Regulation of matrix metalloproteinase activity in ischemic tissue by interleukin-10 - Role in ischemia-induced angiogenesis

We have previously shown that deficiency in the anti-inflammatory cytokine interleukin-10 (IL-10) is responsible for enhanced angiogenesis after hindl imb ischemia. This study examined the putative involvement of matrix metall oproteinase (MMP) activation in this process. Ischemia was produced by arte ry femoral occlusion in both C57BL6 IL-10(+/+) and IL-10(-/-) mice. Angiogr aphic vessel density and laser Doppler perfusion data at day 28 showed sign ificant improvement in ischemic/nonischemic leg ratio by, respectively, 1.8 -fold and 1.4-fold in IL-10(-/-) mice compared with IL-10(+/+) mice. This w as associated with an increase in vascular endothelial growth factor (VEGF) protein content in the ischemic hindlimb. Three days after ischemia, gelat in zymography showed a significant increase in both pro- and active forms o f MMP-2 and MMP-9 in ischemic hindlimbs of IL-10(-/-) mice compared with IL -10(+/+) mice (P<0.01). This increase in MMP activity in IL-10(-/-) mice wa s completely inhibited by treatment with BB-94 (5 mg/kg IP), a specific MMP inhibitor. Furthermore, increases in both vessel density and blood perfusi on indexes at day 28 in IL-10-/- mice were abolished after treatment with B B-94 (0.78+/-0.06 versus 1.17+/-0.09 and 0.62+/-0.02 versus 0.88+/-0.04, fo r vessel density and blood perfusion ratio, respectively, in IL-10-/- mice treated with BB-94 versus untreated IL-10-/- mice, P<0.05). In contrast, BB -94 treatment did not affect the rise in VEGF protein content. These findin gs in IL-10(-/-) mice underscore the critical role of MMP activation, in a context of increased VEGF expression, in promoting ischemia-induced angioge nesis.