Capillary growth in human skeletal muscle: physiological factors and the balance between pro-angiogenic and angiostatic factors.

In human skeletal muscle, the capillary net readily adapts according to the level of muscular activity to allow for optimal diffusion conditions for oxygen from the blood to the muscle. Animal studies have demonstrated that stimulation of capillary growth in skeletal muscle can occur either by mechanical or by chemical signalling. Mechanical signals originate from shear stress forces on the endothelial cell layer induced by the blood flowing through the vessel, but include also mechanical stretch and compression of the vascular structures and the surrounding tissue, as the muscle contracts. Depending on the mechanical signal provided, capillary growth may occur either by longitudinal splitting (shear stress) or by sprouting (passive stretch). The mechanical signals initiate angiogenic processes by up-regulation or release of angioregulatory proteins that either promote, modulate or inhibit angiogenesis. A number of such regulatory proteins have been described in skeletal muscle in animal and cell models but also in human skeletal muscle. Important pro-angiogenic factors in skeletal muscle are vascular endothelial growth factor, endothelial nitric oxide synthase and angiopoietin 2, whereas angiostatic factors include thrombospondin-1 and tissue inhibitor of matrix metalloproteinase. Which of these angiogenic factors are up-regulated in the muscle tissue depends on the mechanical and chemical stimulus provided and, consequently, the process by which capillary growth occurs. The present review addresses physiological signals and angiogenic factors in skeletal muscle with a focus on human data.