Extracellular Matrix, a Hard Player in Angiogenesis

Abstract

The extracellular matrix (ECM) is a complex network of proteins, glycoproteins, proteoglycans, and polysaccharides. Through multiple interactions with each other and the cell surface receptors, not only the ECM determines the physical and mechanical properties of the tissues, but also profoundly influences cell behavior and many physiological and pathological processes. One of the functions that have been extensively explored is its impingement on angiogenesis. The strong impact of the ECM in this context is both direct and indirect by virtue of its ability to interact and/or store several growth factors and cytokines. The aim of this review is to provide some examples of the complex molecular mechanisms that are elicited by these molecules in promoting or weakening the angiogenic processes. The scenario is intricate, since matrix remodeling often generates fragments displaying opposite effects compared to those exerted by the whole molecules. Thus, the balance will tilt towards angiogenesis or angiostasis depending on the relative expression of pro- or anti-angiogenetic molecules/fragments composing the matrix of a given tissue. One of the vital aspects of this field of research is that, for its endogenous nature, the ECM can be viewed as a reservoir to draw from for the development of new more efficacious therapies to treat angiogenesis-dependent pathologies.

Keywords: angiogenesis; extracellular matrix; tumor microenvironment.

Figure 1

Schematic representation of key extracellular matrix (ECM) components involved in angiogenesis. On the left the major classes of ECM proteins that exert a role in angiogenesis are reported. The mechanism of growth factor release from ECM molecules through the action of proteases, activated upon angiogenic stimulus, is highlighted within the baby blue rectangle.

Figure 2

Schematic representation of the expression and degradation of MMRN2 during the steps involved in angiogenesis. (1) Following an angiogenic stimulus the basement membrane and MMRN2 are degraded by MMPs; (2) endothelial tip cells which drive sprouting angiogenesis are formed; (3) stalk cell proliferate and vessels’ lumen is formed; (4) ECs secrete MMRN2 stabilizing the vessels; (5) the quiescent state is restored.

Figure 3

EMILIN2 stimulates angiogenesis via an RTK-dependent cytokine production. Schematic representation of the molecular mechanisms elicited by EMILIN2. The molecule interacts directly with membrane receptors present in both ECs and fibroblast. This leads to the activation of an intracellular signaling cascade that results in the overproduction of angiogenic cytokines that, in turn, boost EC proliferation and migration.