Matrix Metalloproteinases Generate Angiostatin: Effects on Neovascularization

Abstract

Angiostatin, a cleavage product of plasminogen, has been shown to inhibit endothelial cell proliferation and metastatic tumor cell growth. Recently, the production of angiostatin has been correlated with tumor-associated macrophage production of elastolytic metalloproteinases in a murine model of Lewis lung cell carcinoma. In this report we demonstrate that purified murine and human matrix metalloproteinases generate biologically functional angiostatin from plasminogen. Macrophage elastase (MMP-12 or MME) proved to be the most efficient angiostatin-producing MMP. MME was followed by gelatinases and then the stomelysins in catalytic efficiency; interstitial collagenases had little capacity to generate angiostatin. Both recombinant angiostatin and angiostatin generated from recombinant MME-treated plasminogen inhibited human microvascular endothelial cell proliferation and differentiation in vitro. Finally, employing macrophages isolated from MME-deficient mice and their wild-type littermates, we demonstrate that MME is required for the generation of angiostatin that inhibits the proliferation of human microvascular endothelial cells.

The role of microRNAs regulating the expression of matrix metalloproteinases (MMPs) in breast cancer development, progression, and metastasis

“…On the other hand, MMP-3, MMP-9, MMP-12, and MMP-13 can produce endostatin by degrading basement membrane collagen type VIII (Cornelius et al, 1998;Dong, Kumar, Yang, & Fidler, 1997;Ferreras, Felbor, Lenhard, Olsen, & Delaissé, 2000;Gorrin-Rivas et al, 2000). Endostatin reduces angiogenesis by inhibiting cell growth and invading endothelial cells.…”

“…For example, MMP‐2, MMP‐3, MMP‐7, MMP‐9, and MMP‐12 can generate angiostatin, an inhibitor of angiogenesis, by cleaving plasminogen. On the other hand, MMP‐3, MMP‐9, MMP‐12, and MMP‐13 can produce endostatin by degrading basement membrane collagen type VIII (Cornelius et al, ; Dong, Kumar, Yang, & Fidler, ; Ferreras, Felbor, Lenhard, Olsen, & Delaissé, ; Gorrin‐Rivas et al, ). Endostatin reduces angiogenesis by inhibiting cell growth and invading endothelial cells.…”

Contribution of Blood Vessel Activation, Remodeling and Barrier Function to Inflammatory Bowel Diseases

“…In particular, inflammatory cytokines (ICs) such as IFN-γ, TNF-α, and IL1-β can inhibit AGF-induced proliferation and the migration of human ECs in vitro ( Table 2 ) [ 85 , 86 , 87 ]. In addition to ICs, several anti-angiogenic factors are upregulated during intestinal inflammation, including the chemokine CXCL-10, thrombospondin, angiostatin—a cleaved fragment of plasminogen, and endostatin—a cleaved fragment of collagen XVIII [ 63 , 88 , 89 , 90 , 91 , 92 ]. Hence, the balance between angiogenic and inflammatory-associated angiostatic stimuli might explain the relative contribution of angiogenesis to IBD pathogenesis.…”

Remodelage de la matrice extracellulaire dans les valves atteintes de sténose aortique

“…À titre d'exemples, elles clivent notamment l'u-PA dont elles abolissent l'interaction avec u-PAR (Ugwu et al, 1998) et le plasminogène et génèrent ainsi l'angiostatine (Lijnen et al, 1998). À travers toutes leurs actions et en association avec d'autres protéases, dont le système d'activation du plasminogène, les MMP participent à de nombreux processus physiologiques et pathologiques tels que le remodelage tissulaire, l'inflammation, la différenciation, la prolifération et la migration cellulaires (Nagase & Woessner, 1999), la plasticité neuronale (Dzwonek et al, 2004), l'angiogenèse (Cornelius et al, 1998), la croissance et la dissémination tumorale (Nelson et al, 2000) et la mort cellulaire (Schedin et al, 2000 ;Jourquin et al, 2003). Ainsi, les fonctions des MMP vont bien au-delà d'une simple destruction de la MEC (McCawley & Matrisian, 2001).…”