Uncoupling of IL-1 beta and VEGF-A Crosstalk Contributes to Impaired Arteriogenesis Response to Ischemia in Chronic Diabetes Mellitus

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Peripheral artery disease (PAD) caused by atherosclerosis leads to considerable morbidity and mortality throughout the world, in large part, due to tissue damage from both acute and chronic occlusive ischemia. Current treatments are limited to the modification of risk factors and mechanical revascularization by surgical bypass or angioplasty. Preclinical studies have identified mechanisms involving bone marrow derived macrophage (BMDM)-dependent angiogenesis in an inflammation suppressed state, but there is also a role for inflammatory macrophages during acute injury to promote effective angiogenesis. We recently defined a novel IL-1 B-dependent transcriptional regulation of the pro-angiogenic isoform of VEGF-A. Primary macrophages with deletion of IL-1 B demonstrate impaired expression of VEGF-A, and consequently, macrophage IL-1 beta-deleted mice have impaired angio/ arteriogenesis. Recent preliminary data identified that VEGF-R2 (relative to VEGFR1) expression is also elevated in the inflammatory M1 state and is associated with elevations in IL-1 beta and VEGF-A. Inhibition of VEGF-R2 signaling led to reduced VEGF-A expression despite stable IL-1 beta levels, suggesting an uncoupling of the relationship between IL-1 beta and VEGF-A . Additional preliminary data demonstrated that aged (52-week-old) mice or mice with experimental diabetes have reductions angio/ arteriogenesis, using a PAD model of femoral artery ligation that involves macrophage-directed blood flow recovery. Combined aging with chronic diabetes led to further reductions in blood flow recovery consequent to impaired angiogenesis. Further BMDMs from aged, diabetic mice demonstrated an uncoupling of IL-1 beta and VEGF-A expression, with modest reductions in IL-1 beta and yet severe and disproportionately reduced VEGF-A expression. VEGF-R2 was decreased in aged, diabetic BMDMs. Uncoupling of macrophage IL-1 beta-VEGF-A signaling contributes to impairment of inflammatory angio/arteriogenesis in the setting of long-term type 2 diabetes. Our study aims seek to define the mechanism whereby VEGF-R2 facilitates IL-1 beta-dependent VEGF-A production and consequent arteriogenesis and to determine the impairments in this pathway caused by aging and long-term diabetes with the goal of intervening to recover effective angiogenesis in the appropriate clinical context.