Chapter 40

### INTRODUCTION

Peripheral arterial disease (PAD) caused by atherosclerotic occlusions that impair blood flow to the lower extremity is now recognized as a major health care problem. Despite the growing enthusiasm and improvements in both surgical and percutaneous techniques to improve blood flow to ischemic lower extremities in PAD,1,2 a sizeable portion of patients with PAD, and especially those with critical limb ischemia (CLI), cannot benefit from these procedures because of diffuse atherosclerotic disease, poor distal conduits, or comorbid conditions that make them poor revascularization candidates. Angiogenesis can be defined as the growth and proliferation of blood vessels from existing vascular structures, while therapeutic angiogenesis is an investigational method designed to employ the growth of new blood vessels to improve the vascular supply of ischemic tissues.3,4 The purpose of this chapter is to review the evolution of gene therapy as a method to induce therapeutic angiogenesis in patients with PAD. To that end, we will review the mechanisms of new blood vessel growth, gene therapy vectors and delivery techniques, and human clinical trials that have used this technology to date. Finally, we discuss the recent studies of novel gene therapy approaches to therapeutic angiogenesis.

### BIOLOGY OF NEW BLOOD VESSEL FORMATION

#### Angiogenesis, Arteriogenesis, and Vasculogenesis

In the adult organism, blood vessel number is under tight biologic control. New blood vessel formation, or neovascularization, is an extremely complex process that is tightly regulated, both temporally and spatially, and involves the production and interaction of numerous cytokines and signaling molecules. Neovascularization can be categorized into three distinct components: angiogenesis, arteriogenesis, and vasculogenesis (Figure 40-1). Although the term angiogenesis is frequently used to describe the process of new blood vessel growth in general, it specifically denotes the sprouting of new capillaries from existing vascular structures.5 These capillary networks consist of only endothelial cell tubes and lack additional stabilizing components in the vessel wall. Angiogenesis can significantly expand the capillary bed, but the growth of larger vessels is often required to produce a significant increase in total blood flow. Tissue hypoxia or ischemia is considered the most important stimulus for angiogenesis.

###### FIGURE 40-1.

Mechanisms of neovascularization in the adult. (A) Angiogenesis describes the sprouting of new capillaries from existing structures. Smooth muscle cells (SMCs) and other stabilizing components of the vessel wall are necessary to produce mature vessels. (B) Vasculogenesis refers to the recruitment of EPCs from the bone marrow to areas of neovascularization. These cells may become incorporated into nascent capillaries or stimulate vessel growth via the local release of proangiogenic factors. (C) Arteriogenesis, or collateral vessel growth, denotes the maturation of existing collateral conduits upon occlusion of a supply vessel (e.g., by a thrombus). Sheer stress and monocyte recruitment are thought to result in the local production of cytokines that drives arteriogenesis.

Figure reproduced with permission from Carmeliet P. Manipulating angiogenesis in medicine. J Intern ...

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