Matrix and Matrix Metalloproteinases

In order for ECs to migrate, proliferate, and form tubes within the confines of any tissue, they must first forge a path through that tissue. This is achieved by the activation and secretion of matrix metalloproteinases (MMPs) that dissolve the extracellular matrix (ECM). The ECM comprises collagen, fibronectin, elastin, vitronectin, and proteoglycans. MMPs include interstitial collagenase (MMP-1), gelatinase A (MMP-2), stromelysin-1 (MMP-3), matrilysin (MMP-7), and gelatinase B (MMP-9). MMP activity, in turn, is regulated by tissue inhibitors of MMPs (TIMPs). Other proteases that have been implicated in mediating angiogenesis include urokinase-type plasminogen activator (u-PA).

In this context, constituents of the matrix exert a strong influence on angiogenesis. Collagen and procollagen, for example, are required physically for migration to occur. Proteoglycans (PGs), too, are axiomatic in mediating the proliferation and migration of ECs. ECs synthesize heparan sulfate, including the major endothelial extracellular matrix PG, perlecan, members of the syndecan family of transmembrane PGs, and the cell surface-associated PG, glypican-1. Vascular endothelial cells also constitu-tively synthesize and secrete the large aggregating chon-droitin sulfate PG, versican, and the small leucine-rich chondroitin/dermatan sulfate PG, biglycan. In addition, the expression of another small leucine-rich PG, decorin, is induced during formation of neovessels both in vitro and in vivo. Both high-molecular-weight hyaluronate and chon-droitin sulfate elicit a dose-dependent stimulation of tube formation. Heparanase promotes angiogenesis. Chondroitin sulfate is capable of binding fibrinogen/fibrin, thereby mediating endothelial cell migration and invasion into the fibrin provisional matrix during wound repair. Decorin expression seems to be of special importance for the survival of endothelial cells as well as for cord and tube formation. Heparan sulfate proteoglycans act as docking molecules for MMP-7 in the basement membrane.

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