Membrane-type matrix metalloproteinase-mediated angiogenesis in a fibrin-collagen matrix

Abstract

IntroductionAngiogenesis in the adult is associated with specific conditions such as tissue ischemia and wound repair, in which the formation of new blood vessels is temporally and spatially controlled. Tissue injury causes damage of blood vessels and the extravasation of plasma proteins, including fibrinogen, which results in the formation of a fibrin clot in the surrounding interstitium. This extracellular matrix of extravasated fibrin entangled with the existing collagen fibers is furthermore composed of a number of proteins such as vitronectin, fibronectin, laminin, hyaluronic acid, and proteoglycans. The fibrinous matrix formed serves as a provisional matrix, into which cells can infiltrate during the subsequent wound healing. [1][2][3] During the formation of a granulation tissue, a dynamic interaction between microvascular endothelial cells (MVECs) and the surrounding extracellular matrix occurs. The cells disrupt existing cell-matrix interactions and locally degrade the surrounding extracellular matrix; they migrate, proliferate, and form new capillarylike tubular structures, which become stabilized in the course of time. 4,5 The temporary fibrin matrix can be degraded by plasmin, which is activated from its zymogen by 2 types of plasminogen activators, tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). 6 The activity of u-PA is directed to the cell surface by a cellular u-PA receptor (u-PAR). 7 In vitro 8,9 and in vivo 10,11 studies have shown that the u-PA/plasmin system plays a critical role in the process of angiogenesis. In addition to the u-PA/plasmin system, matrix metalloproteinases (MMPs) are also involved in the degradation of the extracellular matrix. [10][11][12][13][14][15] A role for both u-PA/plasmin and MMP systems in angiogenesis is supported by the fact that different components in the extracellular matrix are substrates for plasmin as well as for MMPs, including fibrin, 16 vitronectin, fibronectin, laminin, gelatins, and proteoglycans, whereas plasmin is unable to degrade collagens. 17 Furthermore, endothelial cells at the leading edge of a new blood vessel concomitantly express components of both protease systems, [18][19][20] and their expression is regulated by the same growth factors and cytokines. [21][22][23][24] MMPs are a family of zinc-dependent enzymes that can be divided into 2 structurally distinct groups, the secreted MMPs and the membrane-type MMPs (MT-MMPs). The MMPs are secreted as inactive zymogens, and in vitro studies have shown that the u-PA/plasmin system located at the cell membrane directly or indirectly activates a number of pro-MMPs, such as pro-MMP-1, pro-MMP-3, pro-MMP-9, pro-MMP-10, and pro-MMP-13. 25,26 In addition to zymogen activation, MMP activity is regulated by tissue inhibitors of metalloproteinases (TIMPs), of which to date 4 types have been characterized. 27 MT-MMPs, of which 6 types are known, are transmembrane proteins that are activated intracellularly in the secretory pathway by furinlike enzymes. 28-30 MT1...

Role of TGF-β1 and JNK signaling in capillary tube patterning

“…explants and micro-and macrovascular endothelial cells (11,23,32). The results reported in this study do not indicate that the MMPs analyzed play a direct role in capillary tube patterning.…”

Anti-Plasminogen Antibodies Compromise Fibrinolysis and Associate with Renal Histology in ANCA-Associated Vasculitis

“…It is possible that fibrinoid necrosis is in fact an aberrant repair mechanism that follows vascular injury. This hypothesis would account for histologic and compositional similarities between fibrinoid necrosis and conventional fibrin clots 5,6 and explain the importance of the fibrinolytic system in renal injury, as shown by animal models of rapidly progressive glomerulonephritis. 7,8 Under these circumstances, down-regulation of fibrinolysis by anti-plasminogen antibodies in AAV patients would promote persistent or extensive fibrinoid necrosis.…”

Nutritional factors and progenitor cell differentiation

“…All such events may decide about priming of endothelial cell and its progenitors for migration [24,25]. Beta-carotene, also by stimulation GPCRs (G-protein coupled receptors) and its activators could lead to activation of Rho/Rac/CDC42 small GTPases, and as result of this activation regulate cytoskeletal changes involved in cell migration [26,27].…”