Stimulation of Collateral Vessel Growth by Inhibition of Galectin 2 in Mice Using a Single‐Domain Llama‐Derived Antibody
Background In the presence of arterial stenosis, collateral artery growth (arteriogenesis) can alleviate ischemia and preserve tissue function. In patients with poorly developed collateral arteries, Gal‐2 (galectin 2) expression is increased. In vivo administration of Gal‐2 inhibits arteriogenesis....
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2019-10-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.119.012806 |
| _version_ | 1811321807501787136 |
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| author | Maurits R. Hollander Matthijs F. Jansen Luuk H. G. A. Hopman Edward Dolk Peter M. van de Ven Paul Knaapen Anton J. Horrevoets Esther Lutgens Niels van Royen |
| author_facet | Maurits R. Hollander Matthijs F. Jansen Luuk H. G. A. Hopman Edward Dolk Peter M. van de Ven Paul Knaapen Anton J. Horrevoets Esther Lutgens Niels van Royen |
| author_sort | Maurits R. Hollander |
| collection | DOAJ |
| description | Background In the presence of arterial stenosis, collateral artery growth (arteriogenesis) can alleviate ischemia and preserve tissue function. In patients with poorly developed collateral arteries, Gal‐2 (galectin 2) expression is increased. In vivo administration of Gal‐2 inhibits arteriogenesis. Blocking of Gal‐2 potentially stimulates arteriogenesis. This study aims to investigate the effect of Gal‐2 inhibition on arteriogenesis and macrophage polarization using specific single‐domain antibodies. Methods and Results Llamas were immunized with Gal‐2 to develop anti–Gal‐2 antibodies. Binding of Gal‐2 to monocytes and binding inhibition of antibodies were quantified. To test arteriogenesis in vivo, Western diet‐fed LDLR.(low‐density lipoprotein receptor)–null Leiden mice underwent femoral artery ligation and received treatment with llama antibodies 2H8 or 2C10 or with vehicle. Perfusion restoration was measured with laser Doppler imaging. In the hind limb, arterioles and macrophage subtypes were characterized by histology, together with aortic atherosclerosis. Llama‐derived antibodies 2H8 and 2C10 strongly inhibited the binding of Gal‐2 to monocytes (93% and 99%, respectively). Treatment with these antibodies significantly increased perfusion restoration at 14 days (relative to sham, vehicle: 41.3±2.7%; 2H8: 53.1±3.4%, P=0.016; 2C10: 52.0±3.8%, P=0.049). In mice treated with 2H8 or 2C10, the mean arteriolar diameter was larger compared with control (vehicle: 17.25±4.97 μm; 2H8: 17.71±5.01 μm; 2C10: 17.84±4.98 μm; P<0.001). Perivascular macrophages showed a higher fraction of the M2 phenotype in both antibody‐treated animals (vehicle: 0.49±0.24; 2H8: 0.73±0.15, P=0.007; 2C10: 0.75±0.18, P=0.006). In vitro antibody treatment decreased the expression of M1‐associated cytokines compared with control (P<0.05 for each). Atherosclerotic lesion size was comparable between groups (overall P=0.59). Conclusions Inhibition of Gal‐2 induces a proarteriogenic M2 phenotype in macrophages, improves collateral artery growth, and increases perfusion restoration in a murine hind limb model. |
| first_indexed | 2024-04-13T13:24:16Z |
| format | Article |
| id | doaj.art-cdfb4aae8dd24b3e9f75b612ca8e69bd |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-13T13:24:16Z |
| publishDate | 2019-10-01 |
| publisher | Wiley |
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| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-cdfb4aae8dd24b3e9f75b612ca8e69bd2022-12-22T02:45:13ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802019-10-0182010.1161/JAHA.119.012806Stimulation of Collateral Vessel Growth by Inhibition of Galectin 2 in Mice Using a Single‐Domain Llama‐Derived AntibodyMaurits R. Hollander0Matthijs F. Jansen1Luuk H. G. A. Hopman2Edward Dolk3Peter M. van de Ven4Paul Knaapen5Anton J. Horrevoets6Esther Lutgens7Niels van Royen8Department of Cardiology VU University Medical Centre Amsterdam The NetherlandsDepartment of Cardiology VU University Medical Centre Amsterdam The NetherlandsDepartment of Cardiology VU University Medical Centre Amsterdam The NetherlandsQVQ B.V. Utrecht The NetherlandsDepartment of Epidemiology and Biostatistics VU University Amsterdam The NetherlandsDepartment of Cardiology VU University Medical Centre Amsterdam The NetherlandsDepartment of Molecular Cell Biology and Immunology VU Medical Center Amsterdam The NetherlandsDepartment of Medical Biochemistry Academic Medical Centre Amsterdam The NetherlandsDepartment of Cardiology VU University Medical Centre Amsterdam The NetherlandsBackground In the presence of arterial stenosis, collateral artery growth (arteriogenesis) can alleviate ischemia and preserve tissue function. In patients with poorly developed collateral arteries, Gal‐2 (galectin 2) expression is increased. In vivo administration of Gal‐2 inhibits arteriogenesis. Blocking of Gal‐2 potentially stimulates arteriogenesis. This study aims to investigate the effect of Gal‐2 inhibition on arteriogenesis and macrophage polarization using specific single‐domain antibodies. Methods and Results Llamas were immunized with Gal‐2 to develop anti–Gal‐2 antibodies. Binding of Gal‐2 to monocytes and binding inhibition of antibodies were quantified. To test arteriogenesis in vivo, Western diet‐fed LDLR.(low‐density lipoprotein receptor)–null Leiden mice underwent femoral artery ligation and received treatment with llama antibodies 2H8 or 2C10 or with vehicle. Perfusion restoration was measured with laser Doppler imaging. In the hind limb, arterioles and macrophage subtypes were characterized by histology, together with aortic atherosclerosis. Llama‐derived antibodies 2H8 and 2C10 strongly inhibited the binding of Gal‐2 to monocytes (93% and 99%, respectively). Treatment with these antibodies significantly increased perfusion restoration at 14 days (relative to sham, vehicle: 41.3±2.7%; 2H8: 53.1±3.4%, P=0.016; 2C10: 52.0±3.8%, P=0.049). In mice treated with 2H8 or 2C10, the mean arteriolar diameter was larger compared with control (vehicle: 17.25±4.97 μm; 2H8: 17.71±5.01 μm; 2C10: 17.84±4.98 μm; P<0.001). Perivascular macrophages showed a higher fraction of the M2 phenotype in both antibody‐treated animals (vehicle: 0.49±0.24; 2H8: 0.73±0.15, P=0.007; 2C10: 0.75±0.18, P=0.006). In vitro antibody treatment decreased the expression of M1‐associated cytokines compared with control (P<0.05 for each). Atherosclerotic lesion size was comparable between groups (overall P=0.59). Conclusions Inhibition of Gal‐2 induces a proarteriogenic M2 phenotype in macrophages, improves collateral artery growth, and increases perfusion restoration in a murine hind limb model.https://www.ahajournals.org/doi/10.1161/JAHA.119.012806antibodycollateral circulationmacrophagemurine modelperfusion defect |
| spellingShingle | Maurits R. Hollander Matthijs F. Jansen Luuk H. G. A. Hopman Edward Dolk Peter M. van de Ven Paul Knaapen Anton J. Horrevoets Esther Lutgens Niels van Royen Stimulation of Collateral Vessel Growth by Inhibition of Galectin 2 in Mice Using a Single‐Domain Llama‐Derived Antibody Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease antibody collateral circulation macrophage murine model perfusion defect |
| title | Stimulation of Collateral Vessel Growth by Inhibition of Galectin 2 in Mice Using a Single‐Domain Llama‐Derived Antibody |
| title_full | Stimulation of Collateral Vessel Growth by Inhibition of Galectin 2 in Mice Using a Single‐Domain Llama‐Derived Antibody |
| title_fullStr | Stimulation of Collateral Vessel Growth by Inhibition of Galectin 2 in Mice Using a Single‐Domain Llama‐Derived Antibody |
| title_full_unstemmed | Stimulation of Collateral Vessel Growth by Inhibition of Galectin 2 in Mice Using a Single‐Domain Llama‐Derived Antibody |
| title_short | Stimulation of Collateral Vessel Growth by Inhibition of Galectin 2 in Mice Using a Single‐Domain Llama‐Derived Antibody |
| title_sort | stimulation of collateral vessel growth by inhibition of galectin 2 in mice using a single domain llama derived antibody |
| topic | antibody collateral circulation macrophage murine model perfusion defect |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.119.012806 |
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