Inhibition of Angiogenesis in Vivo by Plasminogen Activator Inhibitor-1

Stefansson, Steingrimur; Petitclerc, Éric; Wong, Michael K.; McMahon, Grainne A.; Brooks, Peter C.; Lawrence, Daniel A.

doi:10.1074/jbc.m007609200

Cited by 157 publications

(161 citation statements)

References 63 publications

(84 reference statements)

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“…Consistent with this, tumor angiogenesis and invasion were observed in vitronectin-deficient mice as well as in wild-type mice [92]. In a separate study using PAI-1 mutants, the inhibition of bFGF-induced angiogenesis in the CAM assay required both the anti-proteinase activity as well as the vitronectin-binding capacity of PAI-1 [98]. Together, these data suggest that depending on the situation, PAI-1 may control angiogenesis by regulating proteolytic and/or nonproteolytic events in endothelial cell migration.…”

Section: Unexpected Role Of Pai-1 In Tumor Angiogenesissupporting

confidence: 62%

“…Addition of exogenous recombinant PAI-1 at a physiological concentration restores microvessel sprouting, while at 'therapeutical' concentrations, angiogenesis is inhibited [96]. Similarly, PAI-1 inhibits bFGF-induced angiogenesis when added at high concentrations [98]. Thus PAI-1 appears to have a dual function displaying pro-an-giogenic activity at physiological concentrations and anti-angiogenic effects at high, pharmacological concentrations.…”

Section: Unexpected Role Of Pai-1 In Tumor Angiogenesismentioning

confidence: 98%

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Role of plasminogen activator-plasmin system in tumor angiogenesis

Rakic¹,

Maillard²,

Jost³

et al. 2003

Cellular and Molecular Life Sciences (CMLS)

118

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New blood formation or angiogenesis has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization. Angiogenesis is associated with important extracellular remodeling involving different proteolytic systems among which the plasminogen system plays an essential role. It belongs to the large serine proteinase family and can act directly or indirectly by activating matrix metalloproteinases or by liberating growth factors and cytokines sequestered within the extracellular matrix. Migration of endothelial cells is associated with significant upregulation of proteolysis and conversely, immunoneutralization or chemical inhibition of the system reduces angiogenesis in vitro. On the other hand genetically altered mice developed normally without overt vascular anomalies indicating the possibility of compensation by other proteases in vivo. Nevertheless, they have in some experimental settings revealed unanticipated roles for previously characterized proteinases or their inhibitors. In this review, the complex mechanisms of action of the serine proteases in pathological angiogenesis are summarized alongside possible therapeutic applications.

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Section: Unexpected Role Of Pai-1 In Tumor Angiogenesissupporting

confidence: 62%

Section: Unexpected Role Of Pai-1 In Tumor Angiogenesismentioning

confidence: 98%

Role of plasminogen activator-plasmin system in tumor angiogenesis

Rakic¹,

Maillard²,

Jost³

et al. 2003

Cellular and Molecular Life Sciences (CMLS)

118

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“…To date, various proteins of the SERPIN family including cleaved AT, 32 PAI-1, 35 and PEDF 36 have been reported to inhibit angiogenesis. In the present study, we compared the anti-angiogenic activity among various SERPIN proteins using in vitro tube formation assay, and found that PCI strongly inhibits angiogenesis, this anti-angiogenic effect being almost similar to that of cleaved AT.…”

Section: Discussionmentioning

confidence: 99%

Protein C inhibitor inhibits breast cancer cell growth, metastasis and angiogenesis independently of its protease inhibitory activity

Asanuma

Yoshikawa

Hayashi

et al. 2007

Intl Journal of Cancer

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Protein C inhibitor (PCI) regulates the anticoagulant protein C pathway and also inhibits urinary plasminogen activator (uPA), a mediator of tumor cell invasion. In the present study, we evaluated the effect of human PCI and its inactive derivatives on tumor growth and metastasis of human breast cancer (MDA-231) cells, and on angiogenesis in vivo. The invasiveness of MDA-231 cells was inhibited by recombinant intact PCI, but not by reactive sitemodified PCI (R354APCI) or by the N-terminal fragment of protease-cleaved PCI (NTPCI). The in vitro invasiveness of MDA-231 cells expressing intact PCI (MDA-PCI) was significantly decreased as compared to MDA-231 cells expressing R354APCI (MDA-R354APCI) or NTPCI (MDA-NTPCI). Further, in vivo growth and metastatic potential of MDA-PCI, MDA-R354APCI and MDA-NTPCI cells in severe combined immunodeficient (SCID) mice were significantly decreased as compared to MDA-Mock cells. Angiogenesis was also significantly decreased in Matrigel implant containing MDA-PCI, MDA-R354APCI or MDA-NTPCI cells as compared to that containing MDA-Mock cells. In vivo angiogenesis in rat cornea and in vitro tube formation were also inhibited by recombinant intact PCI, R354APCI and NTPCI. Furthermore, the anti-angiogenic activity of PCI was strong as cleaved antithrombin (AT), and slightly stronger than that of plasminogen activator inhibitor (PAI)-1 and pigment epitheliumderived factor (PEDF). Overall, this study showed that, in addition to a reactive site-dependent mechanism, PCI may also regulate tumor growth and metastasis independently of its protease inhibitory activity by inhibiting angiogenesis. ' 2007 Wiley-Liss, Inc.Key words: protein C inhibitor; serine protease inhibitor; invasion; metastasis; angiogenesis Protein C inhibitor (PCI) was originally identified as a plasma inhibitor of the anticoagulant protease, activated protein C. 1,2 PCI is a member of the serine protease inhibitor (SERPIN) family (SERPINA5); it is also able to inhibit other proteases of the blood coagulation and fibrinolysis system including thrombin, 3 thrombin-thrombomodulin complex, 4 factor Xa, 3 factor XIa, 5 plasma kallikrein 5 and urinary plasminogen activator (uPA). 6 Human plasma PCI is mainly synthesized in the liver, 7 but it is also produced in kidneys and reproductive organs, including testes, seminal vesicles and ovaries. 8,9 Unlike humans, mice and rats produce PCI only in reproductive organs including testes and ovaries 10,11 ; thus, rodents are inappropriate for studying the physiological role of PCI in plasma and other organs. We recently developed a human PCI gene transgenic (TG) mouse in which the tissue distribution of PCI is similar to humans. Using this animal model, we demonstrated that PCI is the physiological inhibitor of APC in plasma, and that it promotes blood coagulation and inflammation in animals with endotoxemia. 12 PCI appears to have also a function in fertilization; Uhrin et al. 13 reported that PCI knock-out male mice have infertility due to abnormal spermatogenesis caused by destruc...

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“…Purified serpins are as follows: PAI-1 (Molecular Innovations, Southfield, MI); PCI (human wild type recombinant PCI was expressed in Escherichia coli, strain BL21(DE3)pLysS, using the Qiagen pET15b expression vector (with an N-terminal polyhistidine sequence), and purified to homogeneity by Ni 2ϩ -chelate chromatography); 2 ␣ 2 -antiplasmin (Calbiochem); antithrombin III (ICN Biomedicals, Irvine, CA); ␣ 1 -proteinase inhibitor (generous gift from Annemarie Ralston, American Red Cross); ␣ 1 -anti-chymotrypsin (Athens Research and Technology, Athens, GA); and heparin cofactor II (46). PAI-1 mutant serpins used are as follows: PAI-1 A (R346A) and PAI-1 R (T333R/A335R) (47). PCI mutant serpins were P 1 -PCI (R355A) and P 14 -PCI (T342R).…”

Section: Methodsmentioning

confidence: 99%

Mouse DESC1 Is Located within a Cluster of Seven DESC1-like Genes and Encodes a Type II Transmembrane Serine Protease That Forms Serpin Inhibitory Complexes

Hobson

Netzel‐Arnett

Szabo

et al. 2004

Journal of Biological Chemistry

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We report the identification and functional analysis of a type II transmembrane serine protease encoded by the mouse differentially expressed in squamous cell carcinoma (DESC) 1 gene, and the definition of a cluster of seven homologous DESC1-like genes within a 0.5-Mb region of mouse chromosome 5E1. This locus is syntenic to a region of human chromosome 4q13.3 containing the human orthologues of four of the mouse DESC1-like genes. Bioinformatic analysis indicated that all seven DESC1-like genes encode functional proteases. Direct cDNA cloning showed that mouse DESC1 encodes a multidomain serine protease with an N-terminal signal anchor, a SEA (sea urchin sperm protein, enterokinase, and agrin) domain, and a C-terminal serine protease domain. The mouse DESC1 mRNA was present in epidermal, oral, and male reproductive tissues and directed the translation of a membrane-associated 60-kDa N-glycosylated protein with type II topology. Mouse DESC1 was synthesized in insect cells as a zymogen that could be activated by exposure to trypsin. The purified activated DESC1 hydrolyzed synthetic peptide substrates, showing a preference for Arg in the P 1 position. DESC1 proteolytic activity was abolished by generic inhibitors of serine proteases but not by other classes of protease inhibitors. Most interestingly, DESC1 formed stable inhibitory complexes with both plasminogen activator inhibitor-1 and protein C inhibitor that are expressed in the same tissues with DESC1, suggesting that type II transmembrane serine proteases may be novel targets for serpin inhibition. Together, these data show that mouse DESC1 encodes a functional cell surface serine protease that may have important functions in the epidermis, oral, and reproductive epithelium.Pericellular proteolysis is essential to all aspects of vertebrate life, including development, tissue homeostasis, tissue remodeling, tissue repair, and reproduction, and dysregulated pericellular proteolysis is causally related to a large number of diseases in humans. Within the past century, the most extensive studies of pericellular proteolysis in health and disease focused on defining the contribution of a relatively limited number of proteases belonging to the families of plasminogen activators, matrix metalloproteinases, and cathepsins (1-6). However, the recent completion of the mouse and human genome sequences, and the generation of extensive mouse and human EST 1 data bases, facilitated an explosion in the discovery of novel candidate protease genes, indicating that a vastly larger repertoire of pericellular proteases may be engaged in these processes than previously anticipated (7,8). Particularly noteworthy in this context was the unveiling of an unexpectedly large family of type II transmembrane serine proteases (TTSPs) (9 -23). This rapidly expanding family of serine proteases is defined by the presence of an N-terminal signal anchor and a C-terminal serine protease domain, separated by a stem region containing an array of protein domains that varies widely between individual...

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Inhibition of Angiogenesis in Vivo by Plasminogen Activator Inhibitor-1

Cited by 157 publications

References 63 publications

Role of plasminogen activator-plasmin system in tumor angiogenesis

Role of plasminogen activator-plasmin system in tumor angiogenesis

Protein C inhibitor inhibits breast cancer cell growth, metastasis and angiogenesis independently of its protease inhibitory activity

Mouse DESC1 Is Located within a Cluster of Seven DESC1-like Genes and Encodes a Type II Transmembrane Serine Protease That Forms Serpin Inhibitory Complexes

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