastic lamina and the hyperplastic
intima, inflamed arteries are characterized by the emergence of new
intramural capillaries. The normal arterial wall is a relatively
avascular tissue, comparable only to cartilage. Vasa vasorum are
restricted to the adventitial layer, and the media and intima are
supplied via diffusion from either the lumen or the
adventitia.9
Angiogenesis is a physiological process in
embryonic development and wound repair, but it can also contribute to
pathological events.10,11
It can be a primary disease
mechanism, such as in diabetic retinopathy,12
or can play
an indirect role by supporting the growth of pathological tissue, such
as in tumors and in rheumatoid arthritis.13
Growth factors
previously reported as driving microvessel formation include vascular
endothelial growth factor (VEGF) and fibroblast growth factor (FGF),
whereas inflammatory cytokines locally produced in GCA arteries, such
as IFN-, interleukin (IL)-1, and IL-6, do not appear to play a
direct role.12,14-17
The current study was designed to explore whether neoangiogenesis is
regulated by infiltrating inflammatory cells or by arterial wall
stromal cells. In temporal arteries of patients with GCA, new vasa
vasorum appeared primarily in the media and the intima, thereby
supplying blood to formerly avascular areas of the arterial wall. The
degree of neoangiogenesis in the inflamed arteries was closely
correlated with the hyperplastic reaction of the intima and the
fragmentation of the elastic membranes. Tissue transcription of VEGF
and of the T cell product IFN- but not of FGF-2 correlated with the
extent of neovascularization. The major source of VEGF was
multinucleated giant cells and macrophages accumulating at the media
intima junction, suggesting that inflammatory cells and not stromal
cells or endothelial cells regulate vasa vasorum formation in GCA.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Temporal artery specimens were obtained from 40 patients undergoing biopsy for diagnostic purposes. The diagnosis of GCA was confirmed by histopathology. All patients fulfilled the American College of Rheumatology criteria for the diagnosis of GCA.18 None of the patients was on glucocorticoids or other anti-inflammatory medication.
Antibodies
Endothelial cells were identified with a polyclonal rabbit Ab against von Willebrand's factor (vWF), 1:750 (Dako, Carpinteria, CA). The expression of VEGF was visualized with a polyclonal rabbit Ab, 1:100 (Calbiochem, La Jolla, CA). FGF-2 was detected with a polyclonal rabbit Ab, 1:100 (Collaborative Biomedical Products, Bedford, MA). Mouse mAb against CD68 (PG-M1), 1:150, as well as all biotinylated secondary antibodies were obtained from Dako. Streptavidin-conjugated alkaline phosphatase and Vector Red substrate kits were purchased from Vector Laboratories (Burlingame, CA).
Immunohistochemistry
Four-micron sections of paraffin-embedded temporal artery biopsy specimens from 28 GCA patients and 10 normal controls were deparaffinized and endogenous peroxidase was blocked. Slides were steamed in 0.1% citrate buffer for 30 minutes to facilitate antigen recovery. After blocking of non-specific binding with 5% normal goat serum, adjacent sections were incubated overnight (4°C) with antibodies specific for human vWF, FGF-2, and VEGF or 30 minutes at room temperature with anti-CD68 Ab. After incubation with the corresponding secondary Ab for 30 minutes, slides stained for FGF-2 and VEGF were developed with the Vectastain alkaline phosphatase kit and Vector Red. vWF and CD68 stains were visualized with Cy-2 or FITC-labeled goat-anti-rabbit or rabbit-anti-mouse Abs (1:200, Jackson Laboratories, Bar Harbor, ME). Sections were counterstained with DAPI for 10 minutes (Sigma, St. Louis, MO) and coverslipped with Cytoseal (Stephens Scientific, Riverdale, NY) or Vectashield (Vector Laboratories). Parallel sections were stained with hematoxylin/eosin (H&E). Negative controls were included in each series and were incubated with 1% normal goat serum instead of the primary Abs.
vWF and VEGF-stains were visualized by using a confocal Axiphot fluorescent laser-scanning microscope (Carl Zeiss, Inc., Oberkochen, Germany). The total number of lumina was counted for the three layers of the vessel wall over the entire cross-section of the artery.
Quantification of Neointima Formation and Destruction of the Internal Elastic Lamina
For quantification of IEL destruction, digital imaging software (KS400, Kontron Electronics, Eching, Germany) was used. H&E-stained paraffin sections of temporal artery sections were scanned using a confocal laser scanning microscope (Axiphot) and the resulting 256 gray-scale images were analyzed with the KS400 software. The total cross section of the temporal artery, the area of the neointima (lumen to IEL), and the area of the lumen were measured. The extent of IEL-destruction was determined as the percentage of the total circumference of the IEL.
Polymerase Chain Reaction (PCR) Primers and Biotinylated Probes
The following primers and probes were used: ß-actin (5': ATG GCC
ACG GCT GCT TCC AGC; 3': CAT GGT GGT GCC GCC AGA CAG; probe: TTC CTT
CCT GGG CAT GGA GT), IFN- (5': ACC TTA AGA AAT ATT TTA ATG C; 3':
ACC GAA TAA TTA GTC AGC TT; probe: ATT TGG CTC TGC ATT ATT TTT CTG T),
FGF-2 (5': GCA GAA GAG AGA GGA GTT G; 3': TAG CAG AGA TTG GGA GAA A,
probe: TGT GCT AAC CGT TAC CTG GC), and VEGF (5': ATG AAC TTT CTG CTG
TCT TGG; 3': TCA CCG CCT CGG CTT GTC ACA; probe: CAC CAT GCA GAT TAT
GCG GA).
Reverse Transcription (RT)-PCR and Cytokine Semiquantification
Total RNA was extracted from 18 GCA temporal artery samples by using a commercially available reagent (TRIZOL, Life Technologies, Grand Island, NY). cDNA from temporal artery tissue was analyzed for ß-actin transcripts by semiquantitative PCR and then adjusted to contain equal numbers.19 The adjusted cDNA was amplified under nonsaturating conditions with cytokine-specific primers for 30 cycles.
Each PCR amplification cycle consisted of denaturation at 94°C for 30
seconds, annealing at either 52°C (FGF-2), 55°C (ß-actin,
IFN-), or 58°C (VEGF) for 1 minute, and polymerization at 72°C
for 1 minute with a final 10-minute extension at 72°C. Each PCR
included a set of serial dilutions of cytokine cDNA with a known number
of copies.
Amplified products were labeled with digoxygenin-11-dUTP and then
semiquantified in a liquid hybridization assay with biotinylated
internal probes using a PCR enzyme-linked immunosorbent assay kit (both
Roche Molecular Biochemicals-Boehringer Mannheim, Indianapolis, IN). In
these assays, the labeled PCR products were hybridized for 2 hours with
200 ng/ml probe at 42°C for ß-actin and IFN- and at 55°C for
VEGF and FGF-2. Hybrids were immobilized on streptavidin-coated
microtiter plates and, after washing, were detected with a
peroxidase-labeled anti-digoxigenin antibody. The plates were developed
by a color reaction using ABTS (2,2'-azino-di[3-ethylbenzthiazoline
sulfonate] diammonium salt) substrate and quantified using a kinetic
microplate reader (Molecular Devices, Sunnyvale, CA). The number of
cytokine-specific sequences was determined by interpolation onto a
standard curve and was expressed as the number of cytokine sequences
per 2 x 105
ß-actin sequences.19
Statistical Analysis
Statistical analysis was carried out using Sigma Stat software (SPSS, Chicago). The number of blood vessels was correlated with elastic lamina destruction and in situ cytokine production by exponential regression analysis.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Microvessels in the wall of temporal arteries were detected by
staining for vWF. Normal temporal arteries contained a network of vasa
vasorum that was restricted to the adventitial layer (data not shown).
In arteries affected by GCA, microvessels were found in all three
layers of the arterial wall (Figure 1)
.
The extent of neovascularization varied markedly among patients with
pronounced microvessel formation in some cases and minimally increased
vascularization in others. In temporal arteries with minimal intimal
hyperplasia, vasa vasorum were found almost exclusively in the
adventitia (Figure 1A)
. Compared to normal temporal arteries, the
diameter of intramural blood vessels was smaller and they were
increased in number. In contrast, in inflamed arteries with marked
intimal hyperplasia, new vasa vasorum were found throughout the
arterial wall, including the media and the intima (Figure 1B)
. In the
media, clusters of newly formed vessels colocalized with dense
mononuclear infiltrates. In the intima, vasa vasorum displayed a
distinct topography. They were arranged in a circumferential
distribution in the outer one-third of the intima, distant from the
intima-media junction. Vasa vasorum were distinctly absent from the
base of the hyperplastic intima and were not found in the direct
vicinity of the IEL. Also, with loss of arterial lumen, vWF was often
found diffusely under the macroendothelial layer but remained highly
localized to endothelial cells in the newly formed vessels.
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The number of microvessels in the entire circumference of the arterial
wall ranged from 13 to 284. Correlation between the area of arterial
lumen and the area of the intimal layer demonstrated a close
association between intimal hyperplasia and vasa vasorum formation
(P = 0.004). The number of newly formed vasa
vasorum was highest in cases with marked hyperplasia of the intima,
leading to luminal stenosis. Not only did arterial sections with
intimal hyperplasia contain more microvessels, the absence or presence
of a thickened intimal layer was also correlated with the emergence of
capillaries in the otherwise avascular media and intima. Results of 19
patients who had marked intimal hyperplasia (stenosis >50%) and of 9
patients with minimal to moderate stenosis (<50%) are summarized in
Figure 2
. In the absence of hyperplastic
intima and luminal stenosis, microvessels were only found in the
adventitia. Arteries with intimal hyperplasia had a mean of 22 vasa
vasorum per section in the media (P = 0.001,
compared to arteries lacking luminal stenosis) and a mean of 50 vasa
vasorum in the intima (P < 0.0001), confirming
that the hyperplastic intima was a preferred site of neoangiogenesis.
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To identify parameters distinguishing patients with and without
upregulated neoangiogenesis, temporal arteries were analyzed for
characteristic features besides the presence of a lumen-compromising
intimal layer. Comparison of inflamed temporal arteries with and
without angiogenesis in the inner arterial layers indicated that
neovascularization correlated with a high number of multinucleated
giant cells (MGCs). MGCs occur in 50–60% of patients with GCA and
have been implicated in the fragmentation of the IEL, a typical finding
of GCA.20,21
Therefore, we explored whether the extent of
IEL degradation was directly correlated with neoangiogenesis. In Figure 3
, two temporal artery tissues are
compared, one with neoangiogenesis limited to the adventitia and one
with vasa vasorum throughout the entire arterial wall. Giant cell
formation, neovascularization, and disruption of the IEL were closely
correlated. In cases of advanced degradation, new vasa vasorum emerged
in the intimal layer. In temporal arteries with an intact IEL, vasa
vasorum were restricted to the adventitia and were only slightly
increased in number.
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In cases with almost circumferential destruction of the IEL, a high
number of new blood vessels was formed. Conversely, if more than 70%
of the elastic lamina was still intact, the number of microvessels was
low. Nine of the 28 patients had fragmentation of less than 30% of the
lamina perimeter. Most of these patients had fewer than 100
microvessels per arterial circumference. In the two individuals in this
group with 104 and 142 microvessels, all of the vasa vasorum were found
in the adventitia and none in the media and intima. Patients with more
than 70% destruction of the IEL had 100 to 300 microvessels. From the
data shown in Figure 4
, it appears that even with almost complete
disruption of the lamina, the number of capillaries still increased.
This observation raised the possibility that a second factor, besides
the destruction of the elastic membrane, was involved in regulating
angiogenesis. Comparison of the patients in the subset with almost
complete lamina destruction did not reveal a relationship between the
duration of vasculitis and the extent of neovascularization (data not
shown).
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To explore which cytokines and growth factors had a role in
supporting neoangiogenesis, tissue extracts from temporal artery
sections were analyzed for the expression of cytokine and growth factor
transcripts. IFN- has been identified as a key cytokine in GCA and
its tissue expression has been correlated with variations in clinical
disease pattern.8,21
VEGF and FGF-2 are cytokines that
have been implicated in inducing the outgrowth of new
capillaries.14-17
IFN--, FGF-2-, and VEGF-specific
sequences were quantified in tissue extracts of 18 consecutive temporal
artery biopsies from GCA patients. Results are presented in Figure 5
. The transcription of VEGF varied
markedly among patients and ranged from 100 to 10,000 VEGF-specific
sequences/2 x 105
ß-actin sequences. High copy
numbers correlated with increased neovascularization
(R2 = 0.78). In contrast, no correlation was seen for
FGF-2 production (R2 = 0.11). Although IFN- is not
directly angiogenic, copy numbers of tissue IFN- mRNA were also
closely correlated with the number of newly formed microvessels in the
media and intima (R2 =
0.53). Possibly, IFN- has an indirect effect on angiogenesis by
influencing the production of angiogenic growth factors in the arterial
tissue. FGF-2 did not appear to have a role in neovascularization in
GCA whereas VEGF emerged as a prime candidate.
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The close correlation between tissue expression of VEGF and
neovascularization raised the questions whence this growth factor
derived and whether the origin of VEGF could provide information on why
new vasa vasorum displayed a distinct topography in the intimal layer.
Immunohistochemical analysis of tissue sections demonstrated that VEGF
protein was easily detected in the arterial wall. By two-color
staining, more than 90% of the VEGF-positive cells expressed the CD68
marker. Among these, the most intense staining was in MGCs (Figure 6)
. Not all CD68-positive macrophages in
the arterial wall contributed to VEGF production. Expression of VEGF
protein in adventitial or intimal macrophages was the rare exception.
Characteristically, it was found in the MGCs and macrophages aligned
along the media-intima junction. Occasionally, very few smooth muscle
cells and endothelial cells stained weakly positive with anti-VEGF
antibodies. VEGF-positive macrophages and MGCs were arranged along the
medial aspect of the IEL. These findings implicated MGCs in the
regulation of neovascularization in the inflamed arterial wall in GCA.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The arterial wall itself is an unusual site for the formation of microvessels. In normal temporal arteries, vasa vasorum were restricted to the adventitial layer, confirming that the media and the intima are avascular. It is currently believed that the artery wall tissue receives nutrients by diffusion outward from the main lumen and inward from the adventitia.9 Thickening of the arterial wall could therefore be suspected to generate hypoxia-induced angiogenesis. The tendency of new capillaries to form a circular arrangement in the intimal tissue but not at the intima-media junction could be interpreted as indicating a watershed with increased oxygen demands of the expanding intima. Hypoxia-initiated angiogenesis was suggested in a recent study describing abundant development of new vasa vasorum in porcine coronary arteries following experimental hypercholesterolemia.23 Alterations in the arterial wall vascularization preceded the emergence of classical atherosclerotic lesions but were closely correlated to an increase in wall thickness. Data presented here indicate that hypoxia is very unlikely to be the triggering factor inducing neovascularization in vasculitis. Rather, VEGF was supplied by MGCs, which are not a reaction to hypoxic stress but represent a tissue-infiltrating cell. Studies describing an increased number of adventitial vasa vasorum in advanced coronary atherosclerosis24,25 might also indicate that mechanisms other than hypoxia regulate the emergence of new microvessels in the arterial wall.26-29
Variations in the degree of vasa vasorum neovascularization between
patients provided an important clue and an opportunity to search for
parameters associated with intramural angiogenesis. Therefore, we began
to investigate on a molecular level how the outgrowth of new
capillaries was supported. Semiquantification of cytokines and growth
factors led to the identification of VEGF as an angiogenic factor that
was closely correlated with the degree of microvessel formation. More
interestingly, the tissue cytokine expression pattern demonstrated that
the in situ activity of the IFN- gene was associated with
MGC formation/up-regulated neovascularization/intimal hyperplasia.
These results were in line with earlier reports correlating the local
production of IFN- with MGC formation in GCA
patients.21
Full-blown vasculitis with vascular morbidity
requires the transcription of IFN- in the arteries. In the absence
of IFN-, only subclinical vessel wall inflammation is generated,
presenting clinically as polymyalgia rheumatica.30
High
levels of tissue IFN- have been associated with a particular disease
pattern characterized by the development of blindness, stroke, and jaw
claudication.21
Vice versa, low tissue transcription of
IFN- has been encountered in patients with predominantly systemic
manifestations, often lacking localized vascular manifestations. Tissue
production of IFN- has also been associated with the emergence of
MGCs, which are a typical but not a necessary component of vascular
infiltrates in GCA. The questions of why some patients form MGCs and
other do not and how that relates to the clinical picture of GCA has
remained unanswered.
Data presented here allow us to propose a disease model partially
addressing this conundrum (Figure 7)
. The
model predicts that IFN- derives from antigen-specific activation of
CD4+ T cells in the adventitia. This event transmits
signals to other cells, particularly CD68+ macrophages
recruited to the arterial wall. Specialized macrophages in the media
and along the media-intima junction undergo fusion and form MGCs. MGCs
produce VEGF and thus facilitate the growth of new vasa vasorum.
Because the site of the immunological injury is the adventitia and the
new microvessels must sprout from vasa vasorum in the adventitia,
additional signals from the adventitia might come into play. The
molecular basis for the spatial distance between IFN- production and
MGC formation remains to be elucidated. Support for a critical
contribution of IFN- in MGC generation also comes from in
vitro studies. Although many different cytokines have been
suspected to induce monocyte fusion, strong evidence has pointed to
IFN- as the fusogenic mediator.31,32
In this model,
induction of neoangiogenesis would reflect a certain type of
T-cell-mediated immune response and would not be a consequence of
tissue hypoxia resulting from the proliferation of the intimal layer. A
fascinating aspect of this model is that IFN--producing cells have
characteristic features of antigen-activated T cells.8
The
nature and concentration of disease-relevant antigens in GCA may
therefore influence the expression of the disease with its variant
forms of vascular and systemic morbidity.
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The precise function of MGCs in the vascular infiltrates in GCA has not been understood. It has been suggested that MGCs derive from macrophages to provide improved effector function in phagocytosis, intracellular killing of microorganisms, and sequestration of pathogens that are difficult to remove. Conclusive evidence for an infectious etiopathogenesis of GCA has not been forthcoming. Also, in vitro studies have shown that the ability to phagocytose is not maintained in macrophages after cell fusion.32 Two lines of evidence support the hypothesis that MGCs are primarily tissue-destroying cells. First, they can produce matrix metalloproteinase (MMP)-2, an enzyme with substrate specificity for elastin.33,35 MGCs characteristically lie next to fragmented pieces of IEL and could thus be instrumental in digesting the elastic membranes.36 Second, MGCs have been found to be surrounded by lipid peroxidation products, as evidenced by the presence of the toxic aldehyde 4-hydroxynonenal (4-HNE).37 The current study emphasizes a different aspect of the functional profile of MGCs, namely their ability to secrete VEGF. MGCs have been reported to also synthesize other growth factors involved in intimal proliferation, such as PDGF-AA and PDGF-BB.3 Taken together, these data indicate that these peculiar cells have secretory abilities and a dual function in tissue destruction and attempted tissue repair.
Although our results directly implicate MGCs as the critical provider of the angiogenic factor VEGF and provide indirect evidence for a potential role of T cells in regulating the pattern and extent of vasa vasorum formation in the arterial wall, the mechanism(s) by which MGCs are induced and activated and how their function is regulated remain to be elucidated. The experiments reported here did not address the time sequence of neoangiogenesis, intimal hyperplasia, and IEL degradation. The co-occurrence of all three events may reflect shared regulatory pathways or interdependence of these pathological reactions. All of them are part of the arterial wall remodeling process that finally leads to luminal stenosis and eventual ischemia. Because all three tissue response patterns can be linked to MGCs, these unique cells emerge as critical cellular players in GCA. The findings are relevant to the potential for eliminating MGCs or disrupting their generation as novel therapeutic approaches to arteritis.
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Acknowledgements |
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Footnotes |
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Supported in part by the Mayo Foundation and by a grant from the National Institutes of Health (RO1 EY11916).
Accepted for publication May 22, 1999.
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 J. Herrmann, L. O Lerman, M. Rodriguez-Porcel, D. R Holmes Jr., D. M Richardson, E. L Ritman, and A. Lerman Coronary vasa vasorum neovascularization precedes epicardial endothelial dysfunction in experimental hypercholesterolemia Cardiovasc Res, September 1, 2001; 51(4): 762 - 766. [Abstract] [Full Text] [PDF]
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L. Nelimarkka, H. Salminen, T. Kuopio, S. Nikkari, T. Ekfors, J. Laine, L. Pelliniemi, and H. Jarvelainen Decorin Is Produced by Capillary Endothelial Cells in Inflammation-Associated Angiogenesis Am. J. Pathol., February 1, 2001; 158(2): 345 - 353. [Abstract] [Full Text] [PDF]
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