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.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:NSHD.ca#10222/21415 |
| Date | 04 March 2013 |
| Creators | MacMillan, Carolyn Jo-Anne |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
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