batimastat and Ischemia

We have previously shown that deficiency in the anti-inflammatory cytokine interleukin-10 (IL-10) is responsible for enhanced angiogenesis after hindlimb ischemia. This study examined the putative involvement of matrix metalloproteinase (MMP) activation in this process. Ischemia was produced by artery femoral occlusion in both C57BL6 IL-10(+/+) and IL-10(-/-) mice. Angiographic vessel density and laser Doppler perfusion data at day 28 showed significant 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 was associated with an increase in vascular endothelial growth factor (VEGF) protein content in the ischemic hindlimb. Three days after ischemia, gelatin zymography showed a significant increase in both pro- and active forms of 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 was completely inhibited by treatment with BB-94 (5 mg/kg IP), a specific MMP inhibitor. Furthermore, increases in both vessel density and blood perfusion indexes at day 28 in IL-10(-/-) mice were abolished after treatment with BB-94 (0.78+/-0.06 versus 1.17+/-0.09 and 0.62+/-0.02 versus 0.88+/-0.04, for 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 findings in IL-10(-/-) mice underscore the critical role of MMP activation, in a context of increased VEGF expression, in promoting ischemia-induced angiogenesis.

Topics: Angiography; Animals; Blood Flow Velocity; Capillaries; Disease Models, Animal; Endothelial Growth Factors; Enzyme Activation; Femoral Artery; Fibroblast Growth Factor 2; Hindlimb; Interleukin-10; Ischemia; Laser-Doppler Flowmetry; Lymphokines; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Pathologic; Phenylalanine; Platelet Endothelial Cell Adhesion Molecule-1; Protease Inhibitors; Thiophenes; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

To determine the role of extracellular proteinases in ischemia-induced retinal neovascularization in an animal model and to examine the effect of proteinase inhibitors on retinal neovascularization.. Retinal neovascularization was induced in newborn mice exposed to 75% oxygen for 5 days, followed by room air. Retinal extracts underwent zymographic analysis to measure the activity of urokinase and matrix metalloproteinases (MMPs). Some animals under the same conditions also received intraperitoneal injections of an MMP inhibitor. Histological analysis was done to quantitate the neovascular response in these animals.. Levels of urokinase and MMPs (MMP-2 and MMP-9) in retinas were significantly increased in animals with induced retinal neovascularization. Neovascularization was significantly inhibited with intraperitoneal administration of an MMP inhibitor.. Systemic inhibition of MMPs may have therapeutic potential in preventing retinopathy associated with retinal neovascularization.. Because up-regulation and activation of proteinases represents a final common pathway in the process of retinal neovascularization, pharmacological intervention of this pathway may be an alternative therapeutic approach to proliferative retinopathy.

Topics: Animals; Animals, Newborn; Collagenases; Disease Models, Animal; Gelatinases; Injections, Intraperitoneal; Ischemia; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Metalloendopeptidases; Mice; Mice, Inbred C57BL; Phenylalanine; Protease Inhibitors; Retina; Retinal Neovascularization; Retinal Vessels; Thiophenes; Urokinase-Type Plasminogen Activator