Ukr.Biochem.J. 2025; Volume 97, Issue 5, Sep-Oct, pp. 72-87

doi: https://doi.org/10.15407/ubj97.05.072

Proteins of plasminogen/plasmin system: multifaceted roles in health and disease

A. O. Tykhomyrov*, O. I. Yusova, L. G. Kapustianenko, I. I. Patalakh,
T. A. Yatsenko, V. L. Bilous, T. V. Grynenko

Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine,
Department of Enzyme Chemistry and Biochemistry, Kyiv;
*e-mail: artem_tykhomyrov@ukr.net

Received: 20 April 2025; Revised: 02 June 2025;
Accepted: 30 October 2025; Available on-line: 02 December 2025

The plasminogen/plasmin (Pg/Pm) system is a cornerstone of various biological processes, encompassing roles in fibrinolysis, angiogenesis, inflammation, wound healing, and tumor biology. This review consolidates knowledge on the multifaceted functions of the Pg/Pm system proteins in health and disease, highlighting historical developments, recent advancements, and the contributions of the Department of Enzyme Chemistry and Biochemistry to the understanding of their molecular mechanisms of function. We have explored the regulation of fibrinolysis and its intricate interplay with proteins of the Pg/Pm system, delving into their pivotal role in hemostatic balance. Reciprocal interactions between Pg/Pm system proteins and platelets underscore their contribution to thrombosis, fibrinolysis, inflammation, and vascular remodeling. In oncology, Pg/Pm system proteins orchestrate tumor growth and metastasis through their involvement in extracellular matrix remodeling, angiogenesis, and cancer cell survival. However, angiostatins – proteolyti­cally-derived fragments of Pg/Pm – emerge as multifunctional polypeptides, which are known to affect cell migration, angiogenesis, and inflammation, suppress tumor growth and metastasis. Contribution of Pg/Pm to reparative processes, including wound healing, further emphasizes their therapeutic potential in regenerative medicine. Moreover, these proteins play crucial roles in ocular health, where their dysregulation may lead to the pathogenesis of ophthalmic diseases. In conclusion, advancement of our understanding of this versatile system functions through continued research is pivotal for applications of these proteins as diagnostic and prognostic biomarkers for cardiovascular disorders, inflammatory pathologies, cancer, autoimmune conditions, and various diabetic complications, offering insights into early detection of disease and development of innovative therapeutic strategies, ultimately driving progress in personalized medicine.

Keywords: , , , , , , , ,


References:

  1. Tsyperovych AS. About the mechanism of protein denaturation. IV. Post-denaturation changes in protein molecules. Scheme of the denaturation process. Ukr Biokhim Zhurn. 1951;23(1):67-75. (In Ukrainian).
  2. Vynogradova RP, Kolodzeiska MV. Oleksander Solomonovych Tsyperovich a gifted enzymologist, scientist and practician. Ukr Biokhim Zhurn. 2007;79(5):6-26. (In Ukrainian). PubMed
  3. Kudinov SO, Eretska EV, Pozdnyakova TM, Panchenko NE, Matsuy SP, Babenko IM. Affined sorbents for obtaining plasminogen. Ukr Biokhim Zhurn. 1979;51(4):330-334. (In Russian). PubMed
  4. Zhernossekov DD, Yusova EI, Grinenko TV. Role of plasminogen/plasmin in functional activity of blood cells. Ukr Biokhim Zhurn. 2012;84(4):5-19. (In Russian).
  5. Lugovskoy E.V., Makogonenko E.M., Komisarenko S.V. Molecular mechanisms of fibrin formation and degradation. Kyiv: Naukova Dumka, 2013. 230 p.
  6. Franchini M, Zaffanello M, Mannucci PM. Bleeding disorders in primary fibrinolysis. Int J Mol Sci. 2021;22(13):7027. PubMed, PubMedCentral, CrossRef
  7. Verevka SV, Grinenko TV. Pseudo-functional interactions of plasminogen: molecular mechanisms and pathologic appearance. In: Advances in Medicine and Biology. (Berhardt L.V., Ed.), NY-Nova Science Publishers, 2011;34:35-62.
  8. Yatsenko TA, Rybachuk VМ, Yusova OI, Kharchenko SM, Grinenko TV. Effect of fibrin degradation products on fibrinolytic process. Ukr Biochem J. 2016; 88(2):16-24. PubMed, CrossRef
  9. Grinenko TV, Kapustianenko LG, Yatsenko TA, Yusova OI, Rybachuk VN. Plasminogen fragments K 1-3 and K 5 bind to different sites in fibrin fragment DD. Ukr Biochem J. 2016; 88(3):36-45. PubMed, CrossRef
  10. Kapustianenko LG, Iatsenko TA, Iusova OI, Grinenko TV. Isolation and purification of a kringle 5 from human plasminogen using AH-Sepharose. Biotechnol Acta. 2014;7(4):35-42. CrossRef
  11. Kapustianenko L, Grinenko T, Rebriev A, Tykhomyrov A. The sequence 581Ser-610Val in the fibrinogen Aα chain is responsible for the formation of complexes between plasminogen and αC-regions of fibrin(ogen). Heliyon. 2024;10(23):e40852. PubMed, PubMedCentral, CrossRef
  12. Cao Y, Ji RW, Davidson D, Schaller J, Marti D, Söhndel S, McCance SG, O’Reilly MS, Llinás M, Folkman J. Kringle domains of human angiostatin. Characterization of the anti-proliferative activity on endothelial cells. J Biol Chem. 1996;271(46):29461-29467. PubMed, CrossRef
  13. O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994;79(2):315-328. PubMed, CrossRef
  14. Sim BK, MacDonald NJ, Gubish ER. Angiostatin and endostatin: endogenous inhibitors of tumor growth. Cancer Metastasis Rev. 2000;19(1-2):181-190. PubMed, CrossRef
  15. Wahl ML, Moser TL, Pizzo SV. Angiostatin and anti-angiogenic therapy in human disease. Recent Prog Horm Res. 2004;59:73-104. PubMed, CrossRef
  16. Yang X, Cai W, Xu Z, Chen J, Li C, Liu S, Yang Z, Pan Q, Li M, Ma J, Gao G. High efficacy and minimal peptide required for the anti-angiogenic and anti-hepatocarcinoma activities of plasminogen K5. J Cell Mol Med. 2010;14(10):2519-2530. PubMed, PubMedCentral, CrossRef
  17. Chen YH, Wu HL, Chen CK, Huang YH, Yang BC, Wu LW. Angiostatin antagonizes the action of VEGF-A in human endothelial cells via two distinct pathways. Biochem Biophys Res Commun. 2003;310(3):804-810. PubMed, CrossRef
  18. Wajih N, Sane DC. Angiostatin selectively inhibits signaling by hepatocyte growth factor in endothelial and smooth muscle cells. Blood. 2003;101(5):1857-1863. PubMed, CrossRef
  19. Ansell PJ, Zhang H, Davidson DJ, Harlan JE, Xue J, Brodjian S, Lesniewski R, McKeegan E. Recombinant kringle 5 from plasminogen antagonises hepatocyte growth factor-mediated signalling. Eur J Cancer. 2010;46(5):966-973. PubMed,CrossRef
  20. Gonzalez-Gronow M, Kalfa T, Johnson CE, Gawdi G, Pizzo SV. The voltage-dependent anion channel is a receptor for plasminogen kringle 5 on human endothelial cells. J Biol Chem. 2003;278(29):27312-27318. PubMed, CrossRef
  21. Ma J, Li C, Shao C, Gao G, Yang X. Decreased K5 receptor expression in the retina, a potential pathogenic mechanism for diabetic retinopathy. Mol Vis. 2012;18:330-336. PubMed, PubMedCentral
  22. Kato K, Miyake K, Igarashi T, Yoshino S, Shimada T. Human immunodeficiency virus vector-mediated intra-articular expression of angiostatin inhibits progression of collagen-induced arthritis in mice. Rheumatol Int. 2005;25(7):522-529. PubMed, CrossRef
  23. Moulton KS, Vakili K, Zurakowski D, Soliman M, Butterfield C, Sylvin E, Lo KM, Gillies S, Javaherian K, Folkman J. Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis. Proc Natl Acad Sci USA. 2003;100(8):4736-4741. PubMed, PubMedCentral, CrossRef
  24. Matsunaga T, Chilian WM, March K. Angiostatin is negatively associated with coronary collateral growth in patients with coronary artery disease. Am J Physiol Heart Circ Physiol. 2005;288(5):H2042-H2046. PubMed, CrossRef
  25. Radziwon-Balicka A, Moncada de la Rosa C, Zielnik B, Doroszko A, Jurasz P. Temporal and pharmacological characterization of angiostatin release and generation by human platelets: implications for endothelial cell migration. PLoS One. 2013;8(3):e59281. PubMed, PubMedCentral, CrossRef
  26. Tykhomyrov AA, Nedzvetsky VS, Ağca CA, Korsa VV, Grinenko TV. Plasminogen and its fragments in rat brain: a plausible role for astrocytes in angiostatin generation. Ukr Biochem J. 2017;89(2):43-54. CrossRef
  27. Chavakis T, Athanasopoulos A, Rhee JS, Orlova V, Schmidt-Wöll T, Bierhaus A, May AE, Celik I, Nawroth PP, Preissner KT. Angiostatin is a novel anti-inflammatory factor by inhibiting leukocyte recruitment. Blood. 2005;105(3):1036-1043. PubMed, CrossRef
  28. Perri SR, Annabi B, Galipeau J. Angiostatin inhibits monocyte/macrophage migration via disruption of actin cytoskeleton. FASEB J. 2007;21(14):3928-3936. PubMed, CrossRef
  29. Bilous VL, Kapustianenko LG, Tykhomyrov AA. Production and application of angiostatins for the treatment of ocular neovascular diseases. Biotech Acta. 2021;14(1):5-24. CrossRef
  30. Napolitano F, Montuori N. Role of plasminogen activation system in platelet pathophysiology: emerging concepts for translational applications. Int J Mol Sci. 2022;23(11):6065. PubMed, PubMedCentral, CrossRef
  31. Huebner BR, Moore EE, Moore HB, Stettler GR, Nunns GR, Lawson P, Sauaia A, Kelher M, Banerjee A, Silliman CC. Thrombin Provokes Degranulation of Platelet α-Granules Leading to the Release of Active Plasminogen Activator Inhibitor-1 (PAI-1). Shock. 2018;50(6):671-676. PubMed, PubMedCentral, CrossRef
  32. Yusova OI, Grinenko TV, Drobot’ko TF, Tykhomyrov AO. Plasminogen influence on the PAI-1 release by human platelets. Ukr Biochem J. 2024;96(3):13-21. CrossRef
  33. Scridon A. Platelets and their role in hemostasis and thrombosis-from physiology to pathophysiology and therapeutic implications. Int J Mol Sci. 2022;23(21):12772. PubMed, PubMedCentral, CrossRef
  34. Patalakh I, Revka O, Gołaszewska A, Bielicka N, Misztal T. Integration of clotting and fibrinolysis: central role of platelets and factor XIIIa. Biosci Rep. 2024;44(9):BSR20240332. PubMed, PubMedCentral, CrossRef
  35. Talbot K, Meixner SC, Pryzdial EL. Enhanced fibrinolysis by proteolysed coagulation factor Xa. Biochim Biophys Acta. 2010;1804(4):723-730. PubMed, CrossRef
  36. Roka-Moya YM, Zhernossekov DD, Grinenko TV. Plasminogen/plasmin influence on platelet aggregation. Biopolym Cell. 2012;28(5):352-356. CrossRef
  37. Tykhomyrov AA, Zhernosekov DD, Roka-Moya YM, Diordieva SI, Grinenko TV. Effects of Lys-form of plasminogen on platelet actin cytoskeleton. Fiziol Zh. 2014;60(1):25-33. (In Ukrainian). PubMed, CrossRef
  38. Tykhomyrov AA, Zhernosekov DD, Roka-Moya YM, Diordieva SI, Grinenko TV. The effects of Lys-plasminogen on human platelet secretion. Fiziol Zh. 2015;61(6):26-34. (In Ukrainian). PubMed, CrossRef
  39. Arisato T, Hashiguchi T, Sarker KP, Arimura K, Asano M, Matsuo K, Osame M, Maruyama I. Highly accumulated platelet vascular endothelial growth factor in coagulant thrombotic region. J Thromb Haemost. 2003;1(12):2589-2593. PubMed, CrossRef
  40. Tykhomyrov AA, Zhernosekov DD, Grinenko TV. Plasminogen modulates formation and release of platelet angiogenic regulators. Ukr Biochem J. 2020;92(1):31-40. CrossRef
  41. Radziwon-Balicka A, Ramer C, Moncada de la Rosa C, Zielnik-Drabik B, Jurasz P. Angiostatin inhibits endothelial MMP-2 and MMP-14 expression: a hypoxia specific mechanism of action. Vascul Pharmacol. 2013;58(4):280-291. PubMed, CrossRef
  42. Italiano JE Jr, Richardson JL, Patel-Hett S, Battinelli E, Zaslavsky A, Short S, Ryeom S, Folkman J, Klement GL. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood. 2008;111(3):1227-1233. PubMed, PubMedCentral, CrossRef
  43. Tykhomyrov AA, Zhernossekov DD, Grinenko TV. Surface-exposed actin binds plasminogen on the membrane of agonist-activated platelets: a flow cytometry study. Biopolym Cell. 2017;33(3):172-182. CrossRef
  44. Mahmood N, Mihalcioiu C, Rabbani SA. Multifaceted role of the urokinase-type plasminogen activator (uPA) and its receptor (uPAR): diagnostic, prognostic, and therapeutic applications. Front Oncol. 2018;8:24. PubMed, PubMedCentral, CrossRef
  45. Morrow GB, Whyte CS, Mutch NJ. A serpin with a finger in many PAIs: PAI-1’s central function in thromboinflammation and cardiovascular disease. Front Cardiovasc Med. 2021;8:653655. PubMed, PubMedCentral, CrossRef
  46. Yarmolinsky J, Bordin Barbieri N, Weinmann T, Ziegelmann PK, Duncan BB, Inês Schmidt M. Plasminogen activator inhibitor-1 and type 2 diabetes: a systematic review and meta-analysis of observational studies. Sci Rep. 2016;6:17714. PubMed, PubMedCentral, CrossRef
  47. Pavlov M, Ćelap I. Plasminogen activator inhibitor 1 in acute coronary syndromes. Clin Chim Acta. 2019;491:52-58. PubMed, CrossRef
  48. Utility model patent No. u202103403. IPC: G01N 33/50 (2006.01), G01N 33/52 (2006.01), G01N 33/68 (2006.01). [Method for determining the activity of plasminogen activator inhibitor type 1] / Yatsenko T.A., Rybachuk V.M., Kharchenko S.M., Shkrabak M.O., Grynenko T.V., Tykhomyrov A.O., applicant and patent holder – Palladin Institute of Biochemistry of the NAS of Ukraine, application date: June 17, 2021. State registration certificate No. 13522/ZU/21 dated October 21, 2021.
    Ukrainian.
  49. Kuryata O, Sirenko O, Tykhomyrov A, Yatsenko T. Plasminogen activator inhibitor-1 and circulating ceruloplasmin levels in men with iron-deficiency anemia and heart failure with concomitant prostate cancer and their dynamics after treatment. J Med Sci. 2022;42(2):72-80. CrossRef
  50. Yatsenko T, Rios R, Nogueira T, Takahashi S, Tabe Y, Naito T, Takahashi K, Hattori K, Heissig B. Urokinase-type plasminogen activator and plasminogen activator inhibitor-1 complex as a serum biomarker for COVID-19. Front Immunol. 2024;14:1299792. PubMed, PubMedCentral, CrossRef
  51. Yatsenko T, Rios R, Nogueira T, Salama Y, Takahashi S, Adachi E, Tabe Y, Hattori N, Osada T, Naito T, Takahashi K, Hattori K, Heissig B. The influence of 4G/5G polymorphism in the plasminogen-activator-inhibitor-1 promoter on COVID-19 severity and endothelial dysfunction. Front Immunol. 2024;15:1445294. PubMed, PubMedCentral, CrossRef
  52. Fujimura T. Significance of PAI-1 on the development of skin cancer: optimal targets for cancer therapies. Biomed J. 2025:100850.
  53. Hasegawa M, Tone S, Wada H, Naito Y, Matsumoto T, Yamashita Y, Shimaoka M, Sudo A. The Evaluation of Hemostatic Abnormalities Using a CWA-Small Amount Tissue Factor Induced FIX Activation Assay in Major Orthopedic Surgery Patients. Clin Appl Thromb Hemost. 2021;27:10760296211012094. PubMed, PubMedCentral, CrossRef
  54. Patalakh II, Revka OV, Kuchmenko OB, Matova OO, Drobotko TF, Grinenko TV. Clot formation and lysis in platelet rich plasma of healthy donors and patients with resistant hypertension. Ukr Biochem J. 2018;90(2):67-75. CrossRef
  55. Patalakh I, Wandersee A, Schlüter J, Erdmann M, Hackstein H, Cunningham S. Influence of the immune checkpoint inhibitors on the hemostatic potential of blood plasma. Transfus Med Hemother. 2024;52(2):120-131. PubMed, PubMedCentral, CrossRef
  56. Patalakh II, Ryabenko DV, Kornilina EM, Kudinov SA. Protein C in regulation of blood plasma fibrinolytic potential in patients with chronic heart failure. Circulation Haemostasis. 2009;(3-4):95-101. (In Ukrainian).
  57. Patalakh II, Lutai MI, Gavrilenko TI, Lomanovsky ON, Kornilina YeM, Shkrabak MA, Kudinov SA. Activity of the fibrinolytic system in patients with stable angina pectoris with signs of inflammation. Lab Diagnost. 2007;4(42):14-19. (In Ukrainian).
  58. Tykhomyrov AA, Vovchuk IL, Grinenko TV. Plasminogen and angiostatin levels in female benign breast lesions. Ukr Biochem J. 2015;87(5):103-112. PubMed, CrossRef
  59. Tykhomyrov AO, Sirenko OYu, Kuryata OV. Circulating levels of potential markers of ischemic stroke in patients with the different forms of atrial fibrillation and chronic heart failure. Ukr Biochem J. 2024;96(2):62-74. CrossRef
  60. Tykhomyrov AA, Kushnir YuS, Nedzvetsky VS, Grinenko TV, Kuryata OV. Citicoline affects serum angiostatin and neurospecific protein levels in patients with atrial fibrillation and ischemic stroke. Ukr Biochem J. 2019;91(5):34-45. CrossRef
  61. Tykhomyrov AA, Nedzvetsky VS, Bardachenko NI, Grinenko TV, Kuryata OV. Statin treatment decreases serum angiostatin levels in patients with ischemic heart disease. Life Sci. 2015;134:22-29. PubMed, CrossRef
  62. Tykhomyrov AA, Nedzvetsky VS, Zabida AA, Ağca CA, Kuryata OV. l-Arginine treatment improves angiogenic response and reduces matrix metalloproteinase activity in chronic heart failure patients with coronary artery disease. PharmaNutrition. 2018;6(4):137-146. CrossRef
  63. Heissig B, Salama Y, Osada T, Okumura K, Hattori K. The multifaceted role of plasminogen in cancer. Int J Mol Sci. 2021;22(5):2304. PubMed, PubMedCentral, CrossRef
  64. Chi SL, Pizzo SV. Angiostatin is directly cytotoxic to tumor cells at low extracellular pH: a mechanism dependent on cell surface-associated ATP synthase. Cancer Res. 2006;66(2):875-882. PubMed, CrossRef
  65. Chang YC, Wu CZ, Cheng CW, Chen JS, Chang LC. Redrawing urokinase receptor (uPAR) signaling with cancer driver genes for exploring possible anti-cancer targets and drugs. Pharmaceuticals (Basel). 2023;16(10):1435. PubMed, PubMedCentral, CrossRef
  66. Bharadwaj AG, Kempster E, Waisman DM. The ANXA2/S100A10 Complex-regulation of the oncogenic plasminogen receptor.
    Biomolecules. 2021;11(12):1772. PubMed, PubMedCentral, CrossRef
  67. Tykhomyrov AA, Nedzvetsky VS, Aĝca CA, Guzyk MM, Korsa VV, Grinenko TV. Plasminogen/plasmin affects expression of glycolysis regulator TIGAR and induces autophagy in lung adenocarcinoma A549 cells. Exp Oncol. 2020;42(4):270-276. PubMed, CrossRef
  68. Kubala MH, DeClerck YA. The plasminogen activator inhibitor-1 paradox in cancer: a mechanistic understanding. Cancer Metastasis Rev. 2019;38(3):483-492. PubMed, PubMedCentral, CrossRef
  69. Suh YS, Yu J, Kim BC, Choi B, Han TS, Ahn HS, Kong SH, Lee HJ, Kim WH, Yang HK. Overexpression of plasminogen activator inhibitor-1 in advanced gastric cancer with aggressive lymph node metastasis. Cancer Res Treat. 2015;47(4):718-726. PubMed, PubMedCentral, CrossRef
  70. Zheng Y, Meng L, Qu L, Zhao C, Wang L, Liu C, Shou C. Anti-PAI-1 monoclonal antibody inhibits the metastasis and growth of esophageal squamous cell carcinoma. J Cancer. 2023;14(1):114-128. PubMed, PubMedCentral, CrossRef
  71. Li WY, Chong SS, Huang EY, Tuan TL. Plasminogen activator/plasmin system: a major player in wound healing? Wound Repair Regen. 2003;11(4):239-247. PubMed, CrossRef
  72. Fallah M, Viklund E, Bäckman A, Brodén J, Lundskog B, Johansson M, Blomquist M, Wilczynska M, Ny T. Plasminogen is a master regulator and a potential drug candidate for the healing of radiation wounds. Cell Death Dis. 2020;11(3):201. PubMed, PubMedCentral, CrossRef
  73. Romer J, Bugge TH, Pyke C, Lund LR, Flick MJ, Degen JL, Dano K. Impaired wound healing in mice with a disrupted plasminogen gene. Nat Med. 1996;2(3):287-292. PubMed, CrossRef
  74. Shen Y, Guo Y, Mikus P, Sulniute R, Wilczynska M, Ny T, Li J. Plasminogen is a key proinflammatory regulator that accelerates the healing of acute and diabetic wounds. Blood. 2012;119(24):5879-5887. PubMed, CrossRef
  75. Al Kayal T, Buscemi M, Cavallo A, Foffa I, Soldani G, Losi P. Plasminogen-Loaded Fibrin Scaffold as Drug Delivery System for Wound Healing Applications. Pharmaceutics. 2022;14(2):251. PubMed, PubMedCentral, CrossRef
  76. Petrenko O, Badziukh S, Korsa V, Kolosovych I, Tykhomyrov A. Topical application of autologous plasma-derived plasminogen accelerates healing of chronic foot ulcers in type 2 diabetes patients. Int J Low Extrem Wounds. 2024;15347346241256025. PubMed, CrossRef
  77. Decker RW, Parker JM, Lorber J, Crea R, Thibaudeau K. Nonhealing surgical wounds in a patient with plasminogen deficiency type 1 successfully treated with intravenous plasminogen: a case report. Adv Skin Wound Care. 2024;37(7):387-391. PubMed, CrossRef
  78. Smith E, Hoffman R. Multiple fragments related to angiostatin and endostatin in fluid from venous leg ulcers. Wound Repair Regen. 2005;13(2):148-157. PubMed, CrossRef
  79. Petrenko OM, Tykhomyrov AA. Levels of angiogenic regulators and MMP-2, -9 activities in Martorell ulcer: a case report. Ukr Biochem J. 2019;91(1):100-107. CrossRef
  80. Rebalka IA, Raleigh MJ, D’Souza DM, Coleman SK, Rebalka AN, Hawke TJ. Inhibition of PAI-1 via PAI-039 improves dermal wound closure in diabetes. Diabetes. 2015;64(7):2593-2602. PubMed, CrossRef
  81. Gong Y, Zhao Y, Li Y, Fan Y, Hoover-Plow J. Plasminogen regulates cardiac repair after myocardial infarction through its noncanonical function in stem cell homing to the infarcted heart. J Am Coll Cardiol. 2014;63(25 Pt A):2862-2872. PubMed, PubMedCentral, CrossRef
  82. Wang L, Yao L, Duan H, Yang F, Lin M, Zhang R, He Z, Ahn J, Fan Y, Qin L, Gong Y. Plasminogen regulates fracture repair by promoting the functions of periosteal mesenchymal progenitors. J Bone Miner Res. 2021;36(11):2229-2242. PubMed, PubMedCentral, CrossRef
  83. Sepehri E, Tideholm B, Hellström S, Berglin CE. Plasminogen – safe for treatment of chronic tympanic membrane perforation: a phase 1 randomized, placebo-controlled study. Acta Otolaryngol. 2024;144(7-8):439-445. PubMed, CrossRef
  84. Collinge JE, Simirskii VN, Duncan MK. Expression of tissue plasminogen activator during eye development. Exp Eye Res. 2005;81(1):90-96. PubMed, CrossRef
  85. Leonardi A, Brun P, Sartori MT, Cortivo R, Dedominicis C, Saggiorato G, Abatangelo G, Secchi AG. Urokinase plasminogen activator, uPa receptor, and its inhibitor in vernal keratoconjunctivitis. Invest Ophthalmol Vis Sci. 2005;46(4):1364-1370. PubMed, CrossRef
  86. Caputo R, Shapiro AD, Sartori MT, Leonardi A, Jeng BH, Nakar C, Di Pasquale I, Price FW Jr, Thukral N, Suffredini AL, Pino L, Crea R, Mathew P, Calcinai M. Treatment of ligneous conjunctivitis with plasminogen eyedrops. Ophthalmology. 2022;129(8):955-957. PubMed, CrossRef
  87. Lei H, Velez G, Hovland P, Hirose T, Kazlauskas A. Plasmin is the major protease responsible for processing PDGF-C in the vitreous of patients with proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci. 2008;49(1):42-48. PubMed, PubMedCentral, CrossRef
  88. Dan J, Belyea D, Gertner G, Leshem I, Lusky M, Miskin R. Plasminogen activator inhibitor-1 in the aqueous humor of patients with and without glaucoma. Arch Ophthalmol. 2005;123(2):220-224. PubMed, CrossRef
  89. McClintock M, MacCumber MW. Lowered intraocular pressure in a glaucoma patient after intravitreal injection of ocriplasmin. Clin Ophthalmol. 2015;9:1995-1998. PubMed, PubMedCentral, CrossRef
  90. Vandewalle E, Van Bergen T, Van de Veire S, Moons L, Stalmans I. Microplasmin as an antiscarring agent for glaucoma surgery: translation into clinical application. Bull Soc Belge Ophtalmol. 2011;(317):63-64. PubMed
  91. Gabison E, Chang JH, Hernández-Quintela E, Javier J, Lu PC, Ye H, Kure T, Kato T, Azar DT. Anti-angiogenic role of angiostatin during corneal wound healing. Exp Eye Res. 2004;78(3):579-589. PubMed, CrossRef
  92. Sack RA, Beaton AR, Sathe S. Diurnal variations in angiostatin in human tear fluid: a possible role in prevention of corneal neovascularization. Curr Eye Res. 1999;18(3):186-193. PubMed, CrossRef
  93. Ambati BK, Joussen AM, Ambati J, Moromizato Y, Guha C, Javaherian K, Gillies S, O’Reilly MS, Adamis AP. Angiostatin inhibits and regresses corneal neovascularization. Arch Ophthalmol. 2002;120(8):1063-1068. PubMed, CrossRef
  94. Drixler TA, Borel Rinkes IH, Ritchie ED, Treffers FW, van Vroonhoven TJ, Gebbink MF, Voest EE. Angiostatin inhibits pathological but not physiological retinal angiogenesis. Invest Ophthalmol Vis Sci. 2001;42(13):3325-3330. PubMed
  95. Bilous VI, Tykhomyrov AO. Multiple effects of angiostatins in injured cornea. Ukr Biochem J. 2024;96(1):37-48. CrossRef
  96. Bilous VI, Greben NK, Gavryliak IV, Ağca CA. Beneficial effects of angiostatin K1-3 and lactoferrin in alkali-burned rabbit cornea: a comparative study. Biotechnologia Acta. 2024;17(3):47-58. CrossRef
  97. Bilous VL, Kapustianenko LG, Yusova OI, Korsa VV, Nedzvetsky VS, Ağca CA, Ziablitsev SV, Tykhomyrov AO. Angiostatins modulate ACE2 and GFAP levels in injured rat cornea and do not affect viability of retinal pigment epithelial cells. Biopolym Cell. 2023;39(4): 299-310. CrossRef
  98. Igarashi T, Miyake K, Kato K, Watanabe A, Ishizaki M, Ohara K, Shimada T. Lentivirus-mediated expression of angiostatin efficiently inhibits neovascularization in a murine proliferative retinopathy model. Gene Ther. 2003;10(3):219-226. PubMed, CrossRef
  99. Raisler BJ, Berns KI, Grant MB, Beliaev D, Hauswirth WW. Adeno-associated virus type-2 expression of pigmented epithelium-derived factor or Kringles 1-3 of angiostatin reduce retinal neovascularization. Proc Natl Acad Sci USA. 2002;99(13):8909-8914. PubMed, PubMedCentral, CrossRef
  100. Guzyk MM, Tykhomyrov AA, Nedzvetsky VS, Prischepa IV, Grinenko TV, Yanitska LV, Kuchmerovska TM. Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors reduce reactive gliosis and improve angiostatin levels in retina of diabetic rats. Neurochem Res. 2016;41(10):2526-2537. PubMed, CrossRef

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.