**3. Angiogenic growth factors**

94 Novel Insights on Chronic Kidney Disease, Acute Kidney Injury and Polycystic Kidney Disease

cyst growth in ADPKD has been likened to growth of a benign tumor (Grantham & Calvet, 2001). Indeed, there are many similarities between tumor growth and cyst growth, both processes being marked by increased cell proliferation, changes in apoptosis, and angiogenesis. In this chapter we will focus on the process of angiogenesis, defined as the growth of new blood vessels by invasion and sprouting of the existing vessels, as distinct

In order to understand the various signals and processes that define angiogenesis it is necessary to consider the main function of blood vessels, namely the supply of oxygen and nutrients to all the cells in the body. Much of our current knowledge of angiogenesis stems from studies of tumor biology. The fact that the diffusion limit of oxygen is approximately 100m indicates that all blood vessels must be located within 100-200 m of mammalian cells to ensure viability (Torres Filho et al., 1994). Subsequent studies by Judah Folkman et al. determined that tumor growth beyond 1-2-mm was angiogenesis dependent (Folkman, 2006). In health the endothelial cells that line the blood vessel lumen and the pericytes that surround the outer surface of the endothelial cells are in a "quiescent " state. This state is maintained by a balance of "pro" and anti-angiogenic growth factors that include vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and various other chemokines and growth factors. Angiogenesis in the adult is defined by sprout formation or by splitting of a pre-existing blood vessel (Persson & Buschmann, 2011). The process of angiogenesis proceeds in several distinct stages and is initiated by a decrease in partial pressure of oxygen, which is detected by oxygen sensors on the endothelial cell. In the ADPKD kidney the growing cysts compress the renal vasculature resulting in decreased oxygenation. Hypoxia results in stabilization of the hypoxia-inducible factor (HIF-1). The HIF family, which in addition to HIF-1, also includes HIF-2 and HIF-3 are transcription factors. Structurally the HIF's comprise of a heterodimer of a regulatory subunit and a constitutively expressed subunit (Wang & Semenza, 1995). Angiogenesis is initiated by binding of HIF-1 to a hypoxia response element in the promoter of an angiogenic growth factor such as VEGF as reviewed by Hoeben et al. (Hoeben et al., 2004). In the case of new vascular sprout formation, when an angiogenic signal is detected by a quiescent blood vessel, the pericytes detach from the blood vessel wall and from the basement membrane. This is mediated by metalloproteinase (MMP) induced proteolytic degradation (Persson & Buschmann, 2011). Endothelial cells undergo several changes, loosening their cell junctions and allowing dilation of the vessel. VEGF increases endothelial cell permeability allowing escape of plasma proteins and formation of a provisional extracellular matrix (ECM). Endothelial cells next migrate onto the ECM surface mediated by integrin. Degradation of the ECM by proteases releases additional angiogenic growth factors from the ECM providing an angiogenic gradient that mediates migration and proliferation of the endothelial cells. One endothelial cell called a "tip cell" is instrumental in leading the migration, ECM degradation and consequent direction of growth of the vascular sprout. Maturation of the vessel requires return of the endothelial cells to a quiescent state, pericytes to attach and cover the vessel and down regulation of proteases by expression of tissue inhibitors of metalloproteinases (TIMP's). These changes are mediated by downregulated expression of VEGF and increased levels of Ang-1, transforming growth factor (TGF-),

from embryonic vasculogenesis or de novo growth of blood vessels.

and platelet derived growth factor (PDGF) (Chung et al., 2010).

**2. Angiogenesis** 

In this section we will describe some of the most important angiogenic growth factors and their respective receptors with emphasis on the role of VEGF, Ang-1, and Ang-2 in the kidney in health and disease.
