Angiotensin II failitated angiogenesis mediated through macrophage migration inhibitory factor activation in hindlimb ischemic

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Background-Macrophage migration inhibitory factor (MIF), which we have reported to be secreted by oxidative stress, plays a crucial role in several inflammatory conditions such as regulating the activation of macrophages and T cells, and it also acts as a factor stimulating cell growth and inducing other cytokines and enzymes such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). VEGF and MMPs are thought to influence neovascularization in many cell type. Taken together, we assessed the hypothesis that MIF could be an important factor stimulating angiogenesis in response to ischemia. Methods and Results-To test the hypothesis, we examined angiogenesis in response to tissue ischemia in MIF overexpressed (TG) mice. We applied surgically-induced unilateral hindlimb ischemia model to MIF TG and wild type (WT) mice (C57BL/6). Angiogenesis and collateral vessel formation in the ischemic hindlimb were analyzed by using laser Doppler perfusion Imager (ischemic/normal perfusion ratio), angiography (angiogrphic score) and histological capillary density with vWF antibody. Message and protein expression of the VEGF and MMPs (-2 and -9) were determined with RT-PCR. Angiogenesis and collateral vessel formation in response to hindlimb ischemia were markedly increased in MIF TG mice compared with WT mice. VEGF protein levels were not different between the MIF TG mice and WT mice at non-ischemic area. In the ischemic area VEGF mRNA and protein expression levels were increased in the TG mice compared with the WT mice. MMP-9 mRNA expression was increased at non-ischemic region in the TG mice compared with the WT mice. This increased expression was reinforced in the ischmic region in the TG mice, although no difference in MMP-2 between them. A neutralizing antibody against MIF significantly suppressed angiogenesis, VEGF expression, and MMP-9 expression in response to ischemia