Angiogenesis and myogenesis as two facets of inflammatory post-ischemic tissue regeneration

Abstract

Ischemia is known to promote angiogenesis, and the molecular mechanisms and growth factors involved have been thoroughly investigated. Less attention has been paid to the cellular interactions between proliferating capillaries, inflammatory cells and muscle tissue. In the present investigation, we examined ischemia-induced cell injury and subsequent spontaneous regeneration in relation to angiogenesis and myogenesis. Balb/C mice were anesthetized, and the right femoral artery was occluded proximal to the origin of the arteria poplitea; the left femoral artery was sham-operated. One hour to 3 weeks after occlusion, the ischemic burden was assessed by quantifying the lower hindlimb muscle content of high energy phosphates, nucleosides, NAD+, glycogen and lactate. In vivo uptake of propidium iodide was used as a marker of cell injury. Proliferation of different cell types was evaluated immunomorphologically. As soon as 4 h after occlusion, morphological alterations in lower leg muscle occurred. Rupture of sarcolemma and loss of the contractile filaments were followed by plasma exudation, edema and infiltration of leukocytes, which target myofibers. During the first 12 h after occlusion, high energy phosphate and glycogen content decreased gradually. Levels remained low until day 3 and recovered almost completely until day 21. Nucleoside and lactate content peaked between 6 and 12 h following occlusion. Three days after occlusion, mitotic activity began in endothelial and muscle satellite cells, resulting in new formation of capillaries and muscle fibers. Angiogenesis and myogenesis occur concomitantly in regenerating skeletal muscle because of ischemia-induced cell death and inflammation. (Mot Cell Biochem 246: 57-68, 2003)