Mesenchymal stem cells contribute to vascular growth in skeletal muscle in response to eccentric exercise

Huntsman HD, Zachwieja N, Zou K, Ripchik P, Valero MC, De Lisio M, Boppart MD. Mesenchymal stem cells contribute to vascular growth in skeletal muscle in response to eccentric exercise. Am J Physiol Heart Circ Physiol 304: H72-H81, 2013. First published October 26, 2012; doi:10.1152/ajpheart.00541.2012.-The alpha(7)beta(1)-integrin is an adhesion molecule highly expressed in skeletal muscle that can enhance regeneration in response to eccentric exercise. We have demonstrated that mesenchymal stem cells (MSCs), predominantly pericytes, accumulate in muscle (mMSCs) overexpressing the alpha(7B)-integrin (MCK:alpha(7B); alpha(7)Tg) and contribute to new fiber formation following exercise. Since vascularization is a common event that supports tissue remodeling, we hypothesized that the alpha(7)-integrin and/or mMSCs may stimulate vessel growth following eccentric exercise. Wild-type (WT) and alpha(7)Tg mice were subjected to single or multiple (3 times/wk, 4 wk) bouts of downhill running exercise. Additionally, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) -labeled mMSCs were intramuscularly injected into WT recipients. A subset of recipient mice were run downhill before injection to recapitulate the exercised microenvironment. While total number of CD31(+) vessels declined in both WT and alpha(7)Tg muscle following a single bout of exercise, the number of larger CD31(+) vessels with a visible lumen was preferentially increased in alpha(7)Tg mice following eccentric exercise training (P < 0.05). mMSC transplantation similarly increased vessel diameter and the total number of neuron-glial antigen-2 (NG2(+)) arterioles postexercise. Secretion of arteriogenic factors from mMSCs in response to mechanical strain, including epidermal growth factor and granulocyte macrophage-colony stimulating factor, may account for vessel remodeling. In conclusion, this study demonstrates that the alpha(7)-integrin and mMSCs contribute to increased vessel diameter size and arteriolar density in muscle in response to eccentric exercise. The information in this study has implications for the therapeutic treatment of injured muscle and disorders that result in vessel occlusion, including peripheral artery disease.