Metabolic control in vascular remodeling

血管重塑中的代谢控制

基本信息

批准号：
10543542
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 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10543542
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 Invaded Knowledge Label Longevity Mediating Metabolic Control Metabolism Mitochondria Mitochondrial DNA Modeling Mus NADH dehydrogenase (ubiquinone)Neurons Obstruction Oxidative Phosphorylation Oxygen Consumption Pathogenesis Pathogenicity Pathology 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 cell behavior cell growth clinically significant cytokine disability in vivo mechanical force metabolic phenotype migration mouse development mouse model novel oxidation pharmacologic postnatal prevent repaired respiratory response restenosis restraint 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过程中的动脉形成至关重要血管疾病的发病机理，例如动脉粥样硬化，再狭窄和移植 - 成年后相关的动脉硬化。尽管临床意义很高，但我们的不完整了解血管重塑的过程的当前能力预防和治疗策略。血管平滑肌细胞（SMC）是主要驱动因素发育和成人血管重塑，但是SMC活动的基础机制是在这种情况下，线粒体和新陈代谢的作用尤其没有完全阐明，尤其是相关意外。该建议的目的是了解基于线粒体调节血管重塑中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相互作用并限制SMC 通过限制线粒体呼吸扩散，并在动脉损伤。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这一想法。在培养的 SMC降低复合物I水平和活动，限制了超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。 invivo，ndufs4高度高在鼠标发育过程中在SMC中发育时表达，建造动脉壁，成年小鼠 SMC衍生的细胞形成了随着动脉的响应而积累的扩展新内膜的细胞受伤。 SMC中选择性NDUFS4缺失的初步研究表明这些细胞需要呼吸复合物I以正常的胚胎发生。我们假设我的复杂我促进SMC活动对于胚胎发生过程中的血管重塑很重要成年。我们将以三个特定目标来检验这一假设，分别解决受损呼吸复合物I功能1）对关键SMC活动的影响，2）在鼠标上血管发育和3）在成人血管稳态，损伤和动脉粥样硬化疾病。这些研究将增加一个新的基于呼吸复合物的角度 - 容易受到药物干预的影响 - 我们对动脉的形成方式的理解它们如何应对伤害，与组织工程，治疗性血管生成相关，肿瘤血管和血管疾病。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Neutrophil extracellular traps in cardiac hypertrophy: a KLF2 perspective.

DOI：
10.1172/jci156453
发表时间：
2022-02-01
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
Riascos-Bernal DF;Sibinga NE
通讯作者：
Sibinga NE

The FAT1 Cadherin Drives Vascular Smooth Muscle Cell Migration.

DOI：
10.3390/cells12121621
发表时间：
2023-06-14
期刊：
CELLS
影响因子：
6
作者：
Riascos-Bernal, Dario F.;Ressa, Gaia;Korrapati, Anish;Sibinga, Nicholas E. S.
通讯作者：
Sibinga, Nicholas E. S.