Published online before print July 19, 2001, doi: 10.1161/hh1501.094269
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© 2001 American Heart Association, Inc.
Integrative Physiology |
Regulation of Matrix Metalloproteinase Activity in Ischemic Tissue by Interleukin-10
Role in Ischemia-Induced Angiogenesis
From Institut National de la Santé et de la Recherche Médicale U541, Hôpital Lariboisière, Institut Federatif de Recherche Circulation-Lariboisière, Université Paris, France.
Correspondence to Bernard I. Levy, U541-INSERM, Hôpital Lariboisière, 41 Blvd de la Chapelle, 75475 Paris cedex 10, France. E-mail levy@ infobiogen.fr
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Abstract |
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Abstract— We have previously shown that deficiency in the anti-inflammatory cytokine interleukin-10 (IL-10) is responsible for enhanced angiogenesis after hindlimb ischemia. This study examined the putative involvement of matrix metalloproteinase (MMP) activation in this process. Ischemia was produced by artery femoral occlusion in both C57BL6 IL-10+/+ and IL-10-/- mice. Angiographic vessel density and laser Doppler perfusion data at day 28 showed significant improvement in ischemic/nonischemic leg ratio by, respectively, 1.8-fold and 1.4-fold in IL-10-/- mice compared with IL-10+/+ mice. This was associated with an increase in vascular endothelial growth factor (VEGF) protein content in the ischemic hindlimb. Three days after ischemia, gelatin zymography showed a significant increase in both pro- and active forms of MMP-2 and MMP-9 in ischemic hindlimbs of IL-10-/- mice compared with IL-10+/+ mice (P<0.01). This increase in MMP activity in IL-10-/- mice was completely inhibited by treatment with BB-94 (5 mg/kg IP), a specific MMP inhibitor. Furthermore, increases in both vessel density and blood perfusion indexes at day 28 in IL-10-/- mice were abolished after treatment with BB-94 (0.78±0.06 versus 1.17±0.09 and 0.62±0.02 versus 0.88±0.04, for vessel density and blood perfusion ratio, respectively, in IL-10-/- mice treated with BB-94 versus untreated IL-10-/- mice, P<0.05). In contrast, BB-94 treatment did not affect the rise in VEGF protein content. These findings in IL-10-/- mice underscore the critical role of MMP activation, in a context of increased VEGF expression, in promoting ischemia-induced angiogenesis.
Key Words: angiogenesis • ischemia • interleukin-10 • matrix metalloproteinase
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Angiogenesis, defined as the growth of new vessels from existing endothelium-lined vessels, is associated with pathologic conditions such as tumor growth or ischemic disease. Hence, elucidation of the cellular events involved in the angiogenic process is a considerable challenge with major therapeutic consequences.
In ischemic diseases, both hypoxia and inflammation play a major role in the control of new vessel growth.1 The main mechanism of hypoxia-induced angiogenesis involves the rise in hypoxia-inducible factor-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 accumulation of monocytes/macrophages that occurs within the ischemic area.4 The presence of these inflammatory cells is associated with local secretion of several angiogenic factors, including cytokines and growth factors.4,5 Recently, we observed that, during the inflammatory reaction, the anti-inflammatory cytokine interleukin-10 (IL-10) is also produced and downregulates the angiogenic process associated with hindlimb ischemia, in part through regulation of tissue VEGF protein content.6 However, the precise cellular mechanisms of the antiangiogenic effects of IL-10 remain to be defined.
An important effector mechanism in angiogenesis involves matrix metalloproteinase (MMP) production and activation.7 The MMPs are a family of extracellular endopeptidases that selectively degrade components of the extracellular matrix. At least two members of the MMP family, MMP-2 (72 kDa) and MMP-9 (92 kDa), are able to degrade the extracellular matrix components of the basement membrane. MMP-deficient mice exhibit delayed angiogenic responses during development.8 In addition, inhibition of MMP activity is sufficient to block the angiogenic response to basic fibroblast growth factor (bFGF) in rat cornea and to hamper angiogenesis associated with muscular activity.9,10
The inflammatory reaction is known to be associated with MMP activation,5 and the anti-inflammatory cytokine IL-10 has been shown to downregulate MMP-9 synthesis in human mononuclear phagocytes.11 Interestingly, the antitumoral effects of IL-10 resulted from its antiangiogenic activity and were associated with its ability to decrease MMP-2 and MMP-9 synthesis.12,13 We therefore hypothesized that MMP activation plays a critical role in mediating the increase in ischemia-induced angiogenesis in IL-10–deficient mice. To test this hypothesis, we assessed MMP activity in IL-10-/- mice in a model of operatively induced hindlimb ischemia. We then analyzed the effect of chronic in vivo inhibition of MMP by treatment with BB-94, a specific MMP inhibitor, on the angiogenic process observed in the ischemic leg of IL-10-/- mice.
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Materials and Methods |
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Experimental Protocol
The study was conducted in accordance with both institutional guidelines and those formulated by the European Community for experimental animal use (L358-86/609/EEC). Male C57BL/6J IL-10-/- mice and IL-10+/+ mice (Transgenic Alliance) underwent surgery to induce unilateral hindlimb ischemia. Animals were anesthetized by isoflurane inhalation. 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 3 or 28 days. To examine the role of MMP activation in ischemia-induced angiogenesis, a group of mice was treated with BB-94 (5 mg/kg), a specific MMP inhibitor, by intraperitoneal injection. BB-94 contains a peptide backbone that binds to the MMP and a hydroxamic acid group that binds to the catalytically active zinc atom. Control mice received 0.1 mL vehicle by intraperitoneal injection.
Gelatin Zymography
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.14 Samples were mixed in an SDS-PAGE loading buffer (lacking reducing agents) applied to SDS/9% polyacrylamide gels containing 1 mg/mL gelatin (Bio-Rad) and separated by electrophoresis. Subsequently, SDS was removed from the gels by two washes (15 minutes) with 2.5% Triton X-100, and the gels were incubated overnight at 37°C in zymography buffer (50 mmol/L Tris [pH 7.5] and 10 mmol/L CaCl2) and stained with Coomassie Brilliant Blue (Serva). Gelatinolytic activity was visualized as clear areas of lysis in the gel. Densitometric analysis was performed by using NIH Image software.
Quantification of Angiogenesis
Microangiography
Vessel density was evaluated by high-definition microangiography at the end of the treatment period, as previously described.6 Briefly, mice were anesthetized (isoflurane inhalation) and a contrast medium (barium sulfate, 1 g/mL) was injected through a catheter introduced into the abdominal aorta. Images (3 per animals) acquired by a digital X-ray transducer were 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 zone was delineated by the place of the ligature on the femoral artery, the knee, the edge of the femur, and the external limit of the leg.
Capillary Density
Microangiographic analysis was completed by assessment of capillary densities in ischemic and nonischemic muscles, as previously described.6 Frozen tissue sections (7 µm) were incubated with rat monoclonal antibody directed against CD31 (20 µg/mL, Pharmingen) to identify capillaries. Immunostains were visualized by using avidin-biotin horseradish peroxidase visualization systems (Vectastain ABC Kit Elite, Vector Laboratories). Capillary densities were calculated in randomly chosen fields of a definite area, using Histolab software.
Laser Doppler Perfusion Imaging
To provide functional evidence for ischemia-induced changes in vascularization, laser Doppler perfusion imaging experiments were performed, as previously described.15 Briefly, excess hairs were removed by depilatory cream from the limb before imaging, and mice were placed on a heating plate at 37°C to minimize temperature variation. Nevertheless, to account for variables, including ambient light and temperature, calculated perfusion was expressed as a ratio of right (ischemic) to left (nonischemic) leg.
Determination of VEGF and bFGF Protein Expression
VEGF and bFGF protein expression was determined by Western blot analysis in ischemic and nonischemic legs, as previously described.6
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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MMP Activity in the Ischemic Legs
To examine the role of MMP activation in the promotion of excess ischemia-induced angiogenesis in IL-10-/- mice, we determined MMP activity in the ischemic and nonischemic hindlimbs.
Day 3
In IL-10+/+ mice, gelatin zymographic analysis revealed a major lytic band at 62 kDa corresponding to the active form of MMP-2 and a minor lytic band of 72 kDa consistent with the pro- form of MMP2 (Figure 1). A significant increase in 72- and 62-kDa gelatinolytic activities was observed in the ischemic leg when compared with the nonischemic one (143±15% for pro–MMP-2 activity and 158±18% for MMP-2 activity, respectively, P<0.05). Ischemic tissue of IL-10+/+ mice also showed the appearance of lytic bands at 92 and 82 kDa consistent with the pro- and active forms of MMP-9, respectively (Figure 1).
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Interestingly, pro- and active MMP-2 gelatinolytic activities were increased by 1.6-fold in ischemic hindlimbs of IL-10-/- mice compared with IL-10+/+ mice (P<0.01). Similarly, both pro- and active MMP-9 gelatinolytic activities were increased by 1.9-fold and 2-fold, respectively, in IL-10-/- mice compared with IL-10+/+ mice. Moreover, we noted the appearance of several other lytic bands in the ischemic legs of IL-10-/- mice that were not detectable or were barely detectable in IL-10+/+ mice (Figure 1). Importantly, treatment with BB-94 prevented the overall increase in gelatinolytic activity observed in ischemic legs of IL-10-/- mice (Figure 1). No difference in gelatinolytic activity of the nonischemic leg was observed between the groups (data not shown).
Day 28
At this time point, gelatinolytic activity in the ischemic leg of IL-10+/+ mice and IL-10-/- mice with or without BB-94 treatment returned to values observed in the nonischemic leg (Figure 1).
Effects of MMP Inhibition on Ischemia- Induced Angiogenesis
Microangiography
Day 3
Vessel density was markedly reduced in the ischemic leg of IL-10+/+ and IL-10-/- mice compared with the nonischemic leg. Ischemic/nonischemic leg ratios were then 0.31±0.03 in IL-10+/+ and 0.33±0.05 in IL-10-/- mice. In addition, BB-94 treatment did not affect vessel density in IL-10-/- mice (Figure 2).
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Day 28
In agreement with our previous report,6 the ischemic/nonischemic leg ratio at day 28 was significantly higher in IL-10-/- mice (1.7-fold increase) than in IL-10+/+ mice (1.17±0.09 versus 0.64±0.09, respectively, P<0.01). Interestingly, this increase in vessel density in IL-10-/- mice was completely abolished by BB-94 treatment (0.78±0.06 in BB-94–treated IL-10-/- mice as compared with untreated IL-10-/- mice, P<0.05) (Figure 2). It is noteworthy that vessel density in BB-94–treated IL-10-/- mice was not significantly different from that of IL-10+/+ mice (0.78±0.06 versus 0.64±0.09, respectively, NS).
Capillary Density
Microangiographic data were confirmed by capillary density analysis.
Day 3
In IL-10+/+ mice, capillary number (CD31 staining) was markedly decreased in the ischemic leg (278±62 vessels/mm2) compared with the nonischemic leg (797±43 vessels/mm2, P<0.001). Similar values were obtained in IL-10-/- mice with or without BB-94 treatment (data not shown).
Day 28
Capillary density in the ischemic leg of IL-10+/+ mice was still lower at day 28 compared with the nonischemic leg (544±21 versus 788±43 vessels/mm2, P<0.01). However, capillary density in the ischemic leg of IL-10-/- mice was significantly higher (1.3-fold increase) than that in IL-10+/+ mice (710±29 versus 544±21 vessels/mm2, respectively, P<0.05) and reached the level observed in the nonischemic leg. Treatment with BB-94 completely inhibited the increase in capillary density observed in IL-10-/- mice (583±25 versus 710±29 vessels/mm2, respectively, P<0.05). Capillary density of the nonischemic hindlimb did not differ between the groups (data not shown).
Laser Doppler Perfusion Imaging
Microangiographic and capillary density measurements were associated with changes in blood perfusion.
Day 3
Ischemic/nonischemic leg perfusion ratio was not significantly different between the groups (Figure 3).
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Day 28
Conversely, the ischemic/nonischemic leg perfusion ratio at day 28 was significantly increased (1.4-fold increase) in IL-10-/- mice compared with IL-10+/+ mice (0.88±0.04 versus 0.62±0.02, respectively, P<0.05). Again, this rise in blood perfusion was blocked by BB-94 treatment (0.69±0.06, P<0.05 versus untreated IL-10-/- mice) (Figure 3).
Regulation of VEGF Protein Level
Day 3
No change in VEGF protein level was observed at day 3 between the ischemic and nonischemic legs, in either group (data not shown).
Day 28
In IL-10+/+ mice, VEGF protein content in the ischemic leg increased by 1.4-fold when compared with the nonischemic one (P<0.01) (Figure 4). This increase in VEGF content of the ischemic leg almost doubled in IL-10-/- mice (1.8-fold increase, P<0.01 as compared with the increase in the ischemic leg of IL-10+/+ mice). Interestingly, treatment with BB-94 had no effect on the rise in VEGF protein content. Indeed, the ischemic/nonischemic leg protein level of VEGF still showed a significant 1.9-fold increase in IL-10-/- mice treated with BB-94 (NS versus untreated IL-10-/- mice) (Figure 4). VEGF protein level of the nonischemic hindlimb was similar between the different groups (data not shown).
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Regulation of bFGF Protein Level
Day 3
No change in bFGF protein level was observed at day 3 between the ischemic and nonischemic legs, in either group (data not shown).
Day 28
In IL-10+/+ mice, bFGF protein content in the ischemic leg was similar to that of the nonischemic one (112±13 versus 121±21 arbitrary units, respectively, P>0.05). In addition, the ischemic/nonischemic bFGF content ratio was unchanged in IL-10+/+ and IL-10-/- mice with or without BB-94 treatment (0.99±0.21 versus 1.17±0.21 and 1.12±0.34, respectively, P>0.05). bFGF protein level of the nonischemic hindlimb was also similar between the different groups (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The main results of this study are that endogenous IL-10 inhibits ischemia-induced MMP activity and that unabated MMP activation in the absence of IL-10 plays a critical role in the promotion of ischemia-induced angiogenesis. Moreover, the central role of MMP activation in this process is observed despite a sustained increase in VEGF expression.
Inflammatory reaction occurs within the ischemic hindlimb and modulates the angiogenic process.4,16 Recently, we underscored the major role of the inflammatory balance in the modulation of ischemia-induced angiogenesis. We observed that the anti-inflammatory cytokine IL-10 is produced locally within the ischemic area and exerts an antiangiogenic effect.6 However, the precise mechanisms involved in the modulation of angiogenic activity by IL-10 remained unknown.
In the present study, we focused on the role of MMP activation in ischemia-induced angiogenesis for several reasons. MMPs have been shown to play an important role in other models of angiogenesis, in part through matrix degradation and promotion of cell migration.7 Recent findings also suggest that MMP activity may directly influence cell behavior by stimulating the release of proangiogenic factors or by favoring the destruction of angiogenesis inhibitors.7 On the other hand, hypoxia stimulates MMP gene expression in cultured human dermal fibroblasts,17 and MMP expression has been shown to increase after focal cerebral ischemia in rats.18 Also, the inflammatory response that occurs within the ischemic tissue might play a major role in the control of MMP activity. Hence, inflammatory activation of monocytes by LPS results in increased MMP gene expression.19 In addition, inflammatory cells are able to produce cytokines, such as tumor necrosis factor- or IL-1ß, that modulate MMP activity in both endothelial and vascular smooth muscle cells.20,21 The deactivating effects of IL-10 on the inflammatory response may therefore indirectly affect MMP production within the ischemic tissue. Alternatively, IL-10 may directly modulate MMP activity as previously described in human melanoma cells or in mononuclear phagocytes.11,12 In agreement with these data, we found in the present study a significant increase in MMP activity in the ischemic legs of mice. Moreover, IL-10 deficiency led to further significant increase in MMP activity in the ischemic tissue, suggesting an important role for endogenous IL-10 in the regulation of ischemia-induced MMP activity in vivo.
To examine whether this unabated MMP activation was directly involved in enhanced ischemia-induced angiogenesis, IL-10-/- mice were chronically treated with BB-94, a synthetic specific MMP inhibitor.22 Treatment with BB-94 completely abrogated the difference in gelatinolytic activity between IL-10-/- and IL-10+/+ mice. As a result of MMP inhibition, the increase in ischemia-induced angiogenesis, evaluated by three different methods, was prevented. These results suggest a critical role for MMP activation in ischemia-induced angiogenesis. Although only gelatinolytic activities of MMP-2 and MMP-9 were quantified, it is noteworthy that several other lytic bands were upregulated in the ischemic legs of IL-10-/- mice and were inhibited by BB-94 treatment. These bands may represent multimers of smaller gelatinolytic molecules or may reflect the presence of large gelatinases, as previously described in different tissues.23,24 Our findings point to the involvement of a panel of MMPs including MMP-2 and MMP-9 in ischemia-induced angiogenesis but do not allow identification of all the specific MMPs involved in this process. This may be achieved by the development of selective inhibitors of individual MMPs or by the use of genetically modified mouse models.
Regulation of VEGF levels has been shown to be a major event in the angiogenic reaction associated with hindlimb ischemia.25 We have previously demonstrated that IL-10 modulates VEGF expression in this context.6 Therefore, the antiangiogenic effect of IL-10 appears to be mediated at least partly through the VEGF pathway. In the present study, we found that blockade of MMP activity completely attenuated the angiogenic process observed in ischemic leg of IL-10-/- mice despite sustained upregulation of VEGF. This finding is in agreement with previous studies showing that MMP activation or the presence of a cleavable collagen matrix is required for proangiogenic effect of growth factors.26,27 However, blockade of VEGF-related action using neutralizing antibody inhibits endogenous neovascularization in ischemic tissue,15 clearly indicating that VEGF is also crucial in the angiogenic process associated with hindlimb ischemia. Hence, it appears that both MMP- and VEGF-dependent mechanisms are required for ischemia-induced angiogenesis. In addition, our findings that MMPs are activated before VEGF expression suggest that matrix degradation is a rate-limiting event that is required for triggering the angiogenic process and sensitizing tissue to the effects of VEGF. Therefore, we believe that VEGF- and MMP-related pathways act cooperatively during the angiogenic process associated with hindlimb ischemia.
In conclusion, the present study shows an important role for IL-10 in the modulation of MMP activity in ischemic tissues and underscores the critical role of MMP activation, in a context of increased VEGF expression, in promoting ischemia-induced angiogenesis. Further studies are necessary to determine the specific MMPs involved in the process, the cellular type producing these proteases, and the cellular mechanisms driving MMP activation. Our results also underscore the putative beneficial advantage of therapeutic targeting of MMP activity in ischemic tissues.
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Acknowledgments |
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This work was supported by grants from Institut National de la Santé et de la Recherche Médicale and Université Paris VII.
Received March 13, 2001; accepted June 8, 2001.
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L. Waeckel, Z. Mallat, S. Potteaux, C. Combadiere, M. Clergue, M. Duriez, L. Bao, C. Gerard, B. J. Rollins, A. Tedgui, et al. Impairment in Postischemic Neovascularization in Mice Lacking the CXC Chemokine Receptor 3 Circ. Res., March 18, 2005; 96(5): 576 - 582. [Abstract] [Full Text] [PDF]
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R. Kawakami, Y. Saito, I. Kishimoto, M. Harada, K. Kuwahara, N. Takahashi, Y. Nakagawa, M. Nakanishi, K. Tanimoto, S. Usami, et al. Overexpression of Brain Natriuretic Peptide Facilitates Neutrophil Infiltration and Cardiac Matrix Metalloproteinase-9 Expression After Acute Myocardial Infarction Circulation, November 23, 2004; 110(21): 3306 - 3312. [Abstract] [Full Text] [PDF]
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F. Michel, M.-L. Ambroisine, M. Duriez, C. Delcayre, B. I. Levy, and J.-S. Silvestre Aldosterone Enhances Ischemia-Induced Neovascularization Through Angiotensin II-Dependent Pathway Circulation, April 27, 2004; 109(16): 1933 - 1937. [Abstract] [Full Text] [PDF]
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 M. KJAeR Role of Extracellular Matrix in Adaptation of Tendon and Skeletal Muscle to Mechanical Loading Physiol Rev, April 1, 2004; 84(2): 649 - 698. [Abstract] [Full Text] [PDF]
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 T. Yamamoto-Tabata, S. McDonagh, H.-T. Chang, S. Fisher, and L. Pereira Human Cytomegalovirus Interleukin-10 Downregulates Metalloproteinase Activity and Impairs Endothelial Cell Migration and Placental Cytotrophoblast Invasiveness In Vitro J. Virol., March 15, 2004; 78(6): 2831 - 2840. [Abstract] [Full Text] [PDF]
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V. Planat-Benard, J.-S. Silvestre, B. Cousin, M. Andre, M. Nibbelink, R. Tamarat, M. Clergue, C. Manneville, C. Saillan-Barreau, M. Duriez, et al. Plasticity of Human Adipose Lineage Cells Toward Endothelial Cells: Physiological and Therapeutic Perspectives Circulation, February 10, 2004; 109(5): 656 - 663. [Abstract] [Full Text] [PDF]
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R. Tamarat, J.-S. Silvestre, S. Le Ricousse-Roussanne, V. Barateau, L. Lecomte-Raclet, M. Clergue, M. Duriez, G. Tobelem, and B. I. Levy Impairment in Ischemia-Induced Neovascularization in Diabetes: Bone Marrow Mononuclear Cell Dysfunction and Therapeutic Potential of Placenta Growth Factor Treatment Am. J. Pathol., February 1, 2004; 164(2): 457 - 466. [Abstract] [Full Text] [PDF]
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 M. Strasly, G. Doronzo, P. Capello, D. Valdembri, M. Arese, S. Mitola, P. Moore, G. Alessandri, M. Giovarelli, and F. Bussolino CCL16 activates an angiogenic program in vascular endothelial cells Blood, January 1, 2004; 103(1): 40 - 49. [Abstract] [Full Text] [PDF]
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 T Hayashi, K Sohmiya, A Ukimura, S Endoh, T Mori, H Shimomura, M Okabe, F Terasaki, and Y Kitaura Angiotensin II receptor blockade prevents microangiopathy and preserves diastolic function in the diabetic rat heart Heart, October 1, 2003; 89(10): 1236 - 1242. [Abstract] [Full Text] [PDF]
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J.-S. Silvestre, R. Tamarat, T. G. Ebrahimian, A. Le-Roux, M. Clergue, F. Emmanuel, M. Duriez, B. Schwartz, D. Branellec, and B. I. Levy Vascular Endothelial Growth Factor-B Promotes In Vivo Angiogenesis Circ. Res., July 25, 2003; 93(2): 114 - 123. [Abstract] [Full Text] [PDF]
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 R. Tamarat, J.-S. Silvestre, M. Huijberts, J. Benessiano, T. G. Ebrahimian, M. Duriez, M.-P. Wautier, J. L. Wautier, and B. I. Levy Blockade of advanced glycation end-product formation restores ischemia-induced angiogenesis in diabetic mice PNAS, July 8, 2003; 100(14): 8555 - 8560. [Abstract] [Full Text] [PDF]
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 L. Cucullo, N. Marchi, M. Marroni, V. Fazio, S. Namura, and D. Janigro Blood-Brain Barrier Damage Induces Release of {alpha}2-Macroglobulin Mol. Cell. Proteomics, April 1, 2003; 2(4): 234 - 241. [Abstract] [Full Text] [PDF]
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 N. Vila, J. Castillo, A. Davalos, A. Esteve, A. M. Planas, and A. Chamorro Levels of Anti-Inflammatory Cytokines and Neurological Worsening in Acute Ischemic Stroke Stroke, March 1, 2003; 34(3): 671 - 675. [Abstract] [Full Text] [PDF]
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Z. Mallat, J.-S. Silvestre, S. Le Ricousse-Roussanne, L. Lecomte-Raclet, A. Corbaz, M. Clergue, M. Duriez, V. Barateau, S. Akira, A. Tedgui, et al. Interleukin-18/Interleukin-18 Binding Protein Signaling Modulates Ischemia-Induced Neovascularization in Mice Hindlimb Circ. Res., September 6, 2002; 91(5): 441 - 448. [Abstract] [Full Text] [PDF]
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A. Daugherty and D. L. Rateri T Lymphocytes in Atherosclerosis: The Yin-Yang of Th1 and Th2 Influence on Lesion Formation Circ. Res., May 31, 2002; 90(10): 1039 - 1040. [Full Text] [PDF]
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J.-S. Silvestre, R. Tamarat, T. Senbonmatsu, T. Icchiki, T. Ebrahimian, M. Iglarz, S. Besnard, M. Duriez, T. Inagami, and B. I. Levy Antiangiogenic Effect of Angiotensin II Type 2 Receptor in Ischemia-Induced Angiogenesis in Mice Hindlimb Circ. Res., May 31, 2002; 90(10): 1072 - 1079. [Abstract] [Full Text] [PDF]
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 I. Loftus and M. Thompson The role of matrix metalloproteinases in vascular disease Vascular Medicine, May 1, 2002; 7(2): 117 - 133. [Abstract] [PDF]
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 R. Tamarat, J.-S. Silvestre, N. Kubis, J. Benessiano, M. Duriez, M. deGasparo, D. Henrion, and B. I. Levy Endothelial Nitric Oxide Synthase Lies Downstream From Angiotensin II-Induced Angiogenesis in Ischemic Hindlimb Hypertension, March 1, 2002; 39(3): 830 - 835. [Abstract] [Full Text] [PDF]
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P. Libby and U. Schonbeck Drilling for Oxygen: Angiogenesis Involves Proteolysis of the Extracellular Matrix Circ. Res., August 3, 2001; 89(3): 195 - 197. [Full Text] [PDF]
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