Abstract
Angiogenesis is the formation of new blood vessels form pre-existing vasculature whose contribution to inflammatory conditions of the Central Nervous System is being studied in order to generate novel therapeutic targets. This study is the first to investigate the impact of two particular angiogenesis inhibitors on murine Experimental Autoimmune Encephalomyelitis (EAE), an inflammatory disease that mimics aspects of the human disease Multiple Sclerosis. The inhibitors were chosen to reduce angiogenesis by complimentary means. Extrinsic factors were targeted with B20-4.1.1 through its ability to bind to murine Vascular Endothelial Growth Factor (VEGF). Vascular processes connected to angiogenesis were targeted directly with K(1-3), the first three kringle domains of angiostatin. Mice treated with B20-4.1.1 and K(1-3) from onset of signs had reduced clinical scores 18–21 days after EAE induction. Both agents suppressed spinal cord angiogenesis without effect on local VEGF expression. B20-4.1.1 reduced spinal cord vascular permeability while K(1-3) had no effect. T cell infiltration into the spinal cord at day 21 was unaffected by either treatment. B20-4.1.1 reduced peripheral T cell proliferation while K(1-3) had no effect. Lymphoid cells from treated mice produced reduced levels of the T helper-17 (Th-17) cell cytokine interleukin (IL)-17 with no effect on the Th-1 cytokine interferon (IFN)-γ or Th-2 cytokine IL-4. However, when both drugs were added in vitro to naive T cells or to antigen stimulated T cells from mice with untreated EAE they had no effect on proliferation or levels of IL-17 or IFN-γ. We conclude that these angiogenesis inhibitors mitigate EAE by both suppressing spinal cord angiogenesis and reducing peripheral T cell activation.
Highlights
Inflammatory diseases of the central nervous system (CNS) initiate a number of adaptive responses that include angiogenesis, the process by which new blood vessels are formed from preexisting vasculature
We describe the ability of these inhibitors to reduce clinical scores during EAE and explore their mechanism of action through effects on spinal cord angiogenesis, vascular permeability, Vascular Endothelial Growth Factor (VEGF) expression and T cell infiltration as well as their impact on peripheral T cell responses
B20-4.1.1 and K(1-3) Reduce Clinical Scores in EAE Both treatments were given to mice on the day of symptom onset and subsequently administered every 3 days until death
Summary
Inflammatory diseases of the central nervous system (CNS) initiate a number of adaptive responses that include angiogenesis, the process by which new blood vessels are formed from preexisting vasculature. Many factors regulate angiogenesis and include a major role for the 165 amino acid isoform of Vascular Endothelial Growth Factor-A (VEGF-A or VEGF) in humans (164 amino acids in mice). VEGF acts in concert with other mediators to promote new blood vessel formation. These mediators include angiopoietin (Ang)-1, Ang-2, Tumor necrosis factor, matrix metalloproteinases and other growth factors. Despite the multiple factors implicated in the regulation of angiogenesis, the 164/165 amino acid isoform of VEGF-A is regarded as a key orchestrator of angiogenesis in pathologic or inflammatory settings. We propose strategies to inhibit VEGF that hold promise for the treatment of inflammatory disorders
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