ANG1 treatment reduces muscle pathology and prevents a decline in perfusion in DMD mice

Abstract

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.

Targeting angiogenesis in Duchenne muscular dystrophy

“…However, in this study, male dystrophic patients were compared to much older control subjects of both sexes. In contrast to DMD patients, decreased level of VEGF was noticed in gastrocnemius (GM) [ 71 ] and soleus [ 85 ] muscles of mdx mice as well as in the diaphragm of mdx /utrn −/− animals [ 86 ]. Moreover, transcriptome-based analysis of GM performed by our group revealed markedly diminished level of VEGF in mdx mice in comparison to wild-type animals (unpublished data).…”

“…Interestingly, the pro-fibrotic response of skeletal muscle fibroblasts isolated from 10-week-old mdx /utrn +/− mice to VEGF administration, with increased Acta2 expression encoding alpha-smooth muscle actin and enhanced stress-fiber formation, in comparison to untreated control fibroblasts was detected [ 108 ]. Moreover, also Gutpell et al [ 86 ] in another study have shown that although expression of VEGF is significantly decreased in the diaphragm (but not in GM) of mdx /utrn +/− mice, intramuscular, short-term delivery of low dose VEGF does not improve blood flow, as evidenced by applying dynamic contrast-enhanced computed tomography (DCE-CT). Hence, they undermined functional, pro-angiogenic effects of VEGF delivery and blunted an enthusiasm in the field of the potential use of VEGF alone as a treatment option for DMD.…”

“…Instead, they revealed that the administration of another growth factor, angiopoietin 1 (ANG1) alone or in combination with VEGF significantly increased functional parameters of perfusion, such as blood volume. Additionally, VEGF treatment resulted in higher collagen deposition in comparison to ANG1-treated mdx/ utrn +/− animals and ANG1 induced vessel maturation in mdx /utrn +/− hind limb muscle as compared to both sham-injected animals and VEGF-treated mice [ 86 ]. Thus, ANG1 might be another candidate for vascular-based therapy for DMD patients.…”

Therapeutic aspects of cell signaling and communication in Duchenne muscular dystrophy

“…A treatment based on a different growth factor, angiopoietin 1 (ANG1), combined with VEGF or alone, was also proposed. Notably, administration of ANG1 was shown to enhance muscle perfusion and slow the progression of fibrosis [130].…”

VEGFR-1/Flt-1 inhibition increases angiogenesis and improves muscle function in a mouse model of Duchenne muscular dystrophy

“… 8 There is evidence that modulation of VEGF signaling is a potential therapeutic option in DMD, 9 , 10 as seen in a number of animal models in which increased VEGF levels were associated with angiogenesis and reduced muscle injury. 11 However, efficacy appears to be limited following administration of VEGF alone, 12 and toxicities such as vascular leak and disorganized angiogenesis have been observed following VEGF administration. 13 , 14 Additionally, in vivo studies have shown that exogenous VEGF has a short half-life (t 1/2 ) of approximately 30 min, in part, due to its binding to Flt-1.…”