Abstract
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.
Highlights
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
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
Summary
Many types of eye diseases, including age-related macular degeneration, diabetic retinopathy and related disorders of the retina, feature abnormal overgrowth of new retinal blood vessel branches, which can lead to progressive loss of vision and total blindness. Vision in people of working age and are accompanied by the emergence of newly formed vessels Both diabetic retinopathy and macular degeneration are associated with abnormal growth of blood vessels (neovascularization) in the retina. Angiogenesis is strictly controlled by a wide number of pro-angiogenic (VEGF, PDGF, bFGF, EGF, MMP, fibrinogen, fibronectin, etc.) and anti-angiogenic (AS, ES, TSP-1, PF4, PEDF, TGF-b1, PAI-1, 2-AP, TIMP, etc.) factors [39] Imbalance of these factors may occur after eye injuries and promotes the development of various pathologies, such as neovascular glaucoma, diabetic retinopathy, chemical burns, and viral infections of the cornea [40]. The effects of various plasminogen fragments (angiostatins) on proliferation and migration of endothelial cells [12]
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