Angiogenesis as a pathologic mechanism and novel therapeutic target in an animal model of multiple sclerosis
MacMillan, Carolyn Jo-Anne
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Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system. We hypothesize that angiogenesis results in new vessels which serve as a conduit for immune cell recruitment in MS, and contribute to inflammation through the pro-inflammatory properties of angiogenic regulators. This study is one of the first to explore regulation of angiogenesis in a murine model of MS (experimental autoimmune encephalomyelitis, EAE), and its potential as a therapeutic target. Angiogenesis was apparent 21 days following disease induction and correlated with clinical and pathologic scores. We documented alterations in the VEGF and Ang/Tie signaling pathways. Expression of VEGF increased at day 14 then reduced by day 21. At this time point, Ang-2 levels were elevated due to expression by infiltrating macrophages. Ang-1 was significantly reduced at day 14 and increased at day 21 due to expression by CD3+ T-cells. The same expression pattern was validated in inflammatory cells within human MS tissue. Vascular permeability increased at day 14 and returned to control levels at day 21. The volume of permeable tissue weakly correlated with angiogenesis. VEGF blockage with bevacizumab suppressed angiogenesis and reduced clinical scores and vascular permeability. Retention of CD4+ T-cells in peripheral lymph nodes and reduced T-cell proliferation was noted following treatment. Bevacizumab reduced mononuclear cell infiltration into spinal cord. Isolated CD4+ T-cells showed reduced expression of IL-17 and IFN-??. B20-4.1.1 (a monoclonal antibody against murine VEGF) reduced clinical scores and suppressed angiogenesis as did treatment with angiostatin (an inhibitor of endothelial cell proliferation). B20-4.1.1 reduced vascular permeability, induced retention of CD4+ T-cells in peripheral lymph nodes, and inhibited T-cell proliferation, while angiostatin had no effect. Isolated lymphoid cells from mice treated with both agents showed reduced secretion of IL-17, but B20-4.1.1 had no effect on Tcell proliferation or IL-17 secretion when combined with angiostatin. ?? We conclude that these angiogenesis inhibitors are effective in EAE and act by suppressing angiogenesis with a secondary effect on peripheral T-cell activation. To the extent that EAE replicates changes occurring in MS, we have demonstrated that modulation of angiogenesis may represent a promising strategy in the management of disease progression.