Journal articles: 'Angiostatine'

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Dudani, Anil K., Jelica Mehic, and Anthony Martyres. "Interaction of Plasminogen and Angiostatin with Heat Shock Proteins." Blood 108, no. 11 (November 16, 2006): 1622. http://dx.doi.org/10.1182/blood.v108.11.1622.1622.

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Abstract Previous studies from this laboratory have demonstrated that plasminogen and angiostatin bind to endothelial cell (EC) surface-associated actin via their kringles in a specific manner. Heat shock proteins (hsps) like hsp 27 are constitutively expressed by vascular ECs and regulate actin polymerization, cell growth and migration. Since many hsps have also been found to be highly abundant on cell surfaces and there is evidence that bacterial surface hsps may interact with human plasminogen, the purpose of this study was to determine whether human plasminogen and angiostatin would interact with human hsps. ELISAs were developed in our laboratory to assess these interactions. It was observed that plasminogen bound to hsps 27, 60 and 70. In all cases, binding was inhibited (85–90%) by excess (50 mM) lysine indicating kringle involvement. Angiostatin predominantly bound to hsp 27 and to hsp 70 in a concentration- and kringle-dependent manner. As observed previously for actin, there was dose-dependent inhibition of angiostatin’s interaction with hsp 27 by plasminogen. In addition, thirty-fold molar excess actin inhibited (up to 50%), the interaction of plasminogen with all hsps. However, thirty-fold molar excess actin could only inhibit the interaction of angiostatin with hsp 27 by 15–20%. FACS analyses indicated the presence of hsps 27, 60 and 70 on the surface of MCF-7 breast cancer cells but not on human umbilical vein ECs. Polyclonal antibodies to hsp 27 significantly inhibited the interaction of plasminogen and angiostatin with MCF-7 surface-associated hsp27 in a dose-dependent manner. Collectively, these data indicate that while plasminogen interacts specifically with hsp 27, 60 and 70, angiostatin interacts predominantly with hsp 27 and to some extent with hsp 70; plasminogen only partially displaces angiostatins binding to hsp 27; actin only partially displaces plasminogen/angiostatin binding to hsps and surface-associated hsp 27 can mediate the binding of both plasminogen and angiostatin to MCF-7 cells.

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BILOUS, V. L. "PRODUCTION AND APPLICATION OF ANGIOSTATINS FOR THE TREATMENT OF OCULAR NEOVASCULAR DISEASES." Biotechnologia Acta 14, no. 1 (February 2021): 5–24. http://dx.doi.org/10.15407/biotech14.01.005.

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Angiostatins comprise a group of kringle-containing proteolytically-derived fragments of plasminogen/plasmin, which act as potent inhibitory mediators of endothelial cells proliferation and migration. Angiostatins are involved in modulation of vessel growth in healthy tissues and various pathological conditions associated with aberrant neovascularization. The aim of the present paper was to summarize available information, including our own experimental data, on prospects of angiostatin application for treatment of ocular neovascular diseases (OND), focusing on retinal pathologies and corneal injury. In particular, literature data on prospective and retrospective studies, clinical trials and animal models relating to the pathophysiology, investigation and management of OND are described. Special emphasis was made on the laboratory approaches of production of different angiostatin isoforms, as well as comparison of antiangiogenic capacities of native and recombinant angiostatin polypeptides. Several studies reported that angiostatins may completely abolish pathologic angiogenesis in diabetic proliferative retinopathy without affecting normal retinal vessel development and without exhibiting adverse side effects. Angiostatins have been tested as a tool for corneal antiangiogenesis target therapy in order to manage diverse ocular surface pathological conditions induced by traumas, chemical burns, previous surgery, chronic contact lens wear, autoimmune diseases, keratitis and viral infections (herpes, COVID-19), corneal graft rejection, etc. Among all known angiostatin species, isolated K5 plasminogen fragment was shown to display the most potent inhibitory activity against proliferation of endothelial cells via triggering multiple signaling pathways, which lead to cell death and resulting angiogenesis suppression. Application of adenoviral genetic construct encoding angiostatin K5 as a promising tool for OND treatment illustrates a vivid example of upcoming revolution in local gene therapy. Further comprehensive studies are necessary to elucidate the clinical potential and optimal regimes of angiostatinbased intervention modalities for treating ocular neovascularization.

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Lee, Tong-Young, Stefan Muschal, Elke A. Pravda, Judah Folkman, Amir Abdollahi, and Kashi Javaherian. "Angiostatin regulates the expression of antiangiogenic and proapoptotic pathways via targeted inhibition of mitochondrial proteins." Blood 114, no. 9 (August 27, 2009): 1987–98. http://dx.doi.org/10.1182/blood-2008-12-197236.

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Angiostatin, a proteolytic fragment of plasminogen, is a potent endogenous antiangiogenic agent. The molecular mechanisms governing angiostatin's antiangiogenic and antitumor effects are not well understood. Here, we report the identification of mitochondrial compartment as the ultimate target of angiostatin. After internalization of angiostatin into the cell, at least 2 proteins within the mitochondria bind this molecule: malate dehydrogenase, a member of Krebs cycle, and adenosine triphosphate synthase. In vitro and in vivo studies revealed differential regulation of key prosurvival and angiogenesis-related proteins in angiostatin-treated tumors and tumor-endothelium. Angiostatin induced apoptosis via down-regulation of mitochondrial BCL-2. Angiostatin treatment led to down-regulation of c-Myc and elevated levels of another key antiangiogenic protein, thrombospondin-1, reinforcing its antitumor and antiangiogenic effects. Further evidence is provided for reduced recruitment and infiltration of bone marrow–derived macrophages in angiostatin-treated tumors. The observed effects of angiostatin were restricted to the tumor site and were not observed in other major organs of the mice, indicating unique tumor specific bioavailability. Together, our data suggest mitochondria as a novel target for antiangiogenic therapy and provide mechanistic insights to the antiangiogenic and antitumor effects of angiostatin.

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Levine, Howard A., Serdal Pamuk, Brian D. Sleeman, and Marit Nilsen-Hamilton. "Mathematical Modelling of Tumour Angiogenesis and the Action of Angiostatin as a Protease Inhibitor." Journal of Theoretical Medicine 4, no. 2 (2002): 133–45. http://dx.doi.org/10.1080/1027366021000003270.

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Tumour angiogenesis is the process whereby a capillary network is formed from a pre-existing vasculature in response to tumour secreted growth factors (TAF). The capillary network is largely composed of migrating endothelial cells which organise themselves into dendritic structures. In this paper we model angiogenesis via the theory of reinforced random walks, whereby the chemotactic response of the endothelial cells to TAF and their haptotactic response to the matrix macromolecule fibronectin is accomplished through transition probability rate functions. Tumour secreted growth and inhibitory factors are modelled on the basis of Michaelis–Menten kinetics. Particular attention is focussed on the action of anti-angiogenic agents (i.e. angiostatins). That is as a mechanism whereby angiostatin acts as a protease inhibitor. Numerical simulations yield results, which are in good agreement with the experimental observations obtained by Folkman and his co-workers in their classical rabbit eye cornea experiments. The model offers a theoretical understanding of how some angiostatins work to inhibit tumour growth.

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Warejcka, Debra J., and Sally S. Twining. "Specific conformational changes of plasminogen induced by chloride ions, 6-aminohexanoic acid and benzamidine, but not the overall openness of plasminogen regulate, production of biologically active angiostatins." Biochemical Journal 392, no. 3 (December 6, 2005): 703–12. http://dx.doi.org/10.1042/bj20050907.

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The overall conformation of plasminogen depends upon the presence of anions and molecules such as AHA (6-aminohexanoic acid) and BZ (benzamidine). The purpose of the present study was to determine the effect of conformation on the initial and secondary cleavages of plasminogen to generate active angiostatins. Plasminogen was digested with the physiologically relevant neutrophil elastase in one of the four Tris/acetate buffers: buffer alone or buffer plus NaCl, AHA or BZ. The initial cleavage of Glu1-plasminogen was much slower in the tight NaCl-induced α-conformation, fastest in the intermediate BZ-induced β-conformation and intermediate both in the control and in the AHA-induced open γ-conformation. Although the buffer system determined the relative amounts of the initial cleavage products, the same four cleavage sites were utilized under all conditions. A fifth major initial cleavage within the protease domain was observed in the presence of BZ. N-terminal peptide cleavage required for angiostatin formation occurred as either the initial or the secondary cleavage. Angiostatins were generated fastest in the presence of BZ and slowest in the presence of NaCl. Both the initial and secondary cleavages were affected by the modifying agents, indicating that they influence the conformation of both Glu-plasminogen and the initial cleavage products. The angiostatins produced under the different conditions inhibited proliferation of human umbilical-vein endothelial cells. These results suggest that plasminogen conversion into active angiostatins is dependent more on the specific conformation changes induced by the various modifying reagents rather than on the overall openness of the molecule.

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Dorrell, Michael I., Heidi R. Kast-Woelbern, Ryan T. Botts, Stephen A. Bravo, Jacob R. Tremblay, Sarah Giles, Jessica F. Wada, et al. "A novel method of screening combinations of angiostatics identifies bevacizumab and temsirolimus as synergistic inhibitors of glioma-induced angiogenesis." PLOS ONE 16, no. 6 (June 2, 2021): e0252233. http://dx.doi.org/10.1371/journal.pone.0252233.

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Tumor angiogenesis is critical for the growth and progression of cancer. As such, angiostasis is a treatment modality for cancer with potential utility for multiple types of cancer and fewer side effects. However, clinical success of angiostatic monotherapies has been moderate, at best, causing angiostatic treatments to lose their early luster. Previous studies demonstrated compensatory mechanisms that drive tumor vascularization despite the use of angiostatic monotherapies, as well as the potential for combination angiostatic therapies to overcome these compensatory mechanisms. We screened clinically approved angiostatics to identify specific combinations that confer potent inhibition of tumor-induced angiogenesis. We used a novel modification of the ex ovo chick chorioallantoic membrane (CAM) model that combined confocal and automated analyses to quantify tumor angiogenesis induced by glioblastoma tumor onplants. This model is advantageous due to its low cost and moderate throughput capabilities, while maintaining complex in vivo cellular interactions that are difficult to replicate in vitro. After screening multiple combinations, we determined that glioblastoma-induced angiogenesis was significantly reduced using a combination of bevacizumab (Avastin®) and temsirolimus (Torisel®) at doses below those where neither monotherapy demonstrated activity. These preliminary results were verified extensively, with this combination therapy effective even at concentrations further reduced 10-fold with a CI value of 2.42E-5, demonstrating high levels of synergy. Thus, combining bevacizumab and temsirolimus has great potential to increase the efficacy of angiostatic therapy and lower required dosing for improved clinical success and reduced side effects in glioblastoma patients.

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Schmitz, Volker, Wang Lin, Miguel Barajas, Peng Dacheng, Jésus Prieto, and Qian Cheng. "Encymatic release of angiostatin like molecule and characterization of its angiostatic and antitumoral effects." Journal of Hepatology 36 (April 2002): 161. http://dx.doi.org/10.1016/s0168-8278(02)80581-5.

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8

Wajih, Nadeem, and David C. Sane. "Angiostatin selectively inhibits signaling by hepatocyte growth factor in endothelial and smooth muscle cells." Blood 101, no. 5 (March 1, 2003): 1857–63. http://dx.doi.org/10.1182/blood-2002-02-0582.

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Angiostatin, an inhibitor of angiogenesis, contains 3 to 4 kringle domains that are derived from proteolytic cleavage of plasminogen. The antiangiogenic effects of angiostatin occur, in part, from its inhibition of endothelial cell surface adenosine triphosphate synthase, integrin functions, and pericellular proteolysis. Angiostatin has structural similarities to hepatocyte growth factor (HGF; “scatter factor”), a promoter of angiogenesis, that induces proliferation and migration of both endothelial and smooth muscle cells via its cell surface receptor, c-met. We hypothesized that angiostatin might block HGF-induced signaling in endothelial and smooth muscle cells. Angiostatin inhibited HGF-induced phosphorylation of c-met, Akt, and ERK1/2. Angiostatin also significantly inhibited proliferation of human umbilical vein endothelial cells (HUVECs) induced by HGF. In contrast, angiostatin did not inhibit vascular endothelial growth factor (VEGF)–or basic fibroblast growth factor (bFGF)–induced signaling events or HUVEC proliferation. Angiostatin bound to immobilized truncated c-met produced by A431 cells and could be immunoprecipitated as a complex with soluble c-met. HGF inhibited the binding of 125I-angiostatin to HUVECs. Soluble c-met, produced by several tumor cell lines, could inhibit the antiangiogenic effect of angiostatin. The disruption of HGF/c-met signaling is a novel mechanism for the antiangiogenic effect of angiostatin.

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STACK, M. Sharon, Stephen GATELY, Lisa M. BAFETTI, Jan J. ENGHILD, and Gerald A. SOFF. "Angiostatin inhibits endothelial and melanoma cellular invasion by blocking matrix-enhanced plasminogen activation." Biochemical Journal 340, no. 1 (May 10, 1999): 77–84. http://dx.doi.org/10.1042/bj3400077.

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Angiostatin, a kringle-containing fragment of plasminogen, is a potent inhibitor of angiogenesis. The mechanism(s) responsible for the anti-angiogenic properties of angiostatin are unknown. We now report that human angiostatin blocks plasmin(ogen)-enhanced in vitro invasion of tissue plasminogen activator (t-PA)-producing endothelial and melanoma cells. Kinetic analyses demonstrated that angiostatin functions as a non-competitive inhibitor of extracellular-matrix (ECM)-enhanced, t-PA-catalysed plasminogen activation, with a Ki of 0.9±0.03 μM. This mechanism suggests that t-PA has a binding site for the inhibitor angiostatin, as well as for its substrate plasminogen that, when occupied, prevents ternary complex formation between t-PA, plasminogen and matrix protein. Direct binding experiments confirmed that angiostatin bound to t-PA with an apparent Kd [Kd(app)] of 6.7±0.7 nM, but did not bind with high affinity to ECM proteins. Together, these data suggest that angiostatin in the cellular micro-environment can inhibit matrix-enhanced plasminogen activation, resulting in reduced invasive activity, and suggest a biochemical mechanism whereby angiostatin-mediated regulation of plasmin formation could influence cellular migration and invasion.

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10

Dudani, A. K., M. Ben-Tchavtchavadze, S. Porter, and E. Tackaberry. "Angiostatin and plasminogen share binding to endothelial cell surface actin." Biochemistry and Cell Biology 83, no. 1 (February 1, 2005): 28–35. http://dx.doi.org/10.1139/o04-109.

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Previous studies from this laboratory have demonstrated that plasminogen binds to endothelial cell surface-associated actin via its kringles in a dose-dependent and specific manner. The purpose of this study was to determine whether angiostatin, a proteolytic fragment of plasminogen, shares binding properties with plasminogen. Our results indicated that like plasminogen, angiostatin bound to actin in a time-, concentration-, and kringle-dependent manner. Furthermore, this binding was significantly inhibited by excess plasminogen, suggesting that both proteins shared binding motifs on the actin molecule. Fluorescence studies demonstrated that angiostatin bound to intact endothelial cells through its kringles, and this binding was also inhibited by plasminogen but not by unrelated proteins. Ligand blot analyses on endothelial cell lysates indicated that angiostatin interacted with a 42 kDa protein, which was identified as actin. Furthermore, an anti-actin antibody inhibited binding of angiostatin to endothelial cells by approximately 25%. These results suggest that angiostatin and plasminogen share binding to endothelial cell surface actin and, therefore, that angiostatin has the potential to inhibit plasmin-dependent processes such as cell migration–movement.Key words: plasminogen, angiostatin, endothelial cells, actin.

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11

Jurasz, Paul, David Alonso, Susana Castro-Blanco, Ferid Murad, and Marek W. Radomski. "Generation and role of angiostatin in human platelets." Blood 102, no. 9 (November 1, 2003): 3217–23. http://dx.doi.org/10.1182/blood-2003-02-0378.

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AbstractPlatelets regulate new blood vessel growth, because they contain a number of angiogenesis promoters and inhibitors. Additionally, platelets contain matrix metalloproteinases (MMPs), which when released mediate platelet adhesion and aggregation, and plasminogen, a fibrinolytic system enzyme that serves to limit blood clot formation. Enzymatic cleavage of plasminogen by MMPs generates angiostatin, an angiogenesis inhibitor. Therefore, we examined whether platelets generate angiostatin during aggregation in vitro. Platelets were isolated from healthy human donors and then aggregated with collagen, thrombin, or HT-1080 fibrosarcoma cells. Angiostatin was detected by Western blot analysis in the platelet releasates of all blood donors irrespective of the aggregating agent used. Platelet pellet homogenates showed the presence of angiostatin in all donors, which was released upon aggregation. Furthermore, platelet-derived angiostatin was isolated and purified by lysine-Sepharose affinity chromatography from collagen-aggregated platelet releasates. Bioassay of platelet-derived angiostatin showed that it inhibited the formation of capillary structures by human umbilical vein endothelial cells (HUV-EC-Cs) in an in vitro angiogenesis model. Inhibition of angiostatin in platelet releasates promoted the formation of capillary structures by HUV-EC-Cs. We conclude that healthy human platelets contain angiostatin, which is released in active form during platelet aggregation, and platelet-derived angiostatin has the capacity to inhibit angiogenesis.

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12

Troyanovsky, Boris, Tetyana Levchenko, Göran Månsson, Olga Matvijenko, and Lars Holmgren. "Angiomotin." Journal of Cell Biology 152, no. 6 (March 19, 2001): 1247–54. http://dx.doi.org/10.1083/jcb.152.6.1247.

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Angiostatin, a circulating inhibitor of angiogenesis, was identified by its ability to maintain dormancy of established metastases in vivo. In vitro, angiostatin inhibits endothelial cell migration, proliferation, and tube formation, and induces apoptosis in a cell type–specific manner. We have used a construct encoding the kringle domains 1–4 of angiostatin to screen a placenta yeast two-hybrid cDNA library for angiostatin-binding peptides. Here we report the identification of angiomotin, a novel protein that mediates angiostatin inhibition of migration and tube formation of endothelial cells. In vivo, angiomotin is expressed in the endothelial cells of capillaries as well as larger vessels of the human placenta. Upon expression of angiomotin in HeLa cells, angiomotin bound and internalized fluorescein-labeled angiostatin. Transfected angiomotin as well as endogenous angiomotin protein were localized to the leading edge of migrating endothelial cells. Expression of angiomotin in endothelial cells resulted in increased cell migration, suggesting a stimulatory role of angiomotin in cell motility. However, treatment with angiostatin inhibited migration and tube formation in angiomotin-expressing cells but not in control cells. These findings indicate that angiostatin inhibits cell migration by interfering with angiomotin activity in endothelial cells.

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URANO, Tetsumei. "Angiostatin." Japanese Journal of Thrombosis and Hemostasis 9, no. 3 (1998): 196–200. http://dx.doi.org/10.2491/jjsth.9.196.

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Koshida, Ryoji, Jingsong Ou, Toshiro Matsunaga, William M. Chilian, Keith T. Oldham, Allan W. Ackerman, and Kirkwood A. Pritchard. "Angiostatin." Circulation 107, no. 6 (February 18, 2003): 803–6. http://dx.doi.org/10.1161/01.cir.0000057551.88851.09.

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Basile, David P., Katherine Fredrich, Dorothee Weihrauch, Naoichiro Hattan, and William M. Chilian. "Angiostatin and matrix metalloprotease expression following ischemic acute renal failure." American Journal of Physiology-Renal Physiology 286, no. 5 (May 2004): F893—F902. http://dx.doi.org/10.1152/ajprenal.00328.2003.

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Ischemic injury to the kidney results in blood vessel loss and predisposition to chronic renal disease. Angiostatin is a proteolytic cleavage product of plasminogen that inhibits angiogenesis, promotes apoptosis of endothelial cells, and disrupts capillary integrity. A combination of lysine-Sepharose enrichment followed by Western blotting was used to study the expression of angiostatin in response to the induction of ischemic renal injury. No angiostatin products were readily detectable in kidneys of sham-operated control rats. In contrast, both 38- and 50-kDa forms of angiostatin were dramatically enhanced in the first 3 days following 45-min ischemia-reperfusion injury. Renal angiostatin levels declined but remained detectable at late time points postrecovery (8–35 days postischemia). Angiostatin-like immunoreactivity was also elevated in the plasma and in urine for up to 35 days following injury. Lysine-Sepharose extracts of either kidney or urine inhibited vascular endothelial cell growth factor-induced proliferation of human aortic endothelial cells in vitro; an effect that was blocked by coincubation with an angiostatin antibody. RT-PCR verified that mRNA of the parent protein plasminogen was produced in the liver, but it was not present in either sham-operated or postischemic kidney. Matrix metalloproteinase (MMP)-2 and MMP-9, which may mediate angiostatin generation, were enhanced in postischemic kidney tissue and were localized to the renal tubules, interstitial cells, and the tubulo-interstitial space. These data indicate the possible local synthesis of angiostatin following acute renal failure (ARF) and suggest a possible role for MMPs in this activity. Renal angiostatin generation following ARF may modulate renal capillary density postischemia and thereby influence chronic renal function.

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Mu, Wei, David A. Long, Xiaosen Ouyang, Anupam Agarwal, Pedro E. Cruz, Carlos A. Roncal, Takahiko Nakagawa, XueQing Yu, William W. Hauswirth, and Richard J. Johnson. "Angiostatin overexpression is associated with an improvement in chronic kidney injury by an anti-inflammatory mechanism." American Journal of Physiology-Renal Physiology 296, no. 1 (January 2009): F145—F152. http://dx.doi.org/10.1152/ajprenal.90430.2008.

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Angiostatin, a proteolytic fragment of plasminogen, is a potent anti-angiogenic factor recently shown also to have an inhibitory effect on leukocyte recruitment and macrophage migration. Because both angiogenesis and inflammation play key roles in the progression of chronic kidney disease, we evaluated the effect of angiostatin treatment in the rat remnant kidney model. Rats were pretreated for 4 wk with recombinant adeno-associated viruses expressing either angiostatin or green fluorescence protein. Chronic renal disease was then induced by a subtotal nephrectomy, and rats were killed 8 wk later for analysis. Angiostatin treatment was associated with significantly less proteinuria but no alterations in serum creatinine, creatinine clearance, and blood urea nitrogen levels. Treatment with angiostatin reduced renal peritubular capillary number and decreased urinary nitric oxide levels. Despite reducing capillary density, angiostatin diminished interstitial fibrosis in association with reduced macrophage and T-cell infiltration and renal monocyte chemoattractant protein-1 mRNA levels. In conclusion, angiostatin overexpression was associated with attenuated renal disease progression in a model of chronic kidney injury, likely because of its anti-inflammatory actions. However, its anti-angiogenic actions suggest countering effects that could partially offset its benefit in chronic kidney diseases.

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Raskopf, E., M. A. Gonzalez-Carmona, A. Vogt, M. Kornek, L. Leifeld, C. Rabe, T. Sauerbruch, W. H. Caselmann, and V. Schmitz. "77 Kringles 1–5 of plasminogen exert more potent angiostatitc and antitumoral effects than kringles 1–4 (angiostatin)." Journal of Hepatology 44 (April 2006): S34. http://dx.doi.org/10.1016/s0168-8278(06)80078-4.

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Chen, Ya-Huey, Hua-Lin Wu, Ching Li, Yi-Hsien Huang, Chi-Wu Chiang, Ming-Ping Wu, and Li-Wha Wu. "Anti-angiogenesis mediated by angiostatin K1–3, K1–4 and K1–4.5." Thrombosis and Haemostasis 95, no. 04 (2006): 668–77. http://dx.doi.org/10.1160/th05-11-0757.

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SummaryThe molecular mechanism mediated by multiple forms of angiostatin via acting on proliferating vascular endothelium remains elusive. To address whether three forms of angiostatin, K1-3, K1-4 or K1-4.5, utilized similar or distinct pathways to mediate anti-angiogenesis, we adopted an adenoviral expression system to express secretable angiostatin molecules for CM collection. The anti-angiogenic activity of K1-3, K1-4 or K1-4.5 was confirmed by using proliferation, migration, tube formation and apoptotic assays of human endothelial cells. These angiostatin molecules at comparable expression level inhibited various in vitro angiogenesis assays with some variations. Furthermore, K1-3, K1-4 or K1-4.5 increased the expression of p53 protein and its downstream effectors, enhanced FasL-mediated signaling pathways, and decreased activation of AKT. At least three different receptors, Fas, integrin αvβ3 and ATP synthase, were involved in the anti-angiogenic action of angiostatin molecules. Besides, the expression of 189 genes at mRNA level was significantly altered by K1-3, K1-4 or K1-4.5. More than 70% of these genes participate in growth, inflammation, apoptosis, migration and extracellular matrix. Taken together, K1-3, K1-4 and K1-4.5, regardless of the number of kringles in the angiostatin molecules, mediated anti-angiogenesis via mostly similar pathways. We are the first to demonstrate the involvement of DAPK1 in the mediation of anti-angiogenesis by angiostatin.

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Mandic, Aljosa, Tamara Vujkov, Dejan Nincic, and Slobodan Komazec. "Tumor angiogenesis and endometrial cancer." Archive of Oncology 10, no. 2 (2002): 79–81. http://dx.doi.org/10.2298/aoo0202079m.

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Increasing importance is given to the clinical significance of the new formation of vessels (angiogenesis) in the course of physiological inflammatory and neoplastic processes. Angiogenesis is best studied in the growth of malignant tumors, since cancer may be regarded as the most important angiogenesis-dependent disease. Vascular endothelial cell proliferation, migration, and capillary formation are stimulated by angiogenic growth factors, which include the proteins vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and transforming growth factor, and eicosanoids synthesized from n-6 fatty acids. Angiogenesis plays an important role in physiological proliferation of the endometrium and formation of corpus luteum in the second half of menstrual cycle. The present study showed that microvessel counts affect prognosis of patients with endometrial cancer. Analysis of angiogenesis in endometrial cancer may be a useful biologic parameter and additional study of neovascularization is required. Tumor angiogenesis is regulated by the balance of stimulators (e.g., VEGF, bFGF) and inhibitors of angiogenesis (e.g., angiostatin, endostatin, angiostatic steroids). Measuring angiogenesis (blood vessel density) and/or its main regulators such as VEGF and bFGF in solid tumors, or the levels of these growth factors in the serum or urine provides new and sensitive markers for tumor progression, metastasis and prognosis.

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Matsunaga, Toshiro, William M. Chilian, and Keith March. "Angiostatin is negatively associated with coronary collateral growth in patients with coronary artery disease." American Journal of Physiology-Heart and Circulatory Physiology 288, no. 5 (May 2005): H2042—H2046. http://dx.doi.org/10.1152/ajpheart.00669.2004.

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Angiostatin, an inhibitor of tumor angiogenesis, is produced by the actions of matrix metalloproteinases (MMP) on plasminogen. Recently, we reported that angiostatin levels are increased in a model of inadequate coronary collateral growth and angiogenesis in response to ischemia, despite high levels of vascular endothelial growth factor (VEGF). We hypothesized that angiostatin levels are negatively associated with collateral formation in patients. Coronary angiograms from 37 patients undergoing coronary bypass surgery were evaluated for the absence of angiographically visible collaterals (Rentrop scores of 0) or the presence of Rentrop classification grade 3 (well developed) collaterals. Pericardial fluid was obtained from each patient during the bypass procedure, and the sample was analyzed for angiostatin, plasminogen, and VEGF (Western analysis) and for combined activities of MMP-2 and MMP-9 (zymographic analysis). In patients with no collaterals, angiostatin level was greater compared with that in patients with well-developed collaterals (3.1 ± 0.2 vs. 2.3 ± 0.1 optical density units, P < 0.05). Neither MMP activities nor VEGF levels were different between the two groups of patients. The higher levels of angiostatin in patients with no visible collaterals were reflective of a higher concentration of plasmin/plasminogen (6.2 ± 0.7 vs. 4.2 ± 0.5 optical density units, P < 0.05) compared with those in patients with well-developed collateral vessels. Our results support the concept that the growth inhibitor angiostatin may have a negative impact on coronary collateral growth in patients. Perhaps therapies attempting to provoke coronary collateral growth should incorporate approaches to limit or neutralize the effects of growth inhibitors.

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Chavakis, Triantafyllos, Athanasios Athanasopoulos, Joong-Sup Rhee, Valeria Orlova, Thomas Schmidt-Wöll, Angelika Bierhaus, Andreas E. May, Ilhan Celik, Peter P. Nawroth, and Klaus T. Preissner. "Angiostatin is a novel anti-inflammatory factor by inhibiting leukocyte recruitment." Blood 105, no. 3 (February 1, 2005): 1036–43. http://dx.doi.org/10.1182/blood-2004-01-0166.

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AbstractAngiogenesis and inflammation are closely related biologic processes in wound healing and the responses to vascular injury as well as in cardiovascular diseases; however, the molecular connections are poorly defined. In particular, it is yet unclear whether endogenous factors can regulate both angiogenesis and inflammation. Here, we show that the endogenous angiogenesis inhibitor, angiostatin (containing kringle domains 1-4 of plasminogen), serves an anti-inflammatory role, since the kringles 1-3 and its kringle 4 directly interact with leukocyte β1- and β2-integrins, respectively. In particular, a specific interaction between kringle 4 and αMβ2-integrin (Mac-1) but not leukocyte function antigen 1 (LFA-1) was identified. Angiostatin thereby inhibited β1- and β2-integrin–mediated adhesion of leukocytes to extracellular matrix proteins and the endothelium as well as their transmigration through the endothelium in vitro. Moreover, angiostatin blocked the peritonitis-induced neutrophil emigration in vivo. In addition, through its interaction with Mac-1, angiostatin reduced activation of the proinflammatory transcription factor nuclear factor κB (NFκB), as well as the NFκB-related expression of tissue factor, a potent initiator of hemostasis following vascular injury. Finally, angiostatin forms were generated in vivo following skin injury/inflammation and were detectable during the following entire period of wound healing peaking at the terminal phase of the healing process. Taken together, over and above inhibition of neovascularization, angiostatin was identified as an antiadhesive/anti-inflammatory substance. These observations could provide the basis for new therapeutic applications of angiostatin to target chronic inflammatory processes in different pathologic situations.

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Stack, M., Miriam Wahl, Salvatore Pizzo, and Tammy Moser. "The Mechanism of Action of Angiostatin: Can You Teach an Old Dog New Tricks?" Thrombosis and Haemostasis 87, no. 03 (2002): 394–401. http://dx.doi.org/10.1055/s-0037-1613016.

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SummaryWhat is angiostatin? In 1994, Folkman and colleagues published a landmark paper describing anti-tumor effects in mice with a purified fragment of plasminogen they named angiostatin (1). Although many papers have been published describing activities of cryptic polypeptides derived from plasminogen fragments, this was the first report which associated plasminogen kringles 1–4 as a suppressor of metastasis development. This review will describe what is known about the mechanism of action of angiostatin from the current literature.

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Ramsden, JD, S. Yarram, E. Mathews, JC Watkinson, and MC Eggo. "Thyroid follicular cells secrete plasminogen activators and can form angiostatin from plasminogen." Journal of Endocrinology 173, no. 3 (June 1, 2002): 475–81. http://dx.doi.org/10.1677/joe.0.1730475.

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Angiostatin, a 38 kDa fragment of plasminogen, potently inhibits the growth of blood vessels. Angiostatin is generated from plasminogen by urokinase-type (uPA) and tissue-type (tPA) plasminogen activators in the presence of free sulphydryl donors. Angiogenesis inhibitors may be important in regulating angiogenesis in developing goitre. We have examined angiostatin formation in human primary thyrocyte cultures and a rat thyrocyte cell line (FRTL-5). We found that human thyroid cells in culture secrete plasminogen activators (both tPA and uPA) as well as matrix metalloproteinase 2 into the medium. When human thyrocyte conditioned medium was incubated with plasminogen (10 microg/ml) and N-acetylcysteine (100 microM) for 24 h, a 38 kDa fragment of plasminogen, which is consistent with angiostatin, was generated. The appearance of the 38 kDa fragment was increased by agents that increase cAMP (forskolin and 8 BrcAMP). FRTL-5 cells, which do not secrete uPA or tPA, did not generate angiostatin. Thyroid cells produce several angiogenic growth factors, and human thyrocyte conditioned medium stimulated growth of endothelial cells. When the conditioned medium was incubated with plasminogen and N-acetylcysteine, this stimulatory effect was lost, consistent with the production of a growth inhibitory factor. We conclude that thyroid cells can produce angiostatin from plasminogen in vitro, and this may play a role in vivo in limiting goitre size.

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Aulakh, Gurpreet K., Sarabjeet S. Suri, and Baljit Singh. "Angiostatin inhibits acute lung injury in a mouse model." American Journal of Physiology-Lung Cellular and Molecular Physiology 306, no. 1 (January 1, 2014): L58—L68. http://dx.doi.org/10.1152/ajplung.00368.2012.

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Acute lung injury is marked by profound influx of activated neutrophils, which have delayed apoptosis, along with fluid accumulation that impairs lung function and causes high mortality. Inflammatory and antimicrobial molecules, such as reactive oxygen species from activated neutrophils with prolonged lifespan, cause tissue damage and contribute to lung dysfunction. Angiostatin, an endogenous antiangiogenic molecule, is expressed in the lavage fluid of patients with acute respiratory distress syndrome and modifies neutrophil infiltration in a mouse model of peritonitis. Our aim was to investigate the therapeutic role of angiostatin in acute lung injury. We analyzed bronchoalveolar lavage and lung tissues from C57BL/6 mouse model of Escherichia coli LPS-induced acute lung injury to assess the effects of angiostatin treatment. Subcutaneous angiostatin administered at 5 h after LPS treatment reduces histological signs of inflammation, protein accumulation, lung Gr1+ neutrophils, myeloperoxidase activity, and expression of phosphorylated p38 MAPK in lung tissues and peripheral blood neutrophils, while increasing the number of apoptotic cells in the lungs without affecting the levels of macrophage inflammatory protein-1 α, IL-1β, keratinocyte chemoattractant, and monocyte chemoattractant protein-1 in lavage and lung homogenates at 9 and 24 h after LPS treatment. In contrast, angiostatin administered intravenously 5 h after LPS treatment did not reduce histological sign of inflammation, BAL cell recruitment, and protein concentration at 9 h of LPS treatment. We conclude that angiostatin administered subcutaneously after LPS challenge inhibits acute lung inflammation up to 24 h after LPS treatment.

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Jiang, Lianwei, Vivekanand Jha, Mohanraj Dhanabal, Vikas P. Sukhatme, and Seth L. Alper. "Intracellular Ca2+signaling in endothelial cells by the angiogenesis inhibitors endostatin and angiostatin." American Journal of Physiology-Cell Physiology 280, no. 5 (May 1, 2001): C1140—C1150. http://dx.doi.org/10.1152/ajpcell.2001.280.5.c1140.

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Intracellular signaling mechanisms by the angiogenesis inhibitors endostatin and angiostatin remain poorly understood. We have found that endostatin (2 μg/ml) and angiostatin (5 μg/ml) elicited transient, approximately threefold increases in intracellular Ca2+concentration ([Ca2+]i). Acute exposure to angiostatin or endostatin nearly abolished subsequent endothelial [Ca2+]iresponses to carbachol or to thapsigargin; conversely, thapsigargin attenuated the Ca2+signal elicited by endostatin. The phospholipase C inhibitor U-73122 and the inositol trisphosphate (IP3) receptor inhibitor xestospongin C both inhibited endostatin-induced elevation in [Ca2+]i, and endostatin rapidly elevated endothelial cell IP3levels. Pertussis toxin and SB-220025 modestly inhibited the endostatin-induced Ca2+signal. Removal of extracellular Ca2+inhibited the endostatin-induced rise in [Ca2+]i, as did a subset of Ca2+-entry inhibitors. Peak Ca2+responses to endostatin and angiostatin in endothelial cells exceeded those in epithelial cells and were minimal in NIH/3T3 cells. Overnight pretreatment of endothelial cells with endostatin reduced the subsequent acute elevation in [Ca2+]iin response to vascular endothelial growth factor or to fibroblast growth factor by ∼70%. Intracellular Ca2+signaling may initiate or mediate some of the cellular actions of endostatin and angiostatin.

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ZHAO, GAIPING, ERYUN CHEN, XIAOLI YU, HAIPO CUI, JIE LV, and JIE WU. "THREE-DIMENSIONAL MODEL OF METASTATIC TUMOR ANGIOGENESIS IN RESPONSE TO ANTI-ANGIOGENIC FACTOR ANGIOSTATIN." Journal of Mechanics in Medicine and Biology 17, no. 06 (September 2017): 1750094. http://dx.doi.org/10.1142/s0219519417500944.

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Surgeons observed that primary tumors are capable of suppressing the growth of their metastases by generating anti-angiogenic factor angiostatin. A three-dimensional (3D) mathematical model of development of the metastatic tumor vasculature is presented to simulate the morphology and construction of 3D microvascular networks under the inhibitory effect of anti-angiogenic factor angiostatin excreted by the primary tumor. The simulation results demonstrate that metastatic tumor microvascular density (MVD) decreases by about 60%, 58% and 52%, respectively, at [Formula: see text], 7 and 14 days under the effect of anti-angiogenic factor angiostatin. The abnormal geometric and morphological features of 3D microvasculature networks inside and outside the metastatic tumor improve in the presence of angiostatin. The present model may allow to simulate experimental tests and may provide theoretical models for clinical research of anti-angiogenic therapy strategies.

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Mowery, Yvonne M., and Salvatore V. Pizzo. "The antitumorigenic trifecta." Blood 114, no. 9 (August 27, 2009): 1727–28. http://dx.doi.org/10.1182/blood-2009-06-226233.

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The laboratory of Judah Folkman identified the potent endogenous antiangiogenic protein angiostatin in 1994.1 In this issue of Blood, Lee and colleagues propose 2 new mechanisms of action for angiostatin that may represent promising targets for new cancer therapeutics.2

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Lijnen, H., Anthony Suffredini, Michael Pepper, Kenneth Steinberg, Thomas Martin, Jérôme Pugin, and Rudolf Lucas. "Increased Angiostatin Levels in Bronchoalveolar Lavage Fluids from ARDS Patients and from Human Volunteers after Lung Instillation of Endotoxin." Thrombosis and Haemostasis 87, no. 06 (2002): 966–71. http://dx.doi.org/10.1055/s-0037-1613119.

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SummaryAcute respiratory distress syndrome (ARDS) is characterized by a disruption of the alveolar-capillary barrier, due to both an epithelial and an endothelial dysfunction. Whereas epithelial apoptosis seems to be mainly mediated by Fas ligand, the mediators of endothelial damage remain to be identified. Angiostatin, a powerful inhibitor of angiogenesis in vivo, also specifically induces apoptosis in endothelial cells. The concentration of various enzymes that cleave angiostatin from plasminogen was reported to be significantly increased in bronchalveolar lavage (BAL) fluids from patients with ARDS. Therefore, in this study, we investigated whether angiostatin was generated during the pulmonary inflammatory response of both healthy subjects challenged with endobronchial endotoxin and in patients with ARDS. We found significantly elevated angiostatin levels in BAL fluids from patients at risk for and with early ARDS (up to 0.022% and 0.018% of total protein, respectively), as well as in BAL fluids from volunteers treated with endotoxin (up to 1.17% of total protein), as compared to BAL fluids from control patients (<0.005% of total protein). These data suggest that angiostatin may contribute to the endothelial damage observed in ARDS, probably via an increased permeability of the alveolar capillary barrier, allowing for an intra-alveolar processing of its precursor plasminogen.

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SATO, Yasufumi. "Angiostatin and Endostatin." Kagaku To Seibutsu 37, no. 5 (1999): 306–11. http://dx.doi.org/10.1271/kagakutoseibutsu1962.37.306.

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Tykhomyrov, A. A., S. I. Shram, and T. V. Grinenko. "Role of angiostatins in diabetic complications." Biomeditsinskaya Khimiya 61, no. 1 (January 2015): 41–56. http://dx.doi.org/10.18097/pbmc20156101041.

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Angiogenesis is a process through which new blood vessels form from pre-existing vessels. Angiogenesis is regulated by a number of factors of peptide nature. Disbalance of angiogenic system appears to be the major causative factor contributing vascular abnormalities in diabetes mellitus, resulting in various complications. Angiostatins, which are kringle-containing fragments of plasminogen/plasmin, are known to be powerful physiological inhibitors of neovascularization. In the present review, current literature data on peculiarities of production of angiostatins and their functioning at diabetes mellitus are summarized and analyzed for the first time. Also, role of angiostatins in the pathogenesis of typical diabetic complications, including retinopathies, nephropathies and cardiovascular diseases, is discussed. Data presented in this review may be useful for elaboration of novel effective approaches for diagnostics and therapy of vascular abnormalities in diabetes mellitus.

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Weihrauch, Dorothee, Hao Xu, Yang Shi, Jingli Wang, Jennifer Brien, Deron W. Jones, Sushma Kaul, et al. "Effects of D-4F on vasodilation, oxidative stress, angiostatin, myocardial inflammation, and angiogenic potential in tight-skin mice." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 3 (September 2007): H1432—H1441. http://dx.doi.org/10.1152/ajpheart.00038.2007.

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Systemic sclerosis (scleroderma, SSc) is an autoimmune, connective tissue disorder that is characterized by impaired vascular function, increased oxidative stress, inflammation of internal organs, and impaired angiogenesis. Tight skin mice (Tsk−/+) have a defect in fibrillin-1, resulting in replication of many of the myocardial and vascular features seen in humans with SSc. D-4F is an apolipoprotein A-I (apoA-I) mimetic that improves vascular function in diverse diseases such as hypercholesterolemia, influenza, and sickle cell disease. Tsk−/+ mice were treated with either phosphate-buffered saline (PBS) or D-4F (1 mg·kg−1·day−1 for 6–8 wk). Acetylcholine and flow-induced vasodilation were examined in facialis arteries. Proinflammatory HDL (p-HDL) in murine and human plasma samples was determined by the cell-free assay. Angiostatin levels in murine and human plasma samples were determined by Western blot analysis. Hearts were examined for changes in angiostatin and autoantibodies against oxidized phosphotidylcholine (ox-PC). Angiogenic potential in thin sections of murine hearts was assessed by an in vitro vascular endothelial growth factor (VEGF)-induced endothelial cell (EC) tube formation assay. D-4F improved endothelium-, endothelial nitric oxide synthase-dependent, and flow-mediated vasodilation in Tsk−/+ mice. Tsk−/+ mice had higher plasma p-HDL and angiostatin levels than C57BL/6 mice, as did SSc patients compared with healthy control subjects. Tsk−/+ mice also had higher triglycerides than C57BL/6 mice. D-4F reduced p-HDL, angiostatin, and triglycerides in the plasma of Tsk−/+ mice. Tsk−/+ hearts contained notably higher levels of angiostatin and autoantibodies against ox-PC than those of control hearts. D-4F ablated angiostatin in Tsk−/+ hearts and reduced autoantibodies against ox-PC by >50% when compared with hearts from untreated Tsk−/+ mice. Angiogenic potential in Tsk−/+ hearts was increased only when the Tsk−/+ mice were treated with D-4F (1 mg·kg−1·day−1, 6–8 wk), and cultured sections of hearts from the D-4F-treated Tsk−/+ micewere incubated with D-4F (10 μg/ml, 5–7 days). Failure to treat the thin sections of hearts and Tsk−/+ mice with D-4F resulted in loss of VEGF-induced EC tube formation. D-4F improves vascular function, decreases myocardial inflammation, and restores angiogenic potential in the hearts of Tsk−/+ mice. As SSc patients have increased plasma p-HDL and angiostatin levels similar to the Tsk−/+ mice, D-4F may be effective at treating vascular complications in patients with SSc.

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Mogues, Tirsit, Michael Etzerodt, Crystal Hall, Georg Engelich, Jonas H. Graversen, and Kevan L. Hartshorn. "Tetranectin Binds to the Kringle 1-4 Form of Angiostatin and Modifies Its Functional Activity." Journal of Biomedicine and Biotechnology 2004, no. 2 (2004): 73–78. http://dx.doi.org/10.1155/s1110724304307096.

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Tetranectin is a plasminogen kringle 4 domain-binding protein present in plasma and various tissue locations. Decreased plasma tetranectin or increased tetranectin in stroma of cancers correlates with cancer progression and adverse prognosis. A possible mechanism through which tetranectin could influence cancer progression is by altering activities of plasminogen or the plasminogen fragment, angiostatin. Tetranectin was found to bind to the kringle 1-4 form of angiostatin (ASTK1-4). In addition, tetranectin inhibited binding of plasminogen or ASTK1-4to extracellular matrix (ECM) deposited by endothelial cells. Finally, tetranectin partially counteracted the ability of ASTK1-4to inhibit proliferation of endothelial cells. This latter effect of tetranectin was specific for ASTK1-4since it did not counteract the antiproliferative activities of the kringle 1-3 form of angiostatin (ASTK1-3) or endostatin. These findings suggest that tetranectin may modulate angiogenesis through interactions with AST.

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Martinez-Zaguilan;, R. "Angiostatin's Partners." Science 284, no. 5413 (April 16, 1999): 433d—433. http://dx.doi.org/10.1126/science.284.5413.433d.

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Wilczyńska, U., A. Kucharska, J. Szary, and S. Szala. "Combined delivery of an antiangiogenic protein (angiostatin) and an immunomodulatory gene (interleukin-12) in the treatment of murine cancer." Acta Biochimica Polonica 48, no. 4 (December 31, 2001): 1077–84. http://dx.doi.org/10.18388/abp.2001_3868.

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We investigated the feasibility of a novel therapeutic approach to treat neoplastic diseases in mice. This novel strategy consists in delivering a protein (angiostatin) with strong antiangiogenic properties, followed by administration of the interleukin 12 gene that is strongly immunomodulatory and has also some antiangiogenic effects. When angiostatin-mediated antiangiogenic therapy was used in combination with intratumor delivery of the IL-12 gene (a strategy much safer than IL-12 protein administration), this produced a synergistic therapeutic effect.

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&NA;. "Angiostatin enhances antineoplastic treatment." Inpharma Weekly &NA;, no. 1150 (August 1998): 10. http://dx.doi.org/10.2165/00128413-199811500-00016.

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Soff, G. "Angiostatin and hepatocellular carcinoma." Hepatology 37, no. 3 (March 2003): 505–6. http://dx.doi.org/10.1053/jhep.2003.50125.

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Yang, Xiaofei, and Bo Lu. "Global Bounded Classical Solutions for a Gradient-Driven Mathematical Model of Antiangiogenesis in Tumor Growth." Mathematical Problems in Engineering 2020 (January 9, 2020): 1–5. http://dx.doi.org/10.1155/2020/9708201.

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In this paper, we consider a gradient-driven mathematical model of antiangiogenesis in tumor growth. In the model, the movement of endothelial cells is governed by diffusion of themselves and chemotaxis in response to gradients of tumor angiogenic factors and angiostatin. The concentration of tumor angiogenic factors and angiostatin is assumed to diffuse and decay. The resulting system consists of three parabolic partial differential equations. In the present paper, we study the global existence and boundedness of classical solutions of the system under homogeneous Neumann boundary conditions.

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FOLKMAN, JUDAH, and DONALD E. INGBER. "Angiostatic Steroids." Annals of Surgery 206, no. 3 (September 1987): 374. http://dx.doi.org/10.1097/00000658-198709000-00016.

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Dong, Zhongyun, Junya Yoneda, Rakesh Kumar, and Isaiah J. Fidler. "Angiostatin-mediated Suppression of Cancer Metastases by Primary Neoplasms Engineered to Produce Granulocyte/Macrophage Colony–stimulating Factor." Journal of Experimental Medicine 188, no. 4 (August 17, 1998): 755–63. http://dx.doi.org/10.1084/jem.188.4.755.

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We determined whether tumor cells consistently generating granulocyte/macrophage colony– stimulating factor (GM-CSF) can recruit and activate macrophages to generate angiostatin and, hence, inhibit the growth of distant metastasis. Two murine melanoma lines, B16-F10 (syngeneic to C57BL/6 mice) and K-1735 (syngeneic to C3H/HeN mice), were engineered to produce GM-CSF. High GM-CSF (>1 ng/106 cells)– and low GM-CSF (<10 pg/106 cells)–producing clones were identified. Parental, low, and high GM-CSF–producing cells were injected subcutaneously into syngeneic and into nude mice. Parental and low-producing cells produced rapidly growing tumors, whereas the high-producing cells produced slow-growing tumors. Macrophage density inversely correlated with tumorigenicity and directly correlated with steady state levels of macrophage metalloelastase (MME) mRNA. B16 and K-1735 subcutaneous (s.c.) tumors producing high levels of GM-CSF significantly suppressed lung metastasis of 3LL, UV-2237 fibrosarcoma, K-1735 M2, and B16-F10 cells, but parental or low-producing tumors did not. The level of angiostatin in the serum directly correlated with the production of GM-CSF by the s.c. tumors. Macrophages incubated with medium conditioned by GM-CSF– producing B16 or K-1735 cells had higher MME activity and generated fourfold more angiostatin than control counterparts. These data provide direct evidence that GM-CSF released from a primary tumor can upregulate angiostatin production and suppress growth of metastases.

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Sodha, Neel R., Richard T. Clements, Munir Boodhwani, Shu-Hua Xu, Roger J. Laham, Cesario Bianchi, and Frank W. Sellke. "Endostatin and angiostatin are increased in diabetic patients with coronary artery disease and associated with impaired coronary collateral formation." American Journal of Physiology-Heart and Circulatory Physiology 296, no. 2 (February 2009): H428—H434. http://dx.doi.org/10.1152/ajpheart.00283.2008.

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Coronary artery disease (CAD) is the leading cause of mortality in diabetic patients. Because of the diffuse nature of their disease, diabetic patients may be at risk for incomplete revascularization, highlighting a potential role for proangiogenic therapy in this group. This study investigates molecular mechanisms of angiogenesis in diabetic patients. Myocardial tissue was harvested from patients undergoing coronary artery bypass grafting [nondiabetic (ND) 11, type 2 diabetic (DM) 10]. Expression of angiostatin, endostatin, their precursors (plasminogen and collagen XVIII, respectively), enzymes leading to their production [matrix metalloprotease (MMP)-2 and -9, cathepsin L], and an inhibitor of MMPs (tissue inhibitor of metalloproteinase) was assessed with Western blotting. MMP activity was assessed. Coronary collateralization was graded by Rentrop scoring of angiograms. Plasminogen and collagen XVIII expression were similar between groups. Angiostatin expression trended to increase 1.24-fold ( P = 0.07), and endostatin expression increased 2.02-fold in DM patients relative to ND ( P = 0.02). MMP-9 expression was no different between groups, whereas MMP-2 expression decreased 1.8-fold in diabetics ( P = 0.003). MMP-2 and -9 activity decreased 1.33-fold ( P = 0.03) and 1.57-fold ( P = 0.04), respectively, in diabetic patients. Cathepsin L expression was 1.38-fold higher in diabetic patients ( P = 0.02). Coronary collateralization scores were ND 2.1 ± 0.37 vs. DM 1.0 ± 0.4 ( P = 0.05). Myocardial endostatin expression correlated strongly with the percentage of hemoglobin A1c ( r = 0.742, P = 0.0001). Myocardial expression of angiostatin and endostatin demonstrated significant negative linear correlations with coronary collateralization (angiostatin r = −0.531, P = 0.035, endostatin r = −0.794, P = 0.0002). Diabetic patients with CAD exhibit increased levels of the antiangiogenic proteins angiostatin and endostatin and differential regulation of the enzymes governing their production relative to ND patients. Myocardial levels of these proteins show significant correlation to coronary collateralization. These findings offer potential new therapeutic targets for enhancing proangiogenic therapy and insight into the angiogenic impairments seen in diabetes.

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Margetts, Peter J., Steve Gyorffy, Martin Kolb, Lisa Yu, Catherine M. Hoff, Clifford J. Holmes, and Jack Gauldie. "Antiangiogenic and Antifibrotic Gene Therapy in a Chronic Infusion Model of Peritoneal Dialysis in Rats." Journal of the American Society of Nephrology 13, no. 3 (March 2002): 721–28. http://dx.doi.org/10.1681/asn.v133721.

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ABSTRACT. To identify the relative importance of peritoneal fibrosis and angiogenesis in peritoneal membrane dysfunction, adenoviral mediated gene transfer of angiostatin, a recognized angiogenesis inhibitor, and decorin, a transforming growth factor-β–inhibiting proteoglycan, were used in a daily infusion model of peritoneal dialysis. A peritoneal catheter and subcutaneous port were inserted in rats. Five and fourteen d after insertion, adenovirus-expressing angiostatin, decorin, or AdDL70, a null control virus, were administered. Daily infusion of 4.25% Baxter Dianeal was initiated 7 d after catheter insertion and continued until day 35. Three initial doses of lipopolysaccharide were administered on days 8, 10, and 12 to promote an inflammatory response. Net ultrafiltration was used as a measure of membrane function, and peritoneum-associated vasculature and mesenteric collagen content was quantified. Ultrafiltration dysfunction, angiogenesis, and fibrosis were observed in daily infusion control animals. Animals treated with AdAngiostatin demonstrated an improvement in net ultrafiltration (−3.1 versus −7.8 ml for control animals; P = 0.0004) with a significant reduction in vessel density. AdDecorin-treated animals showed a reduction in mesenteric collagen content (1.8 versus 2.9 μg/mg; P = 0.04); however, AdDecorin treatment had no effect on net ultrafiltration. In a rodent model of peritoneal membrane failure, net ultrafiltration was significantly improved and peritoneal-associated blood vessels were significantly reduced by using adenovirus-mediated gene transfer of angiostatin. Decorin, a transforming growth factor-β–inhibiting proteoglycan, reduced collagen content but did not affect net ultrafiltration. Improvement in the function of the peritoneum as a dialysis membrane after treatment with angiostatin has implications for treatment of peritoneal membrane dysfunction seen in patients on long-term dialysis.

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Félez, Jordi, and Mercè Jardí Begoña Arza. "Angiostatina y su actividad antitumoral." Medicina Clínica 114, no. 11 (January 2000): 431–36. http://dx.doi.org/10.1016/s0025-7753(00)71319-4.

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He, Jin, Hong Xiao, Bo Li, Yuan Peng, Xiaoxia Li, Yong Wang, Grazyna Adamus, Marek Kowalczuk, and Xintao Shuai. "The programmed site-specific delivery of the angiostatin sunitinib and chemotherapeutic paclitaxel for highly efficient tumor treatment." Journal of Materials Chemistry B 7, no. 32 (2019): 4953–62. http://dx.doi.org/10.1039/c9tb01159e.

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&NA;. "Angiostatin shrinks tumours in mice." Inpharma Weekly &NA;, no. 1043 (June 1996): 11. http://dx.doi.org/10.2165/00128413-199610430-00021.

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Cao, Yihai, Richard W. Ji, Don Davidson, Johann Schaller, Daniel Marti, Sabine Söhndel, Stephen G. McCance, Michael S. O'Reilly, Miguel Llinás, and Judah Folkman. "Kringle Domains of Human Angiostatin." Journal of Biological Chemistry 271, no. 46 (November 15, 1996): 29461–67. http://dx.doi.org/10.1074/jbc.271.46.29461.

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Grandi, Fabio, Massimo Sandal, Giovanni Guarguaglini, Emidio Capriotti, Rita Casadio, and Bruno Samorì. "Hierarchical Mechanochemical Switches in Angiostatin." ChemBioChem 7, no. 11 (September 22, 2006): 1774–82. http://dx.doi.org/10.1002/cbic.200600227.

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Wu, Pei-Huang, Qing-Hua Zhong, Teng-Hui Ma, Qi-Yuan Qin, Xiao-Yan Huang, Ying-Yi Kuang, Huai-Ming Wang, Zi-Xu Yuan, Lei Wang, and Dai-Ci Chen. "To what extent should the intestinal be resected proximally after radiotherapy: hint from a pathological view." Gastroenterology Report 8, no. 4 (October 16, 2019): 277–85. http://dx.doi.org/10.1093/gastro/goz047.

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Abstract Background Neoadjuvant chemoradiotherapy (nCRT) is associated with post-operative anastomotic complications in rectal-cancer patients. Anastomosis involving at least one non-irradiated margin reportedly significantly reduces the risk of post-operative anastomotic complications in radiation enteritis. However, the exact scope of radiotherapy on the remaining sigmoid colon remains unknown. Methods We evaluated the radiation damage of proximally resected colorectal segments in 44 patients with rectal cancer, who received nCRT followed by conventional resection (nCRT-C, n = 21) or proximally extended resection (nCRT-E, n = 23). The segments from another 13 patients undergoing neoadjuvant chemotherapy (nCT) were used as control. We dissected these samples at a distance of 2 cm between the two adjacent sections. Radiation damage in proximally resected colorectal segments was evaluated using the radiation injury score (RIS) and the concentration and distribution patterns of angiostatin. Results Compared to those in the nCT group, the nCRT group showed higher RIS, levels of angiostatin, and proportion of diffuse pattern of angiostatin. With increasing distance from the tumor site, these parameters all gradually decreased; and the differences came to be not significant at the site that is over 20 cm from the tumor. The nCRT-E group showed lower RIS (median: 2 vs 4, P = 0.002) and a greater proportion of non-diffuse angiostatin (87% vs 55%, P = 0.039) at the proximal margins compared with the nCRT-C group. Conclusions The severity of the radiation damage of the proximal colon is inversely proportional to the proximal-resection margin length. Little damage was left on the proximal margin that was over 20 cm from the tumor. Removal of an initial length of ≥20 cm from the tumor may be beneficial for rectal-cancer patients after nCRT.

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BAHRAMSOLTANI, MAHTAB, and JOHANNA PLENDL. "Different ways to antiangiogenesis by angiostatin and suramin, and quantitation of angiostatin-induced antiangiogenesis." APMIS 115, no. 1 (January 2007): 30–46. http://dx.doi.org/10.1111/j.1600-0463.2007.apm_405.x.

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Tykhomyrov, A. A., I. L. Vovchuk, and T. V. Grinenko. "Plasminogen and angiostatin levels in female benign breast lesions." Ukrainian Biochemical Journal 87, no. 5 (October 26, 2015): 103–12. http://dx.doi.org/10.15407/ubj87.05.103.

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Cao, Yue, Yan Li, Yin Wu, Wenliang Li, Chunlei Yu, Yanxin Huang, Luguo Sun, Yongli Bao, and Yuxin Li. "Correction: Co-Delivery of angiostatin and curcumin by a biodegradable polymersome for antiangiogenic therapy." RSC Advances 6, no. 116 (2016): 115367. http://dx.doi.org/10.1039/c6ra90135b.

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Journal articles on the topic 'Angiostatine'

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