Angiogenic impairment of the vascular endothelium: a novel mechanism and potential therapeutic target in muscular dystrophy.
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.


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.


CONCLUSIONS
These findings demonstrate that impaired angiogenesis is a novel player and potential therapeutic target in Duchenne muscular dystrophy.
From the Division of Cardiovascular Research, Department of Medicine (M.P., V.N., R.C.S., M.S., R.P.), and Center of Cancer Systems Biology (R.C.S., L.H., R.P.), St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA; Laboratory of Vascular Biology and Genetics and Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy (M.P., I.G., V.N., E.G., M.M., I.G., E.S., R.L., R.P.); and Laboratory of Vascular Pathology, IDI Research Institute, Rome, Italy (S.S., M.C.).
Mariangela
M
Palladino
Ilaria
I
Gatto
Valentina
V
Neri
Stefania
S
Straino
Roy C
RC
Smith
Marcy
M
Silver
Eleonora
E
Gaetani
Margherita
M
Marcantoni
Igor
I
Giarretta
Egidio
E
Stigliano
Maurizio
M
Capogrossi
Lynn
L
Hlatky
Raffaele
R
Landolfi
Roberto
R
Pola
D000818:Animals; D017209:Apoptosis; D001241:Aspirin / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D051242:Caveolin 1 / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D018920:Coculture Techniques; D016510:Corneal Neovascularization / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007511:Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D032448:Myoblasts, Skeletal / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D013997:Time Factors
C495541:Cav1 protein, mouse; D051242:Caveolin 1; D016189:Dystrophin; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D006152:Cyclic GMP; D001241:Aspirin
angiogenesis inhibitors; endothelium, vascular; muscle diseases, inflammatory; nitric oxide synthase type III