Therapeutic angiogenesis for peripheral artery disease: Cytokine therapy

Abstract

In recent years the importance of circulating bone marrow-derived cells in angiogenesis and collateral growth has been demonstrated in peripheral artery disease (PAD) and other ischaemic diseases. Although the mechanisms by which these cells exert their angiogenetic/arteriogenetic effects are not completely understood, improving the accumulation of bone marrow-derived cells at the site of vascular growth using cytokines has become one aim in some of the regenerative therapies. Interestingly, recent data indicate that in addition to effects attributed to such accumulated cells there are also direct effects of cytokines used via their receptors. Several investigations in animal hind limb models of ischaemia have demonstrated the beneficial effect of bone marrow mobilisation using colony-stimulating factors (CSF) on collateral growth and perfusion recovery. Clinical studies in PAD patients, however, are still rare and led to inconsistent data, in part due to different application protocols, choice of cytokine and low patient numbers with strong placebo effects. Moreover, the aetiology of the disease in humans differs markedly from the artificial occlusion of the femoral artery in a mostly healthy animal in the preclinical setting. Another approach to enhance arteriogenesis, which has been successful in animal models of hind limb ischaemia, is the local injection of the monocyte chemoattractant protein 1 (MCP-1). This treatment stimulated the invasion of monocytes leading to improved collateral growth and restoration of limb perfusion. Recent reports from animal experiments, in which both treatment strategies were combined (i.e. bone marrow mobilisation and enhancement of cell migration to the site of vascular growth), have shown strong synergistic effects, pointing at the importance to orchestrate the different processes involved in vascular repair in order to achieve maximal therapeutic effects.