Impaired wound healing in mice with a disrupted plasminogen gene

Rømer, John; Bugge, Thomas H.; Pyke, Charles; Lund, Leif R.; Flick, Matthew J.; Degen, Jay L.; Danø, Keld

doi:10.1038/nm0396-287

Cited by 543 publications

(403 citation statements)

References 35 publications

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“…Confirming the absolute requirement of plasminogen for cell migration, neovascularization, and wound healing, 26,27 we found that both Ad-control and Ad-TFPI2-infected cells failed to migrate in the absence of plasminogen even after 48 hours. No significant difference was observed between the healing index values among the time points or the conditions tested (Figure 5f through 5h).…”

Section: Tfpi-2 Inhibits Ec Migration In Vitrosupporting

confidence: 73%

Adenovirus-Mediated Expression of Tissue Factor Pathway Inhibitor-2 Inhibits Endothelial Cell Migration and Angiogenesis

Ivanciu

Gerard

Tang

et al. 2007

ATVB

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Objective-Extracellular matrix (ECM) remodeling during angiogenesis is accomplished through plasmin-dependent pericellular proteolysis and through the action of matrix metalloproteinases (MMPs). Because tissue factor pathway inhibitor-2 (TFPI-2), a Kunitz-type protease inhibitor with prominent ECM localization, inhibits plasmin and MMPs activity, we investigated the role of TFPI-2 in endothelial cell (EC) migration and angiogenesis. Methods and Results-Real-time polymerase chain reaction and immunostaining showed that the expression of TFPI-2 mRNA and protein was upregulated in migrating ECs. The effect of TFPI-2 on angiogenesis was studied in mouse models of Matrigel and polyvinylalcohol sponge implants by overexpressing TFPI-2 through infection with a replication-deficient adenovirus (AdTFPI-2). Using (immuno)fluorescence and confocal microscopy we observed that TFPI-2 reduced neovascularization and promoted ECM deposition. Lateral cell migration and capillary tube formation in vitro also were impaired by TFPI-2, a process reversed by anti-TFPI-2 antibodies. Increased apoptosis occurred both in AdTFPI-2-treated ECs and in the mouse implants. Zymography and assays in the absence of plasminogen confirmed plasmin inhibition as a main mechanism through which TFPI-2 inhibits EC migration. Conclusions-Our data suggest that TFPI-2 may be an important regulator of aberrant angiogenesis associated with tumor growth/metastasis, cardiovascular diseases, chronic inflammation, or diabetes. Key Words: TFPI-2 Ⅲ angiogenesis Ⅲ endothelial cell Ⅲ adenovirus gene delivery Ⅲ mouse model P roteinase inhibitors are involved in blood coagulation, fibrinolysis, angiogenesis, wound healing, and tumor invasion. 1 Tissue factor pathway inhibitor-2 (TFPI-2) is a Kunitz-type serine proteinase inhibitor 2 synthesized by endothelial cells (ECs), smooth muscle cells (SMCs), and syncytiotrophoblasts, 3,4 which associates through ionic interactions 5 with the extracellular matrix (ECM), 6 and inhibits trypsin, plasmin, and plasma kallikrein among others. 7 The ECM is essential for the integrity of the cardiovascular system. ECs use the matrix as scaffolding during invasion, but they also degrade it to provide space for new capillaries. Serine proteases belonging to the plasminogen activator (PA)/plasmin system and (membrane-type)-matrix metalloproteinases [(MT)-MMPs] play major roles in all the steps of angiogenesis 8 : vessel sprouting, cell migration, tube formation, survival, generation of matrikines as angiogenesis inhibitors, and vessel stabilization/maturation and remodeling. 9,10 Matrix metalloproteinase (MMP)-2, MMP-9, and MT1-MMP switch on neovascularization through degradation of the endothelial and interstitial matrix, and activation of growth factors (reviewed in 10 ). Protease activities are controlled by specific activation mechanisms and inhibitors, of which tissue inhibitors of MMPs and serpins, like PA inhibitors (PAIs), represent major classes. MMPs are secreted as inactive zymogens that are activated by other proteinases, s...

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Section: Tfpi-2 Inhibits Ec Migration In Vitrosupporting

confidence: 73%

Adenovirus-Mediated Expression of Tissue Factor Pathway Inhibitor-2 Inhibits Endothelial Cell Migration and Angiogenesis

Ivanciu

Gerard

Tang

et al. 2007

ATVB

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“…However, injection of mBSA into knee joints creates a trauma. Persistent deposition of fibrin has been observed in traumas in plasminogen-deficient mice (18). In this respect, fibrin deposition in plasminogen-deficient mice in AIA may be a consequence of the inflammation associated with trauma rather than being the reason for the inflammation of arthritis, or both.…”

Section: Discussionmentioning

confidence: 97%

“…The main function of the PA system is fibrinolysis, which is important for the maintenance of the hemostatic balance (16). However, by acting in concert with other proteinases, the PA system has also been proposed to play a role in the remodeling and degradation of the ECM during many physiologic and pathologic processes, including ovulation (17), skin wound healing (18), tumor invasion (19,20), and inflammatory cell infiltration, fibrin deposition, and joint destruction associated with RA (21). However, despite the rapid progress in our understanding of the involvement of the PA system in RA, the molecular mechanisms by which the PA system participates in the pathogenesis of RA are still poorly understood.…”

mentioning

confidence: 99%

Contrasting roles of plasminogen deficiency in different rheumatoid arthritis models

Guo

Holmdahl

et al. 2005

Arthritis & Rheumatism

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Objective. To investigate the contrasting roles of plasminogen deficiency between models of collageninduced arthritis (CIA) and antigen-induced arthritis (AIA).Methods. We developed a new animal model of arthritis, which we have called local injection-induced arthritis (LIA). In this model, we replaced methylated bovine serum albumin, which is normally used as an immunogen and is injected intraarticularly into the knee joint, with type II collagen (CII) to induce AIA. The severity of CIA, LIA, and AIA in wild-type and plasminogen-deficient mice was evaluated by clinical scoring or histologic grading. Necrosis was determined by histology and immunohistochemistry.Results. After CII immunization alone, wild-type mice developed arthritis in most of the paws as well as in the knee joints, whereas plasminogen-deficient mice were totally resistant to the disease. Local knee injections of CII or saline slightly enhanced the severity of the knee arthritis in wild-type mice during a 60-day experimental period. Unexpectedly, the plasminogendeficient mice also developed arthritis in joints that were injected with CII or saline. However, the arthritis was milder than that in their wild-type littermates. Sustained tissue necrosis was found only in the plasminogen-deficient mice after the local injection.Conclusion. Our data show that both the antigen and the joint trauma caused by the local injection are critical to explaining the contrasting roles of plasminogen deficiency in CIA and AIA. This further indicates that CIA and AIA have distinct pathogenic mechanisms. The data also suggest that plasmin may be required for the induction of these arthritis models that are critically dependent on complement activation.

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“…Plg deficiency has been associated with defective removal of necrotic debris in experimental models of liver fibrosis and epithelial wound healing. 18,19,23,45,54 Although plasmin has a broad substrate specificity in vitro, its targeted substrates in vivo are not well defined. Fibrin deposition has been proposed as a critical feature in the pathologies associated with plg deficiency.…”

Section: Discussionmentioning

confidence: 99%

Pancreas Recovery Following Cerulein-Induced Pancreatitis Is Impaired in Plasminogen-Deficient Mice

Lugea

French

et al. 2006

Gastroenterology

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Impaired wound healing in mice with a disrupted plasminogen gene

Cited by 543 publications

References 35 publications

Adenovirus-Mediated Expression of Tissue Factor Pathway Inhibitor-2 Inhibits Endothelial Cell Migration and Angiogenesis

Adenovirus-Mediated Expression of Tissue Factor Pathway Inhibitor-2 Inhibits Endothelial Cell Migration and Angiogenesis

Contrasting roles of plasminogen deficiency in different rheumatoid arthritis models

Pancreas Recovery Following Cerulein-Induced Pancreatitis Is Impaired in Plasminogen-Deficient Mice

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