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

由动脉粥样硬化引起的外周动脉疾病（peripheral artery disease，PAD）是一种严重的疾病 在很大程度上是由于急性和慢性闭塞性缺血引起的组织损伤。 目前的治疗方法仅限于通过以下方式来改变危险因素和机械血运重建： 外科搭桥术或血管成形术。临床前研究已经确定了涉及骨髓的机制 衍生的巨噬细胞（BMDM）依赖的血管生成在炎症抑制状态，但有 也是炎性巨噬细胞在急性损伤期间促进有效血管生成的作用。我们 最近定义了一种新的IL-1B依赖的促血管生成亚型的转录调节， VEGF-A。缺失IL-1 B的原代巨噬细胞显示VEGF-A表达受损， 因此，巨噬细胞IL-1 β缺失的小鼠具有受损的血管/动脉生成。最近 初步数据表明，VEGF-R2（相对于VEGFR 1）的表达也升高， 炎症M1状态，并与IL-1 β和VEGF-A的升高有关。抑制 尽管IL-1 β水平稳定，但VEGF-R2信号转导导致VEGF-A表达减少，这表明， IL-1 β和VEGF-A之间关系的解偶联。额外的初步数据显示 老年（52周龄）小鼠或患有实验性糖尿病的小鼠血管/动脉生成减少， 使用股动脉结扎的PAD模型，其涉及巨噬细胞定向的血流恢复。 衰老与慢性糖尿病相结合，导致血流恢复进一步减少， 血管生成受损。来自老年糖尿病小鼠的进一步BMDM显示IL-1 β解偶联 和VEGF-A表达，IL-1 β适度降低，但严重且不成比例 降低VEGF-A表达。VEGF-R2在老年糖尿病BMDM中减少。解偶联 巨噬细胞IL-1 β-VEGF-A信号转导有助于炎症性血管/动脉生成的损伤， 长期2型糖尿病的背景。我们的研究旨在确定 VEGF-R2促进IL-1 β依赖性VEGF-A的产生和随后的动脉生成， 确定由衰老和长期糖尿病引起的这一途径的损伤， 在适当的临床背景下进行干预以恢复有效的血管生成。

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.