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The effect of laminar and disturbed flow on endothelial glucose metabolism

层流和扰动流对内皮葡萄糖代谢的影响

基本信息

批准号：
10335226
负责人：
Alisa S Morss Clyne
金额：
$ 38.29万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10335226
关键词：
Acetyl Coenzyme A Actins Affect Animal Model Area Arterial Fatty Streak Atherosclerosis Blood Vessels Blood flow Caveolae Cell Adhesion Molecules Cell Proliferation Cells Cellular Metabolic Process Collaborations Data Development Disease Endothelial Cells Endothelium Enzymes Epigenetic Process Exposure to Functional disorder Gene Expression Glucose Glycolysis Goals Golgi Apparatus Health Hexosamines Histone Acetylation Homeostasis Hour Impairment In Vitro Inflammation Inflammatory Learning Link Lipids Malignant Neoplasms Mass Spectrum Analysis Mediating Mediator of activation protein Metabolic Metabolic Pathway Metabolism Modeling Morphology Myocardial Infarction NOS3 gene Neoplasm Metastasis Nitric Oxide Oxygen Pathologic Pathway interactions Permeability Phenotype Phosphorylation Post-Translational Protein Processing Production Proteins Regulation Repression Research Research Personnel Side Stress Fibers Stroke Testing Time Vascular remodeling Vasodilation Warburg Effect angiogenesis atheroprotective cancer cell career endothelial dysfunction experience experimental study glucose metabolism glucose uptake hemodynamics in vivo metabolomics novel therapeutics overexpression prevent shear stress therapy development tool

项目摘要

Endothelial metabolism has recently re-emerged as a powerful tool to regulate vascular function. However, studies have focused entirely on glycolytic flux regulation via PFKFB3 and its effects in angiogenesis. Little is known about how endothelial cell metabolism impacts macrovascular endothelial function in health and disease. Endothelial cells are constantly exposed to shear stress from the flowing blood. Endothelial cells in steady laminar flow express a quiescent phenotype, maintaining vascular homeostasis through control of proliferation, permeability, inflammation, and vascular tone. Endothelial cells in oscillating disturbed flow express an athero- prone phenotype with elevated proliferation, permeability, and inflammatory adhesion molecule expression as well as impaired NO production (defined as endothelial dysfunction). Disturbed flow regions are linked to subsequent pathological vascular remodeling including atherosclerotic plaque development. Recently, endothelial cells in steady laminar reduced glycolysis partially via KLF2-mediated repression of PFKFB3. However, concurrent KLF2 and PFKFB3 overexpression did not fully restore glycolytic rate, suggesting that other metabolic mediators are involved. Our data show that endothelial cells in steady laminar flow reduce glycolytic flux at shorter times with no change in PFKFB3 expression, and that endothelial cells in oscillating disturbed flow do not decrease glycolytic flux. Our data also show that flow regulates the hexosamine biosynthetic pathway, a side branch of glycolysis which controls protein O-GlcNAcylation, and acetyl CoA, which is critical to lipid synthesis and histone acetylation. We are only beginning to discover mechanisms by which shear stress affects endothelial glucose metabolism and downstream pathways. Our long term goal is to modulate glucose metabolism to reduce endothelial dysfunction in disturbed flow. The goal of this project is to understand how steady laminar and oscillating disturbed flow differentially affect macrovascular endothelial glycolytic flux, the HBP, and acetyl CoA metabolism. We hypothesize that mean shear stress greater than 12 dynes/cm2 reduces glycolytic flux, eNOS O-GlcNAcylation, and acetyl CoA to promote an athero-protective endothelial phenotype. To test this hypothesis, we will (1) determine how steady laminar and oscillating disturbed flow regulate endothelial glycolytic flux; (2) determine how steady laminar and oscillating disturbed flow affect eNOS O-GlcNAcylation; and (3) determine how altered acetyl CoA in flow impacts lipid synthesis and histone acetylation Since atherosclerosis is a disease of altered metabolism, we will use a combination of in vitro and ex vivo experiments to discover mechanisms underlying changes in glucose metabolism with flow. Our team is uniquely prepared to pursue this research, with expertise in endothelial hemodynamics, metabolic mass spectrometry, O- GlcNAcylation, and ex vivo vessel analysis. These data will transform the field by creating a new research area at the intersection of hemodynamics and metabolomics.

内皮代谢最近重新成为调节血管功能的有力工具。然而,