The role of plasminogen in angiogenesis in vivo

Oh, Chang Wan; Hoover‐Plow, Jane; Plow, EF

doi:10.1046/j.1538-7836.2003.00182.x

Cited by 65 publications

(48 citation statements)

References 43 publications

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“…Within ischemic tissues, we found VEGF-A staining mainly in CD11b ϩ cell by immunohistochemistry ( Figure 4C). VEGF-A administration partially rescued impaired angiogenesis observed in Plg Ϫ/Ϫ HL ischemic mice, as reported, 34 but did not in MMP-9 Ϫ/Ϫ mice ( Figure 4D-H).…”

Section: Inhibition Of Vegf-a Signaling Prevents Tpa-mediated Cell Mosupporting

confidence: 85%

Tissue type plasminogen activator regulates myeloid-cell dependent neoangiogenesis during tissue regeneration

Ohki

Ishihara

et al. 2010

Blood

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Ischemia of the heart, brain, and limbs is a leading cause of morbidity and mortality worldwide. Treatment with tissue type plasminogen activator (tPA) can dissolve blood clots and can ameliorate the clinical outcome in ischemic diseases. But the underlying mechanism by which tPA improves ischemic tissue regeneration is not well understood. Bone marrow (BM)-derived myeloid cells facilitate angiogenesis during tissue regeneration. Here, we report that a serpin-resistant form of tPA by activating the extracellular proteases IntroductionThe fibrinolytic system includes a broad spectrum of proteolytic enzymes with physiologic and pathophysiologic functions in several processes such as hemostatic balance, tissue remodeling, tumor invasion, reproduction, and angiogenesis.The serine protease plasmin is responsible for the degradation of fibrin into soluble degradation products (fibrinolysis). Plasmin is generated through cleavage of the proenzyme plasminogen (Plg) by the urokinase plasminogen activator (uPA) or tissue-type plasminogen activator (tPA). tPA consists of a kringle-and trypsin-like serine protease domain. 1 The activity of uPA and tPA is regulated by specific plasminogen activator inhibitors. In the absence of fibrin, tPA displays low activity toward Plg. 2 In the presence of fibrin this activity is 2 orders of magnitude higher. The catalytic efficiency of tPA for activation of cell-bound Plg is approximately 10-fold higher than that in solution. Most cells bind Plg through its lysine binding sites with a high capacity but a relatively low affinity. 3 Plg receptors such as the integrin ␣M␤2 play an important role in macrophage motility. 4 CD11b/CD18 cells adhere to fibrin, but tPA by its ability to bind to CD11b, has been shown to induce local fibrinolysis and to render adherent cells into migrating cells. 5 tPA has been shown to have numerous biologic functions. For example, within the central nervous system (reviewed by Melchor and Strickland 6 ) tPA is expressed by neurons and microglial cells (resident macrophages of the brain and spinal cord), where it can generate plasmin to degrade a variety of nonfibrin substrates (eg, ␤-amyloid), can act as a direct protease without Plg involvement (eg, for the activation of latent platelet-derived growth factor-CC), or can function as a nonproteolytic modulator (eg, of the N-methyl-D-aspartate receptors).Besides their fibrinolytic activities, plasmin and Plg activators are also implicated in tissue proliferation and cellular adhesion, because they can proteolytically degrade the extracellular matrix (ECM) and regulate the activation of both growth factors and matrix metalloproteinases (MMPs; for review, see Zorio et al 7 ). PAs and plasmin generation in specific microenvironments in the bone marrow (BM) may be one of the factors orchestrating hematopoiesis. 8,9 Plg activation promotes the release of Kit ligand from BM stromal cells. 9,10 Plasmin can cleave thrombopoietin, the master cytokine of megakaryopoiesis and platelet production, thereby decreasing its biol...

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Section: Inhibition Of Vegf-a Signaling Prevents Tpa-mediated Cell Mosupporting

confidence: 85%

Tissue type plasminogen activator regulates myeloid-cell dependent neoangiogenesis during tissue regeneration

Ohki

Ishihara

et al. 2010

Blood

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“…27 The release of the antiangiogenic HRR/PRR fragment from HRG may therefore act to perturb proangiogenic effects associated with activated plasminogen. 46 A gene knock-out study in mice has shown that plasminogen promotes vascular remodeling via both fibrinogendependent and -independent mechanisms. 47 It is also plausible that by reducing the levels of intact HRG, the ability of the full-length protein to promote angiogenesis through its interaction with thrombospondin will For personal use only.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of histidine-rich glycoprotein N2 domain reveals redox activity at an interdomain disulfide bridge: implications for angiogenic regulation

Kassaar¹,

McMahon

Thompson³

et al. 2014

Blood

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Key Points• The x-ray crystal structure of the N2 domain from HRG at 1.93Å resolution is presented.• The structure reveals an S-glutathionyl adduct at Cys185, which has implications for angiogenic regulation.Histidine-rich glycoprotein (HRG) is a plasma protein consisting of 6 distinct functional domains and is an important regulator of key cardiovascular processes, including angiogenesis and coagulation. The protein is composed of 2 N-terminal domains (N1 and N2), 2 proline-rich regions (PRR1 and PRR2) that flank a histidine-rich region (HRR), and a C-terminal domain. To date, structural information of HRG has largely come from sequence analysis and spectroscopic studies. It is thought that an HRG fragment containing the HRR, released via plasmin-mediated cleavage, acts as a negative regulator of angiogenesis in vivo. However, its release also requires cleavage of a disulphide bond suggesting that its activity is mediated by a redox process. Here, we present a 1.93Å resolution crystal structure of the N2 domain of serum-purified rabbit HRG. The structure confirms that the N2 domain, which along with the N1 domain, forms an important molecular interaction site on HRG, possesses a cystatin-like fold composed of a 5-stranded antiparallel b-sheet wrapped around a 5-turn a-helix. A native N-linked glycosylation site was identified at Asn184. Moreover, the structure reveals the presence of an S-glutathionyl adduct at Cys185, which has implications for the redox-mediated release of the antiangiogenic cleavage product from HRG. (Blood. 2014;123(12):1948-1955 Introduction Histidine-rich glycoprotein (HRG) is a plasma protein that regulates angiogenesis, coagulation, and immune function in vertebrates. Human HRG has an approximate mass of 70 kDa and is present in plasma at low micromolar concentrations (ca ;1.5 mM). The protein is arranged into 6 domains: 2 N-terminal domains (N1 and N2), a central histidine-rich region (HRR) flanked by 2 proline rich regions (PRR1 and PRR2), and a C-terminal domain (C). The N1, N2, and C domains are highly conserved between species, as is an arrangement of 6 disulfide bridges (Figure 1). In plasma, HRG binds to and regulates the function of a diverse variety of targets that include fibrinogen, plasminogen, thrombospondin, immunoglobulin G (IgG), complement factors, and heparin as well as cell-surface molecules such as Fcg receptors and heparan sulfate.1-9 HRG binds divalent metal cations within the HRR. 10 In particular, Zn 21 is known to bind this region and can modulate HRG activity by altering the protein's affinity for other targets. 11HRG is heavily glycosylated; the human protein has 6 putative N-linked glycosylation sites.11 The histidine-and proline-rich regions are predicted to be intrinsically disordered but N1, N2, and the C-terminal domains are likely to have ordered structures. The N1 and N2 domains share a high degree of sequence similarity to members of the cystatin superfamily of cysteine protease inhibitors.12 Type 1 cystatins (also known as stefins) are characterized b...

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“…Mice deficient in plasminogen develop normal blood vessels, but are disturbed in VEGF-induced and bFGF-induced angiogenesis in the cornea; data on u-PA-deficient animals are unequivocal. 112,113 Neovascularization after myocardial infarction depends equally on u-PA/plasmin activities as on MMPs. 42 However, one cannot discriminate on the basis of the data available whether the u-PA/plasmin contribution acts largely via endothelial cells on angiogenesis or that the invasion of leukocytes and endothelial progenitor cells, which may supply additional growth factors, also contributes to this effect.…”

Section: The Upar-integrin Complexmentioning

confidence: 99%

Pericellular Proteases in Angiogenesis and Vasculogenesis

Hinsbergh

Engelse

Quax

2006

ATVB

351

258

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Abstract-Pericellular proteases play an important role in angiogenesis and vasculogenesis. They comprise (membranetype) matrix metalloproteinases [(MT-)MMPs], serine proteases, cysteine cathepsins, and membrane-bound aminopeptidases. Specific inhibitors regulate them. Major roles in initiating angiogenesis have been attributed to MT1-matrix metalloproteinase (MMP), MMP-2, and MMP-9. Whereas MT-MMPs are membrane-bound by nature, MMP-2 and MMP-9 can localize to the membrane by binding to ␣v␤3-integrin and CD44, respectively. Proteases switch on neovascularization by activation, liberation, and modification of angiogenic growth factors and degradation of the endothelial and interstitial matrix. They also modify the properties of angiogenic growth factors and cytokines. Neovascularization requires cell migration, which depends on the assembly of protease-protein complexes at the migrating cell front. MT1-MMP and urokinase (u-PA) form multiprotein complexes in the lamellipodia and focal adhesions of migrating cells, facilitating proteolysis and sufficient support for endothelial cell migration and survival. Excessive proteolysis causes loss of endothelial cell-matrix interaction and impairs angiogenesis. MMP-9 and cathepsin L stimulate the recruitment and action of blood-or bone-marrow-derived accessory cells that enhance angiogenesis. Proteases also generate fragments of extracellular matrix and hemostasis factors that have anti-angiogenic properties. See coverpeptides that acquire new and often unexpected biological functions after proteolytic tailoring. In angiogenesis, the formation of new blood vessels from existing ones by sprouting enforced by intussusception of blood-borne cells, 1,2 the involvement of proteases is well-established. 3 Angiogenesis is enforced by vasculogenesis, a process that comprises the recruitment of blood-borne bone marrow-derived cells and the subsequent intussusception of these cells in the newly forming vessels. 2 Recruitment and invasion of cells during vasculogenesis also involve proteolytic activities. New functions of split products of parent matrix molecules, receptors, and growth factors are becoming recognized in conditions Original

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The role of plasminogen in angiogenesis in vivo

Cited by 65 publications

References 43 publications

Tissue type plasminogen activator regulates myeloid-cell dependent neoangiogenesis during tissue regeneration

Tissue type plasminogen activator regulates myeloid-cell dependent neoangiogenesis during tissue regeneration

Crystal structure of histidine-rich glycoprotein N2 domain reveals redox activity at an interdomain disulfide bridge: implications for angiogenic regulation

Pericellular Proteases in Angiogenesis and Vasculogenesis

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