ANG1 treatment reduces muscle pathology and prevents a decline in perfusion in DMD mice.
Vascular endothelial growth factor (VEGF) and other pro-angiogenic growth factors have been investigated to enhance muscle tissue perfusion and repair in Duchenne muscular dystrophy (DMD). Current understanding is limited by a lack of functional data following in vivo delivery of these growth factors. We previously used dynamic contrast-enhanced computed tomography to monitor disease progression in murine models of DMD, but no study to date has utilized this imaging technique to assess vascular therapy in a preclinical model of DMD. In the current study, we locally delivered VEGF and ANG1 alone or in combination to dystrophic hind limb skeletal muscle. Using functional imaging, we found the combination treatment as well as ANG1 alone prevented decline in muscle perfusion whereas VEGF alone had no effect compared to controls. These findings were validated histologically as demonstrated by increased alpha-smooth muscle actin-positive vessels in muscles that received either VEGF+ANG1 or ANG1 alone compared to the sham group. We further show that ANG1 alone slows progression of fibrosis compared to either sham or VEGF treatment. The findings from this study shed new light on the functional effects of vascular therapy and suggest that ANG1 alone may be a candidate therapy in the treatment of DMD.
Lawson Health Research Institute, London, Ontario, Canada.|Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada.
Kelly M
http://orcid.org/0000-0003-4808-0655
KM
Gutpell
Lawson Health Research Institute, London, Ontario, Canada.
Nikola
N
Tasevski
Lawson Health Research Institute, London, Ontario, Canada.
Boaz
B
Wong
Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada.|Robarts Research Institute, London, Ontario, Canada.
William Thomas
WT
Hrinivich
Robarts Research Institute, London, Ontario, Canada.
Feng
F
Su
Lawson Health Research Institute, London, Ontario, Canada.
Jennifer
J
Hadway
Lawson Health Research Institute, London, Ontario, Canada.
Lise
L
Desjardins
Lawson Health Research Institute, London, Ontario, Canada.|Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada.|Robarts Research Institute, London, Ontario, Canada.
Ting-Yim
TY
Lee
Lawson Health Research Institute, London, Ontario, Canada.|Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada.|Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada.
Lisa Marie
LM
Hoffman
D042683:Angiopoietin-1 / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D051379:Mice; D008853:Microscopy; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology*; D020388:Muscular Dystrophy, Duchenne / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D011994:Recombinant Proteins; D014057:Tomography, X-Ray Computed / Q000379:methods; D042461:Vascular Endothelial Growth Factor A / Q000627:therapeutic use
D042683:Angiopoietin-1; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A