The physiological processes of angiogenesis, vasculogenesis and arteriogenesis contribute to the growth of collateral vessels in response to obstructive arterial disease causing lower limb or myocardial ischaemia, but in clinical practice the endogenous angiogenic response is often suboptimal or impaired, e.g. by factors such as ageing, diabetes or drug therapies. Therapeutic angiogenesis is an application of biotechnology to stimulate new vessel formation via local administration of pro-angiogenic growth factors in the form of recombinant protein or gene therapy, or by implantation of endothelial progenitor cells that will synthesize multiple angiogenic cytokines. Numerous experimental and clinical studies have sought to establish 'proof of concept' for therapeutic angiogenesis in PAD and myocardial ischaemia using different treatment modalities, but the results have been inconsistent. This review summarises the mechanisms of angiogenesis and the results of recent trials evaluating the efficacy and safety of different gene therapy, recombinant protein and cellular-based treatment approaches to enhance collateral vessel formation.

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The incidence of type 2 diabetes is increasing at an alarming rate; epidemiological studies indicate that by the year 2010 there will be 300 million people with type 2 diabetes worldwide. The rate of increase is highest in Asia and among young adults with obesity. On average, patients with diabetes live 5À10 years less than their non-diabetic counterparts, mainly because of accelerated atherosclerotic disease.A diagnosis of diabetes confers a two-to fourfold increased risk of intermittent claudication and a 10À16-fold increase in the lifetime risk of a lower limb amputation.

Intermittent claudication is a common, disabling symptom of peripheral arterial disease that limits walking distance and is associated with an increased cardiovascular risk of acute limb- or life-threatening complications. Very few patients with intermittent claudication (<7%) are suitable candidates for surgical revascularization, yet in contrast to the treatment of stable angina, few effective medical therapies (apart from exercise) are available for the symptomatic relief of intermittent claudication. The phosphodiesterase-3 inhibitor, cilostazol (Pletal, Otsuka Pharmaceuticals Ltd), is the first symptom-relieving treatment for intermittent claudication that has been evaluated successfully in large multicenter placebo-controlled, double-blind clinical trials (involving >2000 patients). A meta-analysis of the eight major efficacy studies with cilostazol has shown significant improvements in pain-free and maximum walking distance, and a good overall safety and tolerability profile. Thus, in the UK, USA and Japan, cilostazol administered at 100 mg twice daily is licensed for symptom relief in patients with stable, moderate-to-severe intermittent claudication, as an adjunct to nonpharmacological approaches such as exercise.

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