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Metabolic control in vascular remodeling

血管重塑中的代谢控制

基本信息

批准号：
10330406
负责人：
Nicholas E Sibinga
金额：
$ 59.36万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10330406
关键词：
Address Adult Affect Animals Aorta Area Arterial Injury Arteries Arteriosclerosis Aspartate Atherosclerosis Biological Assay Blood Vessels Cadherins Cardiovascular Diseases Cause of Death Cell Proliferation Cell Wall Cell division Cell physiology Cells Cellular Metabolic Process Cellular biology Complex DNA Damage Data Development Disease Dorsal Elements Embryo Embryonic Development Endothelial Cells Extracellular Matrix FAT gene Frequencies Functional disorder Genetic Goals Growth Health Homeostasis Impairment Injury Intervention Knowledge Label Longevity Mediating Metabolic Control Mitochondria Mitochondrial DNA Modeling Mus NADH dehydrogenase (ubiquinone)Neurons Obstruction Oxidative Phosphorylation Oxygen Consumption Pathogenesis Pathogenicity Pathology Pharmacology Phenotype Play Population Predisposition Preventive Process Proliferating Proteins Reactive Oxygen Species Regulation Research Respiration Role Smooth Muscle Myocytes Structure Testing Therapeutic Time Tissue Engineering Transplantation Tube Vascular Diseases Vascular Smooth Muscle Vascular remodeling Vascularization angiogenesis base cell behavior cell growth clinically significant cytokine disability in vivo mechanical force metabolic phenotype migration mitochondrial metabolism mouse development mouse model novel oxidation postnatal prevent repaired respiratory response restenosis screening therapeutic angiogenesis tumor vascular injury vasculogenesis

项目摘要

Summary Vascular remodeling is essential for artery formation during embryogenesis and in the pathogenesis of vascular diseases such as atherosclerosis, restenosis, and transplant- associated arteriosclerosis in adulthood. Despite this high clinical significance, our incomplete understanding of the process of vascular remodeling limits current abilities to develop preventive and therapeutic strategies. Vascular smooth muscle cells (SMCs) are main drivers of developmental and adult vascular remodeling, but mechanisms underlying SMC activities are not fully elucidated — in particular, the role of mitochondria and metabolism in this context is relatively unexplored. The goal of this proposal is to understand mitochondrion-based mechanisms that regulate SMC phenotype in vascular remodeling. We have shown that the FAT1 cadherin interacts with and inhibits mitochondrial respiratory complex I, limits SMC proliferation by restraining mitochondrial respiration, and opposes vascular occlusion after arterial injury. These findings suggest that respiratory complex I regulates SMC behavior. Our new preliminary data further support this idea. Loss of complex I subunit NDUFS4 in cultured SMCs decreases complex I levels and activity, limits the formation of supercomplexes containing complex I, lowers aspartate levels, and impairs cell growth. In vivo, NDUFS4 is highly expressed during mouse development in SMCs building the arterial wall, and in adult mice in SMC-derived cells that form the expanding neointima that accumulates in response to arterial injury. Preliminary studies with selective NDUFS4 deletion in SMCs suggest that these cells require respiratory complex I for normal embryogenesis. We hypothesize that complex I promotes SMC activities important for vascular remodeling during embryogenesis and in adulthood. We will test this hypothesis in three specific aims that respectively address the effects of impaired respiratory complex I function 1) on key SMC activities, 2) on mouse vascular development, and 3) in models of adult vascular homeostasis, injury, and atherosclerotic disease. These studies will add a new respiratory complex-based angle — susceptible to pharmacological intervention — to our understanding of how arteries form and how they respond to injury, with relevance for tissue engineering, therapeutic angiogenesis, tumor vascularization, and vascular disease.

概括血管重塑对于胚胎发生期间和发育过程中的动脉形成至关重要动脉粥样硬化、再狭窄和移植等血管疾病的发病机制与成年期动脉硬化有关。尽管具有很高的临床意义，但我们的不完整对血管重塑过程的理解限制了当前能力的发展预防和治疗策略。血管平滑肌细胞（SMC）是血管平滑肌细胞的主要驱动力发育和成人血管重塑，但 SMC 活动的机制是尚未完全阐明 - 特别是线粒体和新陈代谢在这方面的作用是相对未经探索。该提案的目标是了解基于线粒体的血管重塑中调节 SMC 表型的机制。我们已经证明了 FAT1 钙粘蛋白与线粒体呼吸复合物 I 相互作用并抑制，限制 SMC 通过抑制线粒体呼吸来促进增殖，并对抗血管闭塞动脉损伤。这些发现表明呼吸复合物 I 调节 SMC 行为。我们的新的初步数据进一步支持了这一想法。培养物中复合物 I 亚基 NDUFS4 的丢失 SMC 降低复合物 I 水平和活性，限制超级复合物的形成含有复合物 I，降低天冬氨酸水平，并损害细胞生长。在体内，NDUFS4 具有高度在小鼠发育过程中，在构建动脉壁的 SMC 中以及在成年小鼠中表达 SMC 衍生细胞形成不断扩张的新内膜，该内膜响应动脉血管而积聚受伤。 SMC 中选择性 NDUFS4 缺失的初步研究表明，这些细胞正常胚胎发生需要呼吸复合物 I。我们假设复合体 I 促进 SMC 活性，对胚胎发生过程中的血管重塑非常重要成年期。我们将在三个具体目标中检验这一假设，分别解决呼吸复合物 I 功能受损的影响 1) 对关键 SMC 活动的影响，2) 对小鼠的影响血管发育，3) 在成人血管稳态、损伤和模型中动脉粥样硬化疾病。这些研究将增加一个新的基于呼吸复合体的角度—— 容易受到药物干预——我们对动脉如何形成和它们如何应对损伤，与组织工程、治疗性血管生成相关，肿瘤血管化和血管疾病。