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Angiogenic impairment of the vascular endothelium: a novel mechanism and potential therapeutic target in muscular dystrophy.
- Source :
-
Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2013 Dec; Vol. 33 (12), pp. 2867-76. Date of Electronic Publication: 2013 Sep 26. - Publication Year :
- 2013
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Abstract
- Objective: Dystrophin, the missing or defective protein in Duchenne muscular dystrophy, is expressed not only in muscle cells but also in vascular endothelial cells (ECs). In this study, we assessed the effects of dystrophin deficiency on the angiogenic capacities of ECs.<br />Approach and Results: We isolated vascular ECs from mdx mice, the murine equivalent of Duchenne muscular dystrophy in humans, and wild-type controls, and we found that mdx-derived ECs have impaired angiogenic properties, in terms of migration, proliferation, and tube formation. They also undergo increased apoptosis in vitro compared with wild-type cells and have increased senescence-associated β-galactosidase activity. Mdx-derived ECs also display reduced ability to support myoblast proliferation when cocultured with satellite cell-derived primary myoblasts. These endothelial defects are mirrored by systemic impairment of angiogenesis in vivo, both on induction of ischemia, stimulation with growth factors in the corneal model and matrigel plug assays, and tumor growth. We also found that dystrophin forms a complex with endothelial NO synthase and caveolin-1 in ECs, and that NO production and cGMP formation are compromised in ECs isolated from mdx mice. Interestingly, treatment with aspirin enhances production of both cGMP and NO in dystrophic ECs, whereas low-dose aspirin improves the dystrophic phenotype of mdx mice in vivo, in terms of resistance to physical exercise, muscle fiber permeability, and capillary density.<br />Conclusions: These findings demonstrate that impaired angiogenesis is a novel player and potential therapeutic target in Duchenne muscular dystrophy.
- Subjects :
- Animals
Apoptosis
Aspirin pharmacology
Carcinoma, Lewis Lung blood supply
Carcinoma, Lewis Lung metabolism
Carcinoma, Lewis Lung pathology
Caveolin 1 metabolism
Cell Movement
Cell Proliferation
Cells, Cultured
Cellular Senescence
Coculture Techniques
Corneal Neovascularization metabolism
Corneal Neovascularization pathology
Corneal Neovascularization physiopathology
Cyclic GMP metabolism
Disease Models, Animal
Dystrophin genetics
Endothelial Cells drug effects
Endothelial Cells pathology
Endothelium, Vascular drug effects
Endothelium, Vascular pathology
Endothelium, Vascular physiopathology
Ischemia metabolism
Ischemia pathology
Ischemia physiopathology
Mice
Mice, Inbred mdx
Muscular Dystrophy, Duchenne drug therapy
Muscular Dystrophy, Duchenne genetics
Muscular Dystrophy, Duchenne pathology
Muscular Dystrophy, Duchenne physiopathology
Mutation
Myoblasts, Skeletal metabolism
Myoblasts, Skeletal pathology
Neovascularization, Pathologic
Nitric Oxide metabolism
Nitric Oxide Synthase Type III metabolism
Time Factors
Dystrophin metabolism
Endothelial Cells metabolism
Endothelium, Vascular metabolism
Muscular Dystrophy, Duchenne metabolism
Neovascularization, Physiologic drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4636
- Volume :
- 33
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Arteriosclerosis, thrombosis, and vascular biology
- Publication Type :
- Academic Journal
- Accession number :
- 24072696
- Full Text :
- https://doi.org/10.1161/ATVBAHA.112.301172