Angiogenesis is Regulated by Angiopoietins During Experimental Autoimmune Encephalomyelitis and is Indirectly Related to Vascular Permeability

The regulation of angiogenesis was studied over the course of the animal model of multiple sclerosis, acute experimental autoimmune encephalomyelitis (EAE) in mice using immunohistochemistry. During EAE, angiogenesis peaked 21 days after disease induction, with significant increases in gray matter and adjacent to the leptomeninges. Angiogenesis correlated with clinical and pathologic scores. Spinal cord expression of angiopoietin 1 (Ang-1) by neurons and glia was reduced at Day 14, but expression by inflammatory cells restored earlier levels at Day 21. Angiopoietin 2 expression increased markedly at Day 21 and was mostly associated with inflammatory cells. Levels of the angiopoietin receptor Tie-2 were reduced at Day 14, but recovered by day D21. Double labeling demonstrated Ang-1 expression on infiltrating CD3-positive T cells; Ang-2 was expressed by monocytes/macrophages. During EAE, the expression of vascular endothelial growth factor peaked at Day 14 and began to decrease by Day 21. Double labeling showed expression of Tie-2 and vascular endothelial growth factor receptor 2 but not Ang-2 in blood vessels at Day 21. Vascular permeability increased early in EAE, but was reduced by Day 21. Although individual values did not correlate with angiogenesis, the volume of permeable tissue showed a weak positive correlation with angiogenesis. These temporal changes in angiogenic factors suggest an integral role during EAE-related angiogenesis.