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

IL-1β 和 VEGF-A 串扰的解偶联导致慢性糖尿病缺血的动脉生成反应受损

• 批准号: 10579818
• 负责人: Elizabeth O Harrington
• 金额: $ 34.98万
• 依托单位: OCEAN STATE RESEARCH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10579818
• 关键词: Acute; Aging; Angioplasty; Atherosclerosis; Biology; Blood Vessels; Blood flow; Bone Marrow; Bone Marrow Involvement; Bypass; Cardiopulmonary; Centers of Research Excellence; Chronic; Clinical; Data; Diabetes Mellitus; Diabetic mouse; Disease model; Experimental Diabetes Mellitus; Goals; Impairment; Inflammation; Inflammatory; Injury; Interleukin-1 beta; Ischemia; Ligation; Mechanics; Modification; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Operative Surgical Procedures; Pathway interactions; Peripheral arterial disease; Production; Protein Isoforms; Recovery; Risk Factors; Role; Signal Transduction; Tissues; Transcriptional Regulation; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Vegf inhibition; aged; angiogenesis; diabetic; femoral artery; macrophage; mortality; novel; preclinical study; response

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.

由动脉粥样硬化引起的外周动脉疾病（PAD）导致相当高的发病率和死亡率 在世界范围内，很大程度上是由于急性和慢性闭塞性缺血造成的组织损伤。 目前的治疗仅限于改变危险因素和机械血运重建 外科搭桥手术或血管成形术。临床前研究已确定涉及骨髓的机制 炎症抑制状态下的衍生巨噬细胞（BMDM）依赖性血管生成，但存在 炎症巨噬细胞在急性损伤期间也发挥着促进有效血管生成的作用。我们 最近定义了一种新的 IL-1 B 依赖性转录调节促血管生成亚型 VEGF-A。 IL-1 B 缺失的原代巨噬细胞表现出 VEGF-A 表达受损，并且 因此，巨噬细胞 IL-1 β 缺失的小鼠血管/动脉生成受损。最近的 初步数据表明，VEGF-R2（相对于 VEGFR1）的表达在 炎症 M1 状态并与 IL-1 β 和 VEGF-A 升高相关。抑制 尽管 IL-1 β 水平稳定，但 VEGF-R2 信号传导导致 VEGF-A 表达减少，这表明 IL-1β 和 VEGF-A 之间关系的解偶联。已证实的其他初步数据 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， 使用涉及巨噬细胞引导血流恢复的股动脉结扎 PAD 模型。 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 证明了 IL-1 β 的解偶联 和 VEGF-A 表达，IL-1 β 适度减少，但严重且不成比例地减少 VEGF-A 表达减少。老年糖尿病 BMDM 中 VEGF-R2 降低。解耦 巨噬细胞 IL-1 beta-VEGF-A 信号传导导致炎症血管/动脉生成受损 长期2型糖尿病的情况。我们的研究目的是寻求定义机制 VEGF-R2 促进 IL-1 β 依赖性 VEGF-A 的产生和随后的动脉生成，并促进 确定衰老和长期糖尿病引起的该通路损伤，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。