Gutpell Kelly M, Tasevski Nikola, Wong Boaz, Hrinivich William Thomas, Su Feng, Hadway Jennifer, Desjardins Lise, Lee Ting-Yim, Hoffman Lisa Marie
Lawson Health Research Institute, London, Ontario, Canada.
Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada.
PLoS One. 2017 Mar 23;12(3):e0174315. doi: 10.1371/journal.pone.0174315. eCollection 2017.
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.
血管内皮生长因子（VEGF）和其他促血管生成生长因子已被研究用于增强杜氏肌营养不良症（DMD）患者的肌肉组织灌注和修复。目前的认识受到这些生长因子体内递送后缺乏功能数据的限制。我们之前使用动态对比增强计算机断层扫描来监测DMD小鼠模型中的疾病进展，但迄今为止尚无研究利用这种成像技术评估DMD临床前模型中的血管治疗。在当前研究中，我们将VEGF和ANG1单独或联合局部递送至营养不良的后肢骨骼肌。通过功能成像，我们发现联合治疗以及单独使用ANG1可防止肌肉灌注下降，而与对照组相比，单独使用VEGF则没有效果。与假手术组相比，接受VEGF+ANG1或单独接受ANG1治疗的肌肉中α-平滑肌肌动蛋白阳性血管增加，组织学验证了这些发现。我们进一步表明，与假手术或VEGF治疗相比，单独使用ANG1可减缓纤维化进程。这项研究的结果为血管治疗的功能效应提供了新的见解，并表明单独使用ANG1可能是治疗DMD的候选疗法。
