Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.7 (plasmin)
9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of vascular therapies could benefit from advanced methods for presentation of angiogenic growth factors, including growth of endothelium on small caliber vascular grafts and revascularization of ischemic tissue through induction of collateral vessels and microvessels. To explore methods to optimize the presentation and release of angiogenic factors in such applications in device integration and tissue repair, we studied three variant forms of vascular endothelial growth factor 121 (VEGF121), each with differential susceptibility to local cellular proteolytic activity, formulated within fibrin matrices. (1) The prototypic variant alpha2PI(1-8)-VEGF121 remains immobilized in fibrin matrices until its liberation by cell-associated enzymes, such as plasmin, that degrade the fibrin network [slow, cell-demanded release; J. Control. Release 72 (2001) 101-113]; the alpha2PI(1-8) domain serves as a site for covalent attachment to fibrin during coagulation. (2) We created a new VEGF variant, alpha2PI(1-8)-Pla-VEGF121 that couples to fibrin via a plasmin-sensitive sequence (Pla). Cleavage of this target site by plasmin enables direct release of alpha2PI(1-8)-Pla-VEGF121 from bulk matrix degradation (accelerated, cell-demanded release). (3) Native VEGF121 (burst, passive release) was considered as a reference. VEGF release profiles were determined experimentally as well as mathematically, alpha2PI(1-8)-Pla-VEGF121 being released ca. fourfold more quickly than alpha2PI(1-8)-VEGF121, both being retained compared to native VEGF121; the differences in release could be accounted for based on knowledge of the plasmin sensitivity of the bound growth factor and the structure of the fibrin network. The bound factors were competent in inducing endothelial cell proliferation, the matrix-bound forms being more effective than native VEGF121; as well as competent in inducing endothelial progenitor cell maturation into endothelial cells. These matrix-bound variants of VEGF121 may be particularly useful where retention in locally applied surgical sites is desired, such as prevention of washout from vascular graft coatings and slowing loss from tissue ingrowth matrices used in local tissue revascularization and repair.
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PMID:Endothelial cell proliferation and progenitor maturation by fibrin-bound VEGF variants with differential susceptibilities to local cellular activity. 1558 97

Chronic hypoxia has been newly proposed as a common mechanism of progressive renal fibrosis where PAI-1 plays important roles in the accumulation of extracellular matrix (ECM) through inhibition of plasmin-dependent ECM degradation. Hypoxia is also presumably associated with macrophage recruitment and angiogenesis that form fibrotic lesions. In the present study, we examined the effects of hypoxia and TNF-alpha on PAI-1, MCP-1 and VEGF expression in cultured human proximal renal tubular cells (HPTECs). We also investigated the presence of PAI-1 in renal tubular cells by immunostaining renal biopsy samples and measuring urinary PAI-1 levels in different kidney diseases. cDNA array analysis identified PAI-1 as a major gene highly induced by hypoxia in HPTECs. Hypoxia, TNF-alpha and their combination induced a 2.8-fold, a 1.8-fold, and a 4.6-fold increase in PAI-1 protein secretion, and produced a 3.6-fold, a 3.3-fold, and a 12.1-fold increase at the PAI-1 mRNA level, respectively. Similar results were confirmed by luciferase assay. Immunoblot analysis and immunocytochemistry revealed that hypoxia-inducible factor-1alpha (HIF-1alpha) was markedly accumulated in nuclei after 16-hours of hypoxia. Hypoxia reduced basal and TNF-alpha-stimulated MCP-1 expression, while it induced VEGF expression in HPTECs. In crescentic glomerulonephritis (CrGN) or diabetic nephropathy (DN) with severe proteinuria, clusters of proximal tubules and a part of the fibrotic interstitium were specifically stained for PAI-1, while no stainings were found in minor glomerular abnormality or minimal change nephrotic syndrome. Urinary PAI-1 levels were significantly higher in CrGN and DN than in healthy controls. In DN, urinary TNF-alpha levels were significantly correlated with urinary PAI-1 levels. PAI-1 induced by hypoxia and inflammation may contribute to further progression of advanced kidney disease, CrGN or DN. Hypoxia together with inflammation may also be involved in promotion of renal fibrosis in part by modulating MCP-1 and VEGF expression.
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PMID:[Increased expression of plasminogen activator inhibitor-1 in hypoxic renal injury and its pathological significance in progression of advanced renal disease]. 1619 Mar 62

Vascular endothelial growth factor-A (VEGF-A) is a crucial mediator of vascular hyperpermeability, angiogenesis, and inflammation, processes intimately involved in tissue repair. Although much emphasis has been placed on understanding the synthesis and stability of VEGF-A mRNA, relatively little attention has been given to the study of the stability and processing of VEGF-A proteins themselves. In recent years, several studies indicated that VEGF-A protein activity is highly controlled through interaction with angiogenic or non-angiogenic mediators. We analyzed mechanisms that might control extracellular VEGF-A processing during wound repair. First, our studies provide evidence that VEGF-A protein is a target of proteases present in the microenvironment of human chronic non-healing wounds. Serine proteases, in particular plasmin cleave VEGF165 and digested VEGF fragments, showed decreased mitogenic activity. Inactivation of the plasmin cleavage site Arg110/Ala111 preserved the structural integrity and increased the angiogenic potency of VEGF165 when tested in an impaired healing mouse model. Secondly, we identified significantly increased levels of the potent VEGF-A inhibitor, the soluble form of the VEGF receptor VEGFR-1 (sVEGFR-1) in non-healing wounds when compared to healing wounds. Wound closure in healing and non-healing wounds correlated significantly with a decline in sVEGFR-1 levels. These observations support the concept that VEGF-A and VEGF-A receptors are important mediators in tissue repair. Further, our data provide mechanisms how VEGF-A-mediated interactions are disturbed during impaired healing.
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PMID:Molecular mechanisms of VEGF-A action during tissue repair. 1706 14

Proteolysis of fibrin matrices by endothelial cells plays essential roles in the migratory and morphogenic differentiation processes underlying angiogenesis. Using an in vitro fibrinolysis model consisting of human umbilical vein endothelial cells (HUVECs) embedded in a three dimensional fibrin matrix, we show that VEGF, an angiogenic cytokine that plays a crucial role in the onset of angiogenesis, is a potent activator of HUVEC-mediated fibrinolysis. This VEGF-dependent fibrin degradation was completely abrogated by inhibitors of either the plasminogen activator/plasmin or matrix metalloproteinases (MMP) proteolytic systems, suggesting the involvement of both classes of proteases in fibrin degradation. Accordingly, VEGF-induced fibrinolysis correlated with an increase in the expression of tPA and of some MMPs, such as MT2-MMP and was completely blocked by a neutralizing antibody against tPA. Overall, these results indicate that efficient proteolysis of three dimensional fibrin matrices during VEGF-mediated angiogenesis involves a complex interplay between the MMP and plasmin-mediated proteolytic systems.
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PMID:VEGF increases the fibrinolytic activity of endothelial cells within fibrin matrices: involvement of VEGFR-2, tissue type plasminogen activator and matrix metalloproteinases. 1751 73

Little is known about angiostatin and its related factors in the hypoxia-reoxygenation of neonates. In this study we compared the effect of 21% and 100% reoxygenation on temporal changes in the plasma level of these factors in newborn piglets subjected to hypoxia. Newborn piglets were subjected to 2 h hypoxia followed by 1 h of reoxygenation with either 21% or 100% oxygen and observed for 4 days. On day 4 of recovery in 100% hypoxic-reoxygenated group, there were increases in total angiostatin, plasminogen/plasmin and MMP-2 levels, and decreases in VEGF levels (vs. respective baseline levels, all P <0.001), whereas no significant temporal changes were found in the 21% hypoxic-reoxygenated and sham-operated groups. Angiostatin levels correlated positively with the levels of MMP-2 and HIF-1alpha and negatively with VEGF levels in 100% hypoxic-reoxygenated group (all P <0.05). In comparison to 21% oxygen, neonatal resuscitation with 100% oxygen was found to increase the levels anti-angiogenic factors.
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PMID:Expression of angiostatin and its related factors in the plasma of newborn pigs with hypoxia and reoxygenation. 1771 98

Hypoxia is a potent stimulus of angiogenic factors and angiostatin can inhibit angiogenesis. Little is known about the expression of angiostatin and its related factors in hypoxic newborns. Using a swine model of neonatal hypoxia, we hypothesized that hypoxia would decrease plasma levels of angiostatin in a time-dependent fashion. In this study newborn piglets underwent hypoxia (15-18% oxygen) for 3 hr, were allowed to recover in 21% oxygen and were then observed for 96 hr. Sham-operated piglets did not experience hypoxia. Plasma levels of angiostatin, plasminogen/plasmin, MMP-2 and -9, and VEGF were determined at normoxic baseline; at the end of hypoxia; at 5 hr; and at 96 hr post-hypoxia. Plasma levels of angiostatin, but not plasminogen/plasmin, decreased significantly at the end of hypoxia and 5 hr after hypoxia compared with the sham-operated group (P < 0.05). Plasma MMP-2 levels at the end of hypoxia were lower in the hypoxic group than in sham animals (P < 0.005). In the hypoxic but not sham-operated group, plasma levels of angiostatin and MMP-2 were positively correlated (r = 0.69; P < 0.001). Plasma MMP-9 and VEGF levels were not different between sham-operated and hypoxic groups and did not correlate with plasma angiostatin levels. In conclusion, hypoxia showed a transient suppressive effect on the expression of plasma angiostatin in newborn piglets. This may imply an inhibitory role of hypoxia on MMP-2 and the proteolytic cleavage of plasminogen to angiostatin.
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PMID:The effect of hypoxia on plasma angiostatin and related factors in newborn pigs. 1860 28

Angiogenesis involves complex processes mediated by several factors and is associated with inflammation and wound healing. High mobility group box 1 (HMGB1) is released from necrotic cells as well as macrophages and plays proinflammatory roles. In the present study, we examined whether HMGB1 would exhibit angiogenic activity in a matrigel plug assay in mice. HMGB1 in combination with heparin strongly induced angiogenesis, whereas neither HMGB1 nor heparin alone showed such angiogenic activity. The heparin-dependent induction of angiogenesis by HMGB1 was accompanied by increases in the expression of tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial growth factor-A120 (VEGF-A120). It is likely that the dependence of the angiogenic activity of HMGB1 on heparin was due to the efficiency of the diffusion of the HMGB1-heparin complex from matrigel to the surrounding areas. VEGF-A165 possessing a heparin-binding domain showed a pattern of heparin-dependent angiogenic activity similar to that of HMGB1. The presence of heparin also inhibited the degradation of HMGB1 by plasmin in vitro. Taken together, these results suggested that HMGB1 in complex with heparin possesses remarkable angiogenic activity, probably through the induction of TNF-alpha and VEGF-A120.
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PMID:High mobility group box 1 complexed with heparin induced angiogenesis in a matrigel plug assay. 1989 1

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 matrix metalloproteinase-9 and plasmin expands the myeloid cell pool and mobilizes CD45(+)CD11b(+) proangiogenic, myeloid cells, a process dependent on vascular endothelial growth factor-A (VEGF-A) and Kit ligand signaling. tPA improves the incorporation of CD11b(+) cells into ischemic tissues and increases expression of neoangiogenesis-related genes, including VEGF-A. Remarkably, transplantation of BM-derived tPA-mobilized CD11b(+) cells and VEGFR-1(+) cells, but not carrier-mobilized cells or CD11b(-) cells, accelerates neovascularization and ischemic tissue regeneration. Inhibition of VEGF signaling suppresses tPA-induced neovascularization in a model of hind limb ischemia. Thus, tPA mobilizes CD11b(+) cells from the BM and increases systemic and local (cellular) VEGF-A, which can locally promote angiogenesis during ischemic recovery. tPA might be useful to induce therapeutic revascularization in the growing field of regenerative medicine.
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PMID:Tissue type plasminogen activator regulates myeloid-cell dependent neoangiogenesis during tissue regeneration. 2011 Apr 20

Vascular endothelial growth factor (VEGF, VEGF-A) is a major regulator of physiological and pathological angiogenesis. One feature of VEGF is the existence of multiple isoforms arising from alternative exon splicing. Our initial biochemical and biological studies indicated that such isoforms are uniquely suited to generate angiogenic gradients by virtue of their differential ability to interact with the extracellular matrix (ECM). Although ECM-bound VEGF was bioactive, processing by physiologically relevant proteases such as plasmin was identified as a key mechanism to convert ECM-bound VEGF into freely diffusible forms. This retrospective article examines the early studies and also emphasizes the subsequent progress in our understanding of these processes in health and disease.
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PMID:Binding to the extracellular matrix and proteolytic processing: two key mechanisms regulating vascular endothelial growth factor action. 2018 70

Extracellular proteolysis is an indispensable requirement for the formation of new blood vessels during neovascularization and is implicated in the generation of several angiogenic regulatory molecules. Anti-proteolytic agents have become attractive therapeutic strategies in diseases associated with excessive neovascularization. Annexin A2 (AnxA2) is an endothelial cell-surface receptor for the generation of active proteolytic factors, such as plasmin. Here, we show that AnxA2 is abundantly expressed in the neovascular tufts in a murine model of neovascularization. Exposure to hypoxic conditions results in elevation of AnxA2 and tissue plasminogen activator (tPA) in human retinal microvascular endothelial cells (RMVECs). We show that the hexapeptide competitive inhibitor LCKLSL, which targets the N-terminal tPA-binding site of AnxA2, binds efficiently to cell-surface AnxA2 compared with binding of the control peptide LGKLSL. Treatment with the competitive peptide inhibits the generation of plasmin and suppresses the VEGF-induced activity of tPA under hypoxic conditions. Application of the competitive peptide in two in vivo models of angiogenesis demonstrated suppression of the angiogenic responses, which was also associated with significant changes in the vascular sprouting. These results suggest that AnxA2-mediated plasmin generation is an important event in angiogenesis and is inhibited by a specific competitive peptide that inhibits the binding of tPA to AnxA2.
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PMID:A competitive hexapeptide inhibitor of annexin A2 prevents hypoxia-induced angiogenic events. 2148 55


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