Integrins and Angiogenesis

Abstract

The growth of new blood vessels is a dynamic yet highly regulated process that depends on coordinated signaling by growth factor and cell adhesion receptors. As part of the molecular program regulating angiogenesis, endothelial cells acquire a proliferative and invasive phenotype but also show increased susceptibility to apoptotic stimuli. Integrins are the principle adhesion receptors used by endothelial cells to interact with their extracellular microenvironment, and integrin-mediated interactions play a critical role in regulating cell proliferation, migration, and survival. Alterations in the repertoire and⧸or activity of integrins, as well as the availability and structural property of their ligands, regulate the vascular cell during the growth or repair of blood vessels.

Introduction

Blood vessels develop from at least two processes, termed vasculogenesis and angiogenesis (Isner and Asahara, 1999). Vasculogenesis is the process by which blood vessels form de novo, during development, as the nascent vascular bed arises from hematopoietic precursor angioblasts (Drake et al., 1995). By contrast, angiogenesis occurs as the growth or sprouting of new blood vessels from a pre-existing vascular bed. Although angiogenesis is generally accepted to be the principle mechanism of blood vessel growth within the adult, it has recently become clear that the recruitment of hematopoietic precursors is a critical event during angiogenesis, suggesting a previously unsuspected vasculogenic component (Ribatti et al., 2001). Thus, the distinction between these processes has blurred somewhat, and many of the mechanisms that regulate angiogenesis may be common to both processes (Rupp et al., 2003).

Neovascularization is a tightly regulated process during development and wound repair but appears considerably less regulated during pathological angiogenesis associated with cancer and inflammatory disease. However, normal or “unactivated” blood vessels in the adult are relatively quiescent and nonproliferative. The endothelial cells lining the inner surface of the blood vessels maintain tight cell–cell junctions and stable interactions with the underlying extracellular matrix (ECM), or basement membrane. These endothelial cells exhibit a very low mitotic index. Cell cycle entry occurs in only about 1 in 1000 cells, replacing endothelial cells lost through routine attrition (Folkman and Klagsbrun, 1987). In contrast to this resting state, endothelial cells stimulated with angiogenic growth factors such as vascular endothelial cell growth factor (VEGF) (Dvorak 1995, Ferrara 2003) or basic fibroblast growth factor (bFGF) (Folkman et al., 1988) become highly proliferative, achieving mitotic indices similar to growing tumors. Concomitant with accelerated proliferation, increased transcription and protein synthesis also occur, as endothelial cells prepare for cell migration⧸invasion and neovessel outgrowth.

In addition to the increased expression of cell cycle proteins, angiogenic endothelial cells express a repertoire of new proteins, including transcription factors such as Hox (Myers et al., 2000) and Id genes (Benezra et al., 2001), which in turn regulate the expression of integrins and production of new provisional ECM components, matrix-proteolyzing enzymes (Heissig et al., 2003), their inhibitors (Mannello and Gazzanelli, 2001), as well as growth factors and apoptosis-regulating proteins (reviewed in Dimmeler and Zeiher, 2000). Physiologically, angiogenic endothelial cells exhibit an increased capacity to proliferate and invade tissue, but perhaps somewhat surprisingly, demonstrate an increased predisposition to undergo apoptosis (Brooks 1994a, Brooks 1994b). Previous reports suggested that proper blood vessel formation depends on a balance between endothelial cell proliferation and apoptosis (reviewed in Stupack and Cheresh, 2003). The regulation of these processes is closely tied to remodeling events in the local ECM and to integrins that enable endothelial cells to respond to the ECM.