Muscle-derived SDF-1α/CXCL12 modulates endothelial cell proliferation but not exercise training-induced angiogenesis

Author:

Yamada Mami1,Hokazono Chihiro1,Tokizawa Ken2,Marui Shuri3,Iwata Masahiro4,Lira Vitor A.5,Suzuki Katsuhiko6,Miura Shinji7,Nagashima Kei3,Okutsu Mitsuharu1

Affiliation:

1. Graduate School of Natural Sciences, Nagoya City University, Nagoya, Japan

2. National Institute of Occupational Safety and Health, Tokyo, Japan

3. Faculty of Human Sciences, Waseda University, Tokorozawa, Japan

4. Faculty of Health Sciences, Department of Rehabilitation, Nihon Fukushi University, Handa, Japan

5. Department of Health & Human Physiology, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa

6. Faculty of Sport Sciences, Waseda University, Tokorozawa, Japan

7. Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, Shizuoka, Japan

Abstract

Chemokines are critical mediators of angiogenesis in several physiological and pathological conditions; however, a potential role for muscle-derived chemokines in exercise-stimulated angiogenesis in skeletal muscle remains poorly understood. Here, we postulated that the chemokine stromal cell-derived factor-1 (SDF-1α/C-X-C motif chemokine ligand 12: CXCL12), shown to promote neovascularization in several organs, contributes to angiogenesis in skeletal muscle. We found that CXCL12 is abundantly expressed in capillary-rich oxidative soleus and exercise-trained plantaris muscles. CXCL12 mRNA and protein were also abundantly expressed in muscle-specific peroxisome proliferator-activated receptor γ coactivator 1α transgenic mice, which have a high proportion of oxidative muscle fibers and capillaries when compared with wild-type littermates. We then generated CXCL12 muscle-specific knockout mice but observed normal baseline capillary density and normal angiogenesis in these mice when they were exercise trained. To get further insight into a potential CXCL12 role in a myofiber-endothelial cell crosstalk, we first mechanically stretched C2C12 myotubes, a model known to induce stretch-related chemokine release, and observed increased CXCL12 mRNA and protein. Human umbilical vein endothelial cells (HUVECs) exposed to conditioned medium from cyclically stretched C2C12 myotubes displayed increased proliferation, which was dependent on CXCL12-mediated signaling through the CXCR4 receptor. However, HUVEC migration and tube formation were unaltered under these conditions. Collectively, our findings indicate that increased muscle contractile activity enhances CXCL12 production and release from muscle, potentially contributing to endothelial cell proliferation. However, redundant signals from other angiogenic factors are likely sufficient to sustain normal endothelial cell migration and tube formation activity, thereby preserving baseline capillary density and exercise training-mediated angiogenesis in muscles lacking CXCL12.

Funder

Japan Society for the Promotion of Science

The Descent and Ishimoto Memorial Foundation

Publisher

American Physiological Society

Subject

Physiology (medical),Physiology

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