ECM Remodeling in Angiogenesis

Abstract

Remodeling of the extracellular matrix (ECM) is an essential component of the complex vascular biology that drives each step within the angiogenic cascade. The process of angiogenesis involves a series of events that depend heavily on proteinases and their ability to remodel the ECM, originating with degradation of the basement membrane to allow for endothelial cell (EC) breakthrough, migration, and proliferation. This is followed by organization into nascent blood vessel sprouts, vessel maturation and stabilization, deposition of basement membrane around the new vessels, and finally pruning or remodeling of the new vasculature for physiological needs. There is evidence that ECs cooperate with supporting stromal cells to orchestrate these remodeling events and ultimately to create pericyte-stabilized functional networks of vessels. During angiogenesis, proteinases not only directly breakdown the ECM to create a physical path for new EC sprouts, they also indirectly expose cryptic sites hidden within the ECM to alter the adhesive microenvironment for pericytes and endothelial cells during sprouting. Physiological control of angiogenesis is achieved in part by the angiogenic switch, in which a balance of pro- and anti-angiogenic factors serves to maintain vessel homeostasis under normal conditions. Proteinases, and certain matrix metalloproteinases (MMPs) in particular, function on both sides of the angiogenic switch. They degrade the basement membrane and nearby ECM surrounding established blood vessels at the onset of angiogenesis, and release pro-angiogenic growth factors that would remain otherwise bound to the ECM. However, they also negatively control angiogenesis, as some proteolytic fragments of the ECM possess anti-angiogenic properties. In addition to the chemical specificity of proteinases, emerging evidence suggests that their ability to proteolytically remodel the ECM during angiogenesis may also depend on the physical properties of the ECM. In this chapter, we will discuss the important factors that govern ECM remodeling during angiogenesis, focusing on the links between proteinases, stromal cells, and matrix physical properties. The impact of these possible links on therapeutic and pathologic angiogenesis will also be discussed.