Translation of Pro-Angiogenic and Anti-Angiogenic Therapies into Clinical Use - Mechanical and Chemical Signaling in Angiogenesis - page 256

1 Introduction
Angiogenesis plays a pivotal role in human health and human disease. Elucidated by
the legendary biomedical scientist Judah Folkman [ 1 ], angiogenesis is the process of
vascular generation which enables blood supply to tissues. Sufficient vascular
supply is essential throughout life for the growth and maintenance of bodily
structures. Angiogenesis not only establishes a vascular network during embryonic
development, angiogenesis also operates following injuries to re-establish a
vascular network. Deficient angiogenesis can lead to abnormalities in would
healing, as well as insufficient recovery after an ischemic insult. Yet excessive
angiogenesis can also be pathological; such is the case in retinopathies, malignan-
cies, and inflammatory diseases [ 2 ]. Angiogenesis must therefore be tightly
regulated to achieve an appropriate balance: either too much or too little angio-
genesis results in disease (Fig. 1 ).
Indeed, imbalanced angiogenesis is a factor in several of the leading killers
worldwide [ 3 ], including coronary artery disease, stroke, emphysema, cancer, and
diabetes (Table 1 ). For instance, the clinical manifestations of diabetes mellitus
demonstrate the centrality and complexity of angiogenesis: the diabetic patient
simultaneously suffers inadequate angiogenesis in some tissues, along with excess
angiogenesis in other tissues. The result is that such patients concomitantly
experience impaired wound healing and ulcer formation due to insufficient
angiogenesis, with retinopathy and nephropathy due to excess angiogenesis [ 4 ].
The ubiquity of angiogenesis makes this process a prime target for novel thera-
peutics. Based on the World Health Organization's report of the Global Burden of
Disease [ 5 ], effective treatments that modulate angiogenesis could eliminate up to
31 % of all deaths globally, saving 18.3 million lives each year. Control of the
angiogenic process, through pro-angiogenic and anti-angiogenic therapies, there-
fore represents a breakthrough treatment paradigm which could address many of
the world's chronic diseases.
This chapter will provide an overview of the molecular biology and physiology
of angiogenesis, and delineate the major molecular targets of pro-angiogenic and
anti-angiogenic treatments. The chapter will then discuss the specific cases of pro-
angiogenic therapy for coronary artery disease, and anti-angiogenic therapy for
cancerous tumors; these cases are exemplary of the strategies and challenges of
angiogenesis-targeting agents. The chapter will describe current progress in
translating pro-angiogenic therapies and anti-angiogenic therapies into clinical
usage for these specific diseases; the discussion will include pre-clinical trials,
initial clinical trials, and large randomized trials. Finally, the chapter will identify
shortcomings of contemporary approaches, and suggest future basic research and
clinical research efforts for tuning angiogenesis to address clinical needs.