-
International Journal of Molecular... Jan 2019Systemic sclerosis (SSc) is a connective tissue disease of autoimmune origin characterized by vascular dysfunction and extensive fibrosis of the skin and visceral... (Review)
Review
Systemic sclerosis (SSc) is a connective tissue disease of autoimmune origin characterized by vascular dysfunction and extensive fibrosis of the skin and visceral organs. Vascular dysfunction is caused by endothelial cell (EC) apoptosis, defective angiogenesis, defective vasculogenesis, endothelial-to-mesenchymal transition (EndoMT), and coagulation abnormalities, and exacerbates the disease. Fibrinolytic regulators, such as plasminogen (Plg), plasmin, α2-antiplasmin (α2AP), tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plasminogen activator inhibitor 1 (PAI-1), and angiostatin, are considered to play an important role in the maintenance of endothelial homeostasis, and are associated with the endothelial dysfunction of SSc. This review considers the roles of fibrinolytic factors in vascular dysfunction of SSc.
Topics: Angiostatins; Apoptosis; Endothelium; Fibrinolysin; Fibrinolytic Agents; Humans; Plasminogen; Plasminogen Activator Inhibitor 1; Receptors, Urokinase Plasminogen Activator; Scleroderma, Systemic; Signal Transduction; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator; alpha-2-Antiplasmin
PubMed: 30709025
DOI: 10.3390/ijms20030619 -
Oxidative Medicine and Cellular... 2019Angiogenesis is the process of new vessel formation, which sprouts from preexisting vessels. This process is highly complex and primarily involves several key steps,... (Review)
Review
Angiogenesis is the process of new vessel formation, which sprouts from preexisting vessels. This process is highly complex and primarily involves several key steps, including stimulation of endothelial cells by growth factors, degradation of the extracellular matrix by proteolytic enzymes, migration and proliferation of endothelial cells, and capillary tube formation. Currently, it is considered that multiple cytokines play a vital role in this process, which consist of proangiogenic factors (e.g., vascular endothelial growth factor, fibroblast growth factors, and angiopoietins) and antiangiogenic factors (e.g., endostatin, thrombospondin, and angiostatin). Angiogenesis is essential for most physiological events, such as body growth and development, tissue repair, and wound healing. However, uncontrolled neovascularization may contribute to angiogenic disorders. In physiological conditions, the above promoters and inhibitors function in a coordinated way to induce and sustain angiogenesis within a limited period of time. Conversely, the imbalance between proangiogenic and antiangiogenic factors could cause pathological angiogenesis and trigger several diseases. With insights into the molecular mechanisms of angiogenesis, increasing reports have shown that a close relationship exists between angiogenesis and oxidative stress (OS) in both physiological and pathological conditions. OS, an imbalance between prooxidant and antioxidant systems, is a cause and consequence of many vascular complains and serves as one of the biomarkers for these diseases. Furthermore, emerging evidence supports that OS and angiogenesis play vital roles in many dermatoses, such as psoriasis, atopic dermatitis, and skin tumor. This review summarizes recent findings on the role of OS as a trigger of angiogenesis in skin disorders, highlights newly identified mechanisms, and introduces the antiangiogenic and antioxidant therapeutic strategies.
Topics: Humans; Neovascularization, Pathologic; Oxidation-Reduction; Oxidative Stress; Skin Diseases
PubMed: 31178954
DOI: 10.1155/2019/2304018 -
Reumatologia 2018Inflammation has been revealed to be associated with angiogenesis. Granulomatosis with polyangiitis (GPA) and immune complex small vessel vasculitis (ICSVV) are forms of...
OBJECTIVES
Inflammation has been revealed to be associated with angiogenesis. Granulomatosis with polyangiitis (GPA) and immune complex small vessel vasculitis (ICSVV) are forms of systemic vasculitides of different pathogenesis. GPA is a necrotizing granulomatosis and ICSVV is associated with inflammation of postcapillary venules induced by deposits of immune complexes. The aim of the study was to determine serum levels of angiostatin and endostatin, natural angiogenesis inhibitors, in patients with GPA and ICSVV as well as healthy individuals.
MATERIAL AND METHODS
Two groups of patients with GPA (20 patients) and ICSVV (20 patients) as well as 20 controls were investigated. All patients were investigated before initiation of immunosuppressive therapy or administration of corticosteroids. Angiostatin and endostatin levels were assayed with the ELISA method.
RESULTS
Enhanced serum levels of angiostatin and endostatin were found in patients with GPA but not in those suffering from ICSVV. In patients with GPA increased levels of angiogenesis inhibitors correlated with the disease activity. A correlation between angiostatin and endostatin levels was observed in all groups of investigated individuals.
CONCLUSIONS
It is suggested that formation of necrotizing granulation is associated with profound activation of angiogenesis and an increase in serum levels of inhibitors is a phenomenon occurring during blood vessel formation in the granulation tissue. The obtained results confirm involvement of angiogenesis in pathogenesis of at least some forms of vasculitides and suggest the need for continuation of investigations in this field.
PubMed: 30505009
DOI: 10.5114/reum.2018.79498 -
Joint Bone Spine Jan 2010Angiogenesis is the formation of new capillaries from pre-existing vessels. A number of soluble and cell-bound factors may stimulate neovascularization. The perpetuation... (Review)
Review
Angiogenesis is the formation of new capillaries from pre-existing vessels. A number of soluble and cell-bound factors may stimulate neovascularization. The perpetuation of angiogenesis involving numerous soluble and cell surface-bound mediators has been associated with rheumatoid arthritis (RA). These angiogenic mediators, among others, include growth factors, primarily vascular endothelial growth factor (VEGF) and hypoxia-inducible factors (HIFs), as well as pro-inflammatory cytokines, various chemokines, cell adhesion molecules, proteases and others. Among the several potential angiogenesis inhibitors, targeting of VEGF, HIF-1, angiopoietin and the alpha(V)beta(3) integrin, as well as some endogenous or synthetic compounds including angiostatin, endostatin, paclitaxel, fumagillin analogues, 2-methoxyestradiol and thalidomide seems to be promising for the management of synovial inflammation and angiogenesis. A complete review of antiangiogenic drugs used in animal models of arthritis or human RA is available in a table.
Topics: Angiogenesis Inhibitors; Animals; Arthritis, Rheumatoid; Disease Models, Animal; Humans; Neovascularization, Pathologic; Synovial Membrane; Vascular Endothelial Growth Factor A
PubMed: 20022538
DOI: 10.1016/j.jbspin.2009.05.011 -
Journal of Clinical and Diagnostic... Jun 2015Angiogenesis is a complex process depending on the coordination of many regulators and there by activating angiogenic switch. Recent advances in understanding of... (Review)
Review
Angiogenesis is a complex process depending on the coordination of many regulators and there by activating angiogenic switch. Recent advances in understanding of angiogenic mechanism have lead to the development of several anti-angiogenic and anti-metastatic agents that use the strategy of regulation of angiogenic switch. Antiangiogenic therapy is a form of treatment not cure for cancer and represents a highly effective strategy for destroying tumour because vascular supply is the fundamental requirement for growth of tumour. Because of the quiescent nature of normal adult vasculature, angiogenic inhibitors are expected to confer a degree of specificity when compared to nonspecific modalities of chemo and radiotherapy, so it has the advantage of less toxicities, does not induce drug resistance and deliver a relatively non toxic, long term treatment of tumour.
PubMed: 26266204
DOI: 10.7860/JCDR/2015/12016.6135 -
Cellular and Molecular Life Sciences :... Jan 2022In the cartilage matrix, complex interactions occur between angiogenic and anti-angiogenic components, growth factors, and environmental stressors to maintain a proper... (Review)
Review
In the cartilage matrix, complex interactions occur between angiogenic and anti-angiogenic components, growth factors, and environmental stressors to maintain a proper cartilage phenotype that allows for effective load bearing and force distribution. However, as seen in both degenerative disease and tissue engineering, cartilage can lose its vascular resistance. This vascularization then leads to matrix breakdown, chondrocyte apoptosis, and ossification. Research has shown that articular cartilage inflammation leads to compromised joint function and decreased clinical potential for regeneration. Unfortunately, few articles comprehensively summarize what we have learned from previous investigations. In this review, we summarize our current understanding of the factors that stabilize chondrocytes to prevent terminal differentiation and applications of these factors to rescue the cartilage phenotype during cartilage engineering and osteoarthritis treatment. Inhibiting vascularization will allow for enhanced phenotypic stability so that we are able to develop more stable implants for cartilage repair and regeneration.
Topics: Aggrecans; Angiogenesis Inhibitors; Angiostatins; Animals; Apoptosis; Cartilage; Chondrocytes; Cytokines; Endostatins; Humans; Inflammation; Low Density Lipoprotein Receptor-Related Protein-1; Mice; Osteoarthritis; Osteogenesis; Regeneration; Serine Proteinase Inhibitors; Stem Cells; Thrombospondins; Tissue Engineering; Tissue Extracts; Troponin I; Vascular Endothelial Growth Factor A
PubMed: 35029764
DOI: 10.1007/s00018-021-04105-0 -
Journal of Thrombosis and Haemostasis :... Jan 2004Originally discovered in 1994 by Folkman and coworkers, angiostatin was identified through its antitumor effects in mice and later shown to be a potent inhibitor of... (Review)
Review
Originally discovered in 1994 by Folkman and coworkers, angiostatin was identified through its antitumor effects in mice and later shown to be a potent inhibitor of angiogenesis. An internal fragment of plasminogen, angiostatin consists of kringle domains that are known to be lysine-binding. The crystal structure of angiostatin was the first multikringle domain-containing structure to be published. This review will focus on what is known about the structure of angiostatin and its implications in function from the current literature.
Topics: Angiogenesis Inhibitors; Angiostatins; Animals; Binding Sites; Humans; Kringles; Models, Molecular; Protein Binding; Protein Conformation
PubMed: 14717962
DOI: 10.1111/j.1538-7836.2004.00544.x -
Neoplasia (New York, N.Y.) 2001Coagulopathy and angiogenesis are among the most consistent host responses associated with cancer. These two respective processes, hitherto viewed as distinct, may in... (Review)
Review
Coagulopathy and angiogenesis are among the most consistent host responses associated with cancer. These two respective processes, hitherto viewed as distinct, may in fact be functionally inseparable as blood coagulation and fibrinolysis, in their own right, influence tumor angiogenesis and thereby contribute to malignant growth. In addition, tumor angiogenesis appears to be controlled through both standard and non-standard functions of such elements of the hemostatic system as tissue factor, thrombin, fibrin, plasminogen activators, plasminogen, and platelets. "Cryptic" domains can be released from hemostatic proteins through proteolytic cleavage, and act systemically as angiogenesis inhibitors (e.g., angiostatin, antiangiogenic antithrombin III aaATIII). Various components of the hemostatic system either promote or inhibit angiogenesis and likely act by changing the net angiogenic balance. However, their complex influences are far from being fully understood. Targeted pharmacological and/or genetic inhibition of pro-angiogenic activities of the hemostatic system and exploitation of endogenous angiogenesis inhibitors of the angiostatin and aaATIII variety are under study as prospective anti-cancer treatments.
Topics: Animals; Hemostasis; Humans; Neoplasms; Neovascularization, Pathologic
PubMed: 11687948
DOI: 10.1038/sj.neo.7900184 -
PloS One 2013Platelets play an important role in thrombosis and in neo-vascularisation as they release and produce factors that both promote and suppress angiogenesis. Amongst these...
Platelets play an important role in thrombosis and in neo-vascularisation as they release and produce factors that both promote and suppress angiogenesis. Amongst these factors is the angiogenesis inhibitor angiostatin, which is released during thrombus formation. The impact of anti-thrombotic agents and the kinetics of platelet angiostatin release are unknown. Hence, our objectives were to characterize platelet angiostatin release temporally and pharmacologically and to determine how angiostatin release influences endothelial cell migration, an early stage of angiogenesis. We hypothesized anti-platelet agents would suppress angiostatin release but not generation by platelets. Human platelets were aggregated and temporal angiostatin release was compared to vascular endothelial growth factor (VEGF). Immuno-gold electron microscopy and immunofluorescence microscopy identified α-granules as storage organelles of platelet angiostatin. Acetylsalicylic acid, MRS2395, GPIIb/IIIa blocking peptide, and aprotinin were used to characterize platelet angiostatin release and generation. An endothelial cell migration assay was performed under hypoxic conditions to determine the effects of pharmacological platelet and angiostatin inhibition. Compared to VEGF, angiostatin generation and release from α-granules occurred later temporally during platelet aggregation. Consequently, collagen-activated platelet releasates stimulated endothelial cell migration more potently than maximally-aggregated platelets. Platelet inhibitors prostacyclin, S-nitroso-glutathione, acetylsalicylic acid, and GPIIb/IIIa blocking peptide, but not a P2Y12 inhibitor, suppressed angiostatin release but not generation. Suppression of angiostatin generation in the presence of acetylsalicylic acid enhanced platelet-stimulated endothelial migration. Hence, the temporal and pharmacological modulation of platelet angiostatin release may have significant consequences for neo-vascularization following thrombus formation.
Topics: Adenine; Angiogenesis Inhibitors; Angiostatins; Aspirin; Blood Platelets; Cell Hypoxia; Cell Line; Cell Movement; Collagen; Culture Media, Conditioned; Endothelial Cells; Endothelium, Vascular; Epoprostenol; Humans; Peptides; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; S-Nitrosoglutathione; Valerates; Vascular Endothelial Growth Factor A
PubMed: 23555012
DOI: 10.1371/journal.pone.0059281 -
BMC Cancer Jun 2006Upregulation of endogenous angiostatin levels may constitute a novel anti-angiogenic, and therefore anti-tumor therapy. In vitro, angiostatin generation is a two-step... (Comparative Study)
Comparative Study
BACKGROUND
Upregulation of endogenous angiostatin levels may constitute a novel anti-angiogenic, and therefore anti-tumor therapy. In vitro, angiostatin generation is a two-step process, starting with the conversion of plasminogen to plasmin by plasminogen activators (PAs). Next, plasmin excises angiostatin from other plasmin molecules, a process requiring a donor of a free sulfhydryl group. In previous studies, it has been demonstrated that administration of PA in combination with the free sulfhydryl donor (FSD) agents captopril or N-acetyl cysteine, resulted in angiostatin generation, and anti-angiogenic and anti-tumour activity in murine models.
METHODS
In this study we have investigated the angiostatin generating capacities of several FSDs. D-penicillamine proved to be most efficient in supporting the conversion of plasminogen to angiostatin in vitro. Next, from the optimal concentrations of tPA and D-penicillamine in vitro, equivalent dosages were administered to healthy Balb/c mice to explore upregulation of circulating angiostatin levels. Finally, anti-tumor effects of treatment with tPA and D-penicillamine were determined in a human melanoma xenograft model.
RESULTS
Surprisingly, we found that despite the superior angiostatin generating capacity of D-penicillamine in vitro, both in vivo angiostatin generation and anti-tumour effects of tPA/D-penicillamine treatment were impaired compared to our previous studies with tPA and captopril.
CONCLUSION
Our results indicate that selecting the most appropriate free sulfhydryl donor for anti-angiogenic therapy in a (pre)clinical setting should be performed by in vivo rather than by in vitro studies. We conclude that D-penicillamine is not suitable for this type of therapy.
Topics: Angiostatins; Animals; Antineoplastic Combined Chemotherapy Protocols; Humans; In Vitro Techniques; Melanoma; Mice; Mice, Inbred BALB C; Mice, Nude; Penicillamine; Plasminogen Activators; Xenograft Model Antitumor Assays
PubMed: 16753063
DOI: 10.1186/1471-2407-6-149