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

动脉粥样硬化引起的外周动脉疾病(PAD)具有相当高的发病率和死亡率。 在全世界，这在很大程度上是由于急性和慢性闭塞缺血造成的组织损伤。 目前的治疗仅限于通过以下方式改变危险因素和机械血运重建 手术搭桥或血管成形术。临床前研究已经确定了与骨髓有关的机制 炎症抑制状态下的衍生巨噬细胞(BMDM)依赖的血管生成，但存在 炎症巨噬细胞在急性损伤中也有促进有效血管生成的作用。我们 最近发现了一种新的IL-1B依赖的促血管生成异构体的转录调控 血管内皮生长因子-AIL-1B缺失的原代巨噬细胞表现出VEGF-A的表达受损，以及 因此，巨噬细胞IL-1β缺失的小鼠已经损害了血管/动脉的形成。近期 初步数据表明，血管内皮生长因子-R2(相对于血管内皮细胞生长因子受体1)的表达在 炎症性M1状态，并与IL-1β和VEGF-A升高有关。抑制 尽管IL-1β水平稳定，但血管内皮生长因子R2信号转导导致血管内皮生长因子A表达减少，提示 IL-1β与血管内皮生长因子-A的关系解偶联。展示了其他初步数据 老年(52周龄)小鼠或实验性糖尿病小鼠血管/动脉生成减少， 使用包括巨噬细胞定向血流恢复的股动脉结扎的PAD模型。 衰老和慢性糖尿病导致血流恢复进一步减少，从而导致 血管生成受损。进一步的来自老年糖尿病小鼠的BMDM显示IL-1β的解偶联 和血管内皮生长因子-A的表达，IL-1β略有下降，但严重且不成比例 降低血管内皮生长因子-A的表达。血管内皮生长因子-R2在老年糖尿病BMDM中降低。解耦 巨噬细胞IL-1β-VEGF-A信号转导在炎性血管/动脉形成中的作用 长期2型糖尿病的发病环境。我们的研究目的是试图定义 血管内皮生长因子-R2促进IL-1β依赖的血管内皮生长因子-A的产生和随后的动脉形成 确定衰老和长期糖尿病引起的这一途径中的损害，目标是 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.