Therapeutic Angiogenesis for Critical Limb Ischemia

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Abstract
Espite progressive insights into the pathologies underly- ing coronary, cerebral, and peripheral artery atheroscle- rosis, these conditions continue to cause critical tissue ische- mia and disability on an epidemic scale. For the past several decades, research and therapeutic development have focused on preventing or reversing occlusive disease in conduit vessels. The ultimate failure of macrovessel-targeted thera- pies is never more evident than in peripheral arterial disease, in which progressive disease leads to amputation at rates that have not changed significantly in 30 years. Despite modern therapy, up to 8 million Americans with peripheral arterial disease are devastated by immobility, intractable ischemia, ulceration, impaired wound healing, or amputation,1 and the lack of additional treatment options leaves many patients with little hope for relief. Article p 58 The concept of therapeutic angiogenesis evolved from pioneering work in the 1970s by Folkman,2 who observed that the development and maintenance of an adequate micro- vascular supply is essential for the growth of neoplastic tissue. His hypothesis that the inhibition of "tumor angiogenic factors" would be effective against solid tumors was met with widespread skepticism, but 30 years of persistent research led to the development and approval of antiangiogenic treatments that now constitute a significant portion of the anticancer armamentarium. Soon after the identification of angiogenic growth factors, cardiovascular investigators began testing the hypothesis that stimulating angiogenesis could improve per- fusion and function in ischemic tissues independent of mac- rovessel manipulation.3 Abundant preclinical data supported the safety and clinical potential of therapeutic angiogenesis that used growth factors or cellular-based strategies.4,5 Ac-