The lymphatic and blood vascular system penetrates every tissue and organ in order to supply cells with oxygen and nutrients, providing for fluids circulation and various signaling molecules. The emergence of the blood vascular system is one of the earliest events during embryogenesis and is called vasculogenesis. This involves vascular cells differentiating from undifferentiated precursors and forming the initial vascular network. The term angiogenesis is referred to the formation of new blood vessels from pre-existing ones. Angiogenesis is required for many pathological and physiological conditions, including embryonic development, tissue growth, tissue repair, wound healing, tumour growth and tissue regeneration (Goodwin, 2007; reviewed by Karamysheva, 2008).
A variety of events are involved during angiogenesis including activation of endothelial cells, degradation of both the endothelial basement membrane and surrounding ECM, endothelial proliferation and migration, followed by the assembly of endothelial cells into tubular structures with lumens. Finally, construction of the mural cell layer of the vessel wall, which consists of smooth muscle cells and pericytes occurs (Figure 1.7). A balance between pro- and anti-angiogenic agents regulate the whole process of angiogenesis including many pro- angiogenic growth factors such as vascular endothelial growth factor (VEGF), acidic and basic fibroblast growth factor (aFGF, bFGF), angiopoietin, platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) (Goodwin, 2007; Lamalice et al., 2007; reviwed by Karamysheva, 2008).
Figure 1.7 Schematic images of angiogenesis process. Angiogenesis is the formation of new blood vessels from pre-existing ones. Angiogenesis is a multistep process. Activated ECs migrate, proliferate, and re-organise into tubular structures with lumens. The recruitment of pericytes and SMCs to the vessel wall results in vessel maturation and stabilisation.
VEGF is the most well studied and potent growth factor, which plays a crucial role in regulating endothelial cell function. VEGF regulates proliferation and migration of endothelial cells during angiogenesis. Thus endothelial cells are the primary and most important constituents of vessels and have many essential functions during angiogenesis, including matrix degradation, migration, proliferation and morphogenesis (Goodwin, 2007; Lamalice et al., 2007; van Hinsbergh and Koolwijk, 2008).
There are some diseases related to angiogenesis in which the new blood vessels form and grow insufficiently or excessively. The generation of blood vessels are not only required for embryonic development but is also known to be involved in the pathogenesis of some diseases such as many cancers, rheumatoid arthritis and diabetic retinopathy. In these conditions, there is excessive formation of blood vessels, which can in turn damage normal tissues (Karagiannis and Popel, 2008). Angiogenesis is triggered during tumours growth and expansion. The induction of angiogenesis in cancer cells has been shown in many humans and animals models (Folkman, 1995; Khurana et al., 2005). Anti-angiogenic therapy has become an interesting and widely used approach. Avastin is an anti-angiogenic drug (antibody specific for VEGF) used in the treatment of some cancers (e.g. kidney, lung and ovarian cancers) and has been approved by the Federal Drug Administration (FDA) (Khurana et al., 2005).
1.9.1 Role of angiogenesis in cardiovascular disease
The coronary artery disease can be used as an example of insufficient angiogenesis. Left ventricular remodelling, dilation, myocyte hypertrophy and contractile dysfunction are some of the characteristic of MI. Infarct size is one major factor in ventricular remodelling. Myocyte loss happens as a result of infarction, which in turn causes ventricular dysfunction and myocyte hypertrophy. After the damage or blockage of blood vessels in coronary artery disease, there is insufficient oxygen and nutrient supply to cells like myocytes and this leads to tissue cell death. The angiogenesis process can re-vascularise the damaged tissue helping the deprived heart muscles regain sufficient blood flow (Maulik, 2004; Simons and Ware, 2003; Ucuzian and Greisler, 2007).
Therefore there is a need for angiogenesis after injury to the heart and coronary artery in order to repair the tissue damage to enable cardiac regeneration (Al Sabti, 2007). Therapeutic angiogenesis has proven to be a promising method for treatment of patients with CVD who are not responding well to conventional therapies (Al Sabti, 2007). Mechanical influences such as shear stress, chemical influences including hypoxia and NO production as well as molecular influences such as inflammation and angiogenic growth factors (e.g. VEGF, FGF and angiopoietin) are major angiogenesis triggering factors. Moreover, tissue ischemia and injury are factors stimulating angiogenesis and neovascularisation (Al Sabti, 2007). A variety of angiogenic therapies involving genes, proteins and cells are being investigated in patients with coronary heart diseases and myocardial infarction to stimulate angiogenesis thereby increasing perfusion of ischemic heart areas that are unable to re-vascularise (Chachques et al., 2004).
1.9.1.1 Effects of radiation in angiogenesis and wound healing
As mentioned before, radiotherapy also affects normal tissues surrounding the tumour leading to acute and long-term side effects. Moreover radiation induces EC changes and apoptosis followed by persistent decrease in capillary density. It has been observed in various studies that exposure of the vasculature to radiation results in inhibition of angiogenesis. Impaired angiogenesis and EC dysfunction could contribute to radiation-induced late tissue damage including tissue fibrosis and perturbed wound healing (Dormand et al., 2005; Imaizumi et al., 2010; Park et al., 2012). Impaired wound healing can be frequently observed in irradiated tissues. However the underlying molecular and cellular mechanisms including cytokines and growth factor interactions still needed to be studied in more detail (Haubner et al., 2012). Cardiac regeneration can occur after injury to the heart and this regeneration is dependent on angiogenesis, which plays a role in tissue repair. Therefore, angiogenesis is as an important feature of the reparative response, which can be triggered by microvascular injury to the heart and mediate cardiac regeneration. Radiation may compromise Cardiac EC (CEC) angiogenic functions since ECs play an important role during angiogenesis. Therefore, any damage to
endothelial cells may result in insufficient vascularisation, which in turn contributes to the development of cardiac diseases (Ucuzian and Greisler, 2007).