Muscle‐derived SDF‐1α/CXCL12 modulates endothelial cell proliferation but is not required for exercise training‐induced angiogenesis

Chronic elevations in contractile activity, as observed with exercise training, increase capillarity density in skeletal muscle. Here, we demonstrate that the stromal cell‐derived factor‐1 alpha (SDF‐1α/CXCL12) is the most abundantly expressed angiogenesis‐associated chemokine in capillary‐rich oxidative soleus and exercise‐trained plantaris muscles. CXCL12 is also increased in muscle‐specific peroxisome proliferator‐activated receptor γ coactivator 1α transgenic mice (PGC‐1α mTg) when compared to wild‐type littermates. Additionally, CXCL12 is increased in C2C12 myotubes by cyclic mechanical stretch. Furthermore, exposure of human umbilical vein endothelial cells (HUVEC) to conditioned medium from cyclically stretched C2C12 myotubes enhanced cell proliferation. Such an effect was specific to CXCL12 signaling because co‐treatment with AMD3100, an antagonist of the CXCL12 receptor CXCR4, disrupted the proliferative response. To gain further insight into a potential role for CXCL12 in modulating chronic contractile activity‐induced angiogenesis in vivo , we studied muscle‐specific CXCL12 knockout mice (CXCL12 mKO). Interestingly, our results demonstrate that these mice have normal baseline capillary density and preserved angiogenesis when exercise‐trained. These findings are consistent with a muscle‐derived CXCL12‐dependent modulatory role of endothelial cell proliferation in response to increased contractile activity. However, muscle‐derived CXCL12 is not required for exercise training‐induced angiogenesis in skeletal muscle. Support or Funding Information This study was supported by Grant‐in‐Aid for Challenging Exploratory Research (16K13019) and Grant‐in‐Aid for Scientific Research (B) (15H03080) (18H03153) to Mitsuharu Okutsu. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .