© 2000 American Heart Association, Inc.
Integrative Physiology |
Antiangiogenic Effect of Interleukin-10 in Ischemia-Induced Angiogenesis in Mice Hindlimb
From INSERM U541, Hôpital Lariboisière, Institut Fédératif de Recherche "Circulation, Paris 7" (J.S.S., Z.M., M.D., R.T., A.T., B.I.L.), Paris; Unité Mixte de Recherche 7001, Centre National de la Recherche Scientifique/ENSCP/Aventis, Aventis Gencell (M.F.B., D.S.), Vitry; and Aventis Gencell (N.D., D.B.), Vitry, France.
Correspondence to Bernard I. Levy, U541-INSERM, Hôpital Lariboisière, 41 Boulevard de la Chapelle, 75475 Paris cedex 10, France. E-mail levy{at}infobiogen.fr
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Abstract |
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Abstract—Ischemia induces both hypoxia and inflammation that trigger angiogenesis. The inflammatory reaction is modulated by production of anti-inflammatory cytokines. This study examined the potential role of a major anti-inflammatory cytokine, interleukin (IL)–10, on angiogenesis in a model of surgically induced hindlimb ischemia. Ischemia was produced by artery femoral occlusion in both C57BL/6J IL-10+/+ and IL-10–/– mice. After 28 days, angiogenesis was quantified by microangiography, capillary, and arteriole density measurement and laser Doppler perfusion imaging. The protein levels of IL-10 and vascular endothelial growth factor (VEGF) were determined by Western blot analysis in hindlimbs. IL-10 was markedly expressed in the ischemic hindlimb of IL-10+/+ mice. Angiogenesis in the ischemic hindlimb was significantly increased in IL-10–/– compared with IL-10+/+ mice. Indeed, angiographic data showed that vessel density in the ischemic leg was 10.2±0.1% and 5.7±0.4% in IL-10–/– and IL-10+/+ mice, respectively (P<0.01). This corresponded to improved ischemic/nonischemic leg perfusion ratio by 1.4-fold in IL-10–/– mice compared with IL-10+/+ mice (0.87±0.05 versus 0.63±0.01, respectively; P<0.01). Revascularization was associated with a 1.8-fold increase in tissue VEGF protein level in IL-10–/– mice compared with IL-10+/+ mice (P<0.01). In vivo electrotransfer of murine IL-10 cDNA in IL-10–/– mice significantly inhibited both the angiogenic process and the rise in VEGF protein level observed in IL-10–/– mice. No changes in vessel density or VEGF content were observed in the nonischemic hindlimb. These findings underscore the antiangiogenic effect of IL-10 associated with the downregulation of VEGF expression and suggest a role for the inflammatory balance in the modulation of ischemia-induced angiogenesis.
Key Words: angiogenesis • ischemia • inflammation • interleukin-10
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Angiogenesis is the development of new vessels from preexisting blood vessels. This tightly controlled process is associated with pathological conditions such as tumor growth, diabetic retinopathy, and ischemic diseases. Hence, understanding the mechanism of angiogenesis is of major therapeutic interest.
In ischemic diseases, both hypoxia and inflammation are
generally considered to represent fundamental stimuli for
angiogenesis.1 The main mechanism of
hypoxia-induced angiogenesis involves the rise in
hypoxia-inducible factor-1
(HIF-1) protein resulting in
increased expression of vascular endothelial growth
factor (VEGF), a specific angiogenic factor.2 3
Neovascularization appears to be also controlled by the inflammatory
process that occurs in the ischemic area.
Monocytes/macrophages accumulate during vessel growth in
ischemic tissues.4 The presence of these
inflammatory cells is associated with local secretion of several
angiogenic factors, including cytokines such as interleukin
(IL)–2 and tumor necrosis factor- (TNF-), growth factors such as
VEGF and basic fibroblast growth factor (bFGF), and matrix
metalloproteinases (MMPs).4 5 Recently, a
macrophage-derived peptide, PR39, has been shown to inhibit
the degradation of HIF-1, leading to increased VEGF expression and
accelerated formation of vascular structures in
vitro.6
During the inflammatory reaction, anti-inflammatory cytokines
are also produced and tend to modulate the inflammatory process.
However, little information is available regarding the potential role
of anti-inflammatory cytokines in ischemia-induced
angiogenesis. IL-10, secreted by macrophages and by lymphocytes
of the T helper 2 subtype, is an anti-inflammatory
cytokine with potent deactivating properties on
macrophages. In addition, antitumoral effects of IL-10 have
been recently associated with its ability to decrease VEGF, TNF-, or
MMP-9 synthesis and to prevent angiogenesis associated with tumor
growth.7 8
We therefore hypothesized that the anti-inflammatory cytokine IL-10 may affect ischemia-induced angiogenesis. We analyzed the angiogenic process in IL-10–deficient (IL-10–/–) C57BL/6J mice in a model of operatively induced hindlimb ischemia and assessed the effect of in vivo electrotransfer of murine IL-10 cDNA in IL-10–/– mice. We also determined the VEGF protein level in hindlimbs of IL-10–/– mice and IL-10+/+ mice.
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Materials and Methods |
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Experimental Protocol
Male C57BL/6J IL-10–/– mice and IL-10+/+ mice (Transgenic Alliance) underwent surgery to induce unilateral hindlimb ischemia. Animals were anesthetized by inhalation of isoflurane. The ligature was performed on the right femoral artery, 0.5 cm proximal to the bifurcation of the saphenous and popliteal arteries. Mice (7 animals per group) were then housed under specific pathogen–free conditions for 28 days. Animals were cared for in accordance with guidelines published by the National Institutes of Health (NIH publication No. 85-23, revised 1985), and the study protocol was approved by the local ethics committee.
Quantification of Angiogenesis
Microangiography
Vessel density was evaluated by high-definition microangiography
(Trophy system) at the end of the 28-day treatment period. Mice were
anesthetized (isoflurane inhalation), and a longitudinal
laparotomy was performed to introduce a polyethylene catheter into the
abdominal aorta and to inject a contrast medium (barium sulfate, 1
g/mL). Angiography of hindlimbs was then assessed and images (3 per
animal) were acquired by a digital x-ray transducer. Images were then
assembled to obtain a complete view of the hindlimbs. The vessel
density was expressed as a percentage of pixels per image occupied by
vessels in the quantification area. Quantification area was
limited by the place of the ligature on the femoral artery, the knee,
the edge of the femur, and the external limit of the leg. The time
between artery femoral ligature and angiography (28 days) was
determined as being optimal for vascularization after ischemia
(data not shown).
Capillary and Arteriole Densities
Microangiographic analysis was completed by assessment
of capillary and arteriole densities. Ischemic and
nonischemic muscles were dissected and progressively frozen in
isopentane solution cooled in liquid nitrogen. Sections (7 µm)
were first incubated for 30 minutes in PBS containing 5% BSA at room
temperature and then 1 hour with either mouse monoclonal antibody
directed against human smooth muscle actin 1
(dilution 1:50) to identify arterioles or with rabbit polyclonal
antibody directed against total fibronectin (dilution 1:50) to identify
capillaries. Arteriole immunohistochemistry was achieved by treating
sections with H2O2 3% and
with a biotinylated secondary antibody with a horseradish
peroxidase–streptavidin conjugate (dilution 1:50). Capillaries were
revealed with a fluorescent FITC anti-rabbit antibody (dilution
1:10). Capillary and arteriole densities were then calculated in
randomly chosen fields of a definite area using Optilab/Pro
software.
Laser Doppler Perfusion Imaging
To provide functional evidence for ischemia-induced
changes in vascularization, laser Doppler perfusion imaging
experiments were performed in IL-10–/– and
IL-10+/+ mice (n=3) as previously
described.9
Intramuscular Electrotransfer of Expression Plasmid IL-10
cDNA
IL-10–/– mice were injected at day 1
after femoral artery occlusion with the IL-10 expression plasmid,
pCor–IL-10, and with the control empty plasmid, pCor, into tibial
cranial muscles of ischemic and nonischemic legs of the
mouse (7 animals per group), as previously described.10 We
previously showed that IL-10 cDNA transfection results in a marked
increase in IL-10 plasma level up to 21 days.10
Determination of IL-10 and VEGF Protein Expression
Tissue samples were thawed and homogenized in 300
µL of buffer (200 mmol/L sucrose and 20 mmol/L HEPES [pH
7.4]) containing protease inhibitors. Protein content was
then determined by the method of Bradford.11 Proteins were
separated in denaturing SDS/12% polyacrylamide gels and then
blotted onto a nitrocellulose sheet (Hybond enhanced chemiluminescence
[ECL], Amersham). Antibodies against IL-10 (Pharmingen) and VEGF
(Santa Cruz Biotechnology) were used at a dilution of 1:2000. Specific
protein was detected by chemiluminescent reaction
(ECL+ kit, Amersham) followed by exposure of the
membranes to Hyperfilm ECL (Amersham). The proteins were then stained
with Ponceau Red (Sigma) for 5 minutes. Quantifications were performed
by densitometric analysis after scanning using the Bio-Rad gel
Doc 1000. Results are expressed as a ratio of quantification of the
specific band on autoradiogram to quantification of the
transferred total protein bands stained with Ponceau Red.
Statistical Analysis
Results are expressed as mean±SEM. One-way ANOVA was used to
compare each parameter. Post hoc Bonferroni
t-test comparisons were then performed to identify which
group differences accounted for the significant overall ANOVA. A value
of P<0.05 was considered significant.
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Results |
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Expression of IL-10 in Ischemic Hindlimb of IL-10+/+ Mice
We first verified whether ischemia-induced angiogenesis was associated with a rise in IL-10 expression in the ischemic tissue. In IL-10+/+ mice, a marked expression of IL-10 was detected in the ischemic leg compared with the nonischemic leg. As expected, in IL-10–/– mice, IL-10 protein level was undetectable in both ischemic and nonischemic hindlimbs (Figure 1
).
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Vessel Density in IL-10–/– Mice
Microangiography
In IL-10+/+ mice, vessel density was reduced
in the ischemic (right) leg compared with the
nonischemic (left) leg (5.7±0.4% versus 9.3±0.7%,
respectively, P<0.05). In the ischemic hindlimb,
vessel density was increased by 1.8-fold in
IL-10–/– mice compared with
IL-10+/+ mice (10.2±0.5% versus 5.7±0.4%,
respectively, P<0.01) and was similar to that observed in
the nonischemic leg (10.2±0.5% versus 9.8±0.4%,
respectively, NS). In the nonischemic hindlimb, vessel density
was not different in IL-10–/– mice and
IL-10+/+ mice (9.8±0.4% versus 9.3±0.7%,
respectively, NS) (Figure 2).
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<P<0.05 vs IL-10–/– mice.
Capillary and Arteriole Densities
Microangiographic data were confirmed by capillary and arteriole
density analysis. In IL-10+/+ mice,
capillary and arteriole density was decreased in the ischemic
leg compared with the nonischemic one (434±15 and 5.3±0.3
vessels/mm2 versus 864±34 and 12±3
vessels/mm2, respectively, P<0.01).
In ischemic hindlimb, the number of capillaries and arterioles
was raised by 1.4-fold in IL-10–/– mice
compared with IL-10+/+ mice (P<0.01)
(Figure 3). In the nonischemic
hindlimb, capillary and arteriole density remained unchanged in
IL-10–/– and IL-10+/+
mice (data not shown). Similar results were obtained with CD31
immunostaining to stain specifically
endothelial cells (data not shown).
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Laser Doppler Perfusion Imaging
Microangiographic and capillary density measurements corresponded
to improved perfusion in ischemic hindlimb of
IL-10–/– mice. Indeed,
ischemic/nonischemic leg perfusion ratio increased by
1.4-fold in IL-10–/– mice compared with
IL-10+/+ mice (0.87±0.05 versus 0.63±0.01,
respectively, P<0.01).
Effect of Electrotransfer of pCor–IL-10 in
IL-10-/- Mice
To demonstrate that enhanced ischemia-induced angiogenesis
in IL-10–/– mice was due to the IL-10
deficiency, in vivo intramuscular electrotransfer of pCor IL-10 was
performed in IL-10–/– mice.
Microangiography
In the ischemic hindlimb of transfected
IL-10–/– mice, vessel density was significantly
reduced (7.4±0.5% versus 10.2±0.5% in nontransfected
IL-10–/– mice, P<0.05) in such a
way that it was no longer significantly different from that in
IL-10+/+ mice (7.4±0.5% versus 5.7±0.4%, NS).
In contrast, electrotransfer of the control expression plasmid (pCor)
did not affect the angiogenic process in
IL-10–/– mice (9.7±0.9% in mice transfected
with the control pCor plasmid versus 10.2±0.5% in nontransfected
mice).
In the nonischemic hindlimb of IL-10–/–
mice, intramuscular administration of IL-10 or empty pCor did not
affect vessel density (Figure 2
).
Capillary and Arteriole Densities
In the ischemic hindlimb of transfected
IL-10–/– mice, capillary and arteriole
densities were decreased by 1.3-fold compared with nontransferred
IL-10–/– mice (P<0.05). The number
of capillaries and arterioles became not significantly different from
that of IL-10+/+ mice (Figure 3).
In the nonischemic hindlimb of IL-10–/– mice, injection of IL-10 did not change capillary and arteriole densities (data not shown).
Regulation of VEGF Protein Level
In the ischemic hindlimb of
IL-10–/– mice, VEGF level was increased by
179±21% (P<0.01) compared with
IL-10+/+ mice. Interestingly, intramuscular
electrotransfer of pCor–IL-10 in IL-10–/– mice
prevented this increase; VEGF level in IL-10–/–
mice transfected with pCor–IL-10 was similar to that in
IL-10+/+ mice (125±18% versus 100±15%, NS)
(Figure 4). In the nonischemic
hindlimb, VEGF protein level was much lower than in the
ischemic hindlimb and was similar in
IL-10+/+ and IL-10–/–
mice injected with pCor IL-10 or empty pCor (Figure 4).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The main results of this study are that IL-10 negatively modulates ischemia-induced angiogenesis and that this effect is associated with the downregulation of VEGF expression.
Signs of inflammation are present in the ischemic hindlimb.4 However, although evidence is accumulating on the activating role of proinflammatory cytokines in angiogenesis, little is known about the role of the anti-inflammatory component of the reaction. Among the anti-inflammatory cytokines, we considered IL-10 as a cytokine with a putative antiangiogenic effect. IL-10 is produced by macrophages and could therefore be produced locally within the angiogenic area. Indeed, in the present study, we detected marked levels of IL-10 in the ischemic tissue of IL-10+/+ mice.
Our study demonstrates that in IL-10–/– mice,
vessel growth was specifically increased in the ischemic
hindlimb with no effect in the nonischemic contralateral
hindlimb. This suggests that hypoxia was the primary event
leading to a local inflammatory reaction and angiogenesis.
Ischemic tissue may produce chemoattractant proteins favoring
monocyte migration.12 Monocytes that are activated
to remove necrotic tissue may also contribute to angiogenesis through
the production of proinflammatory cytokines with
angiogenic properties. In addition, it has been shown that
cytokines, such as IL-1ß, strongly increase HIF-1 activity
in human hepatoma cells in culture, emphasizing a possible role of
HIF-1 as a trans-acting factor in the inflammatory
process as well.13 Interestingly, in vivo LPS
administration increases capillary density, as well as the number of
macrophages in nonoccluded hindlimb.4 It is
therefore likely that recruitment and activation of resident
macrophages are sufficient to activate the angiogenic
process.
Our finding of enhanced angiogenesis in ischemic hindlimb of IL-10–/– mice underscores the importance of the inflammatory balance in the control of the angiogenic process. The marked angiogenesis associated with tissue ischemia in IL-10–/– mice was due to the deficiency in IL-10. Indeed, in vivo electrotransfer of murine IL-10 cDNA in IL-10–/– mice was able to prevent the increased angiogenesis observed in the ischemic hindlimb of these animals.
IL-10 may act by deactivating macrophages14 15
with decreased production of angiogenic factors, including bFGF
and TNF-, as previously shown in ischemic cardiac
tissue.16 Interestingly, antibodies to proinflammatory
cytokines blunt the angiogenic response to VEGF and bFGF in a
model of ocular angiogenesis, which suggests that proinflammatory
cytokines are instrumental in triggering the angiogenic
process.17 18 IL-10 may also directly modulate several
cellular pathways that play an important role in the regulation of
angiogenesis. Regulation of VEGF protein level has been shown to be a
key event in the angiogenic process associated with hindlimb
ischemia.19 Interestingly, VEGF protein level was
markedly enhanced in the ischemic hindlimb of
IL-10–/– mice and returned to baseline level in
IL-10–/– mice transfected with pCor–IL-10.
This finding indicates that the antiangiogenic effect of IL-10 was
likely due to a downregulation of VEGF expression. In addition, IL-10
might inhibit cyclooxygenase-2, which has been
reported to affect the angiogenic process.20 21 An
important effector mechanism in angiogenesis involves MMP
production and activation.1 Inhibition of MMP
activity is sufficient to block the angiogenic response to bFGF in rat
cornea.22 IL-10 could therefore exert its antiangiogenic
activity by inhibiting MMP synthesis and/or stimulating tissue
inhibitors of MMPs, as previously described in human
mononuclear phagocytes.23
In conclusion, the present study demonstrates the antiangiogenic effect of IL-10 in mice with operatively induced hindlimb ischemia. This antiangiogenic effect was associated with the downregulation of VEGF content. The present work underscores the major role of the inflammatory balance in the modulation of ischemia-induced angiogenesis. Further studies are necessary to determine the exact mechanism of the antiangiogenic effect of IL-10. Our results open the way for therapeutic strategies aimed at decreasing IL-10 production to activate the angiogenic process in ischemic tissues.
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Acknowledgments |
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This study was supported by grants from INSERM and Université Paris 7-Denis Diderot.
Received June 7, 2000; revision received July 27, 2000; accepted August 4, 2000.
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