Exercise-Induced Shear Stress Modulates Metabolic Pathways for Vascular Repair and Protection

运动性剪应力调节血管修复和保护的代谢途径 年从战场归来的退伍军人中心血管和代谢性疾病呈上升趋势 在阿富汗和中东，运动干预仍然是一种有效的生活方式改变。 血流动力学应力力调节血管内皮细胞的代谢和机械效应， 调节动脉粥样硬化病变的局灶性和偏心性。代谢组学和新陈代谢学的出现 图谱分析导致了新的代谢生物标记物和治疗靶点的发现。我们确定了 双向振荡流损害自噬通量，扰乱线粒体动态平衡。相比之下， 单向脉动血流减轻线粒体DNA损伤以维持内皮细胞动态平衡。在……里面 同时，我们开发了用于检测代谢活性的灵活的微型电化学阻抗传感器 新西兰白(NZW)兔模型的动脉粥样硬化病变。我们证明了氧化低- 动脉粥样硬化病变中的密度脂蛋白(OxLDL)表现出明显的频率依赖性电学和 介电性能。我们的初步研究表明，脉动流和振荡流是不同的 调节代谢途径，促进血管再生和动脉粥样硬化保护。我们证明了这一点 用电化学阻抗谱(EIS)检测血流敏感的动脉代谢变化。 此外，我们的代谢组学分析表明，Pss和Oss对PKCɛ-6有不同的激活作用 Phosphofructo-2-kinase/fructose-2，6-biphosphatase 3(PFKFB3)信号转导增加糖酵解代谢产物， 而是减少糖异生代谢产物，用于血管修复和再生。代谢组学分析 进一步发现流动敏感型核激素受体过氧化体增殖物激活受体 (PPAR)依赖的脂肪酸代谢产物可减少单核细胞募集。在这种情况下，我们假设 运动增强的脉动切应力(PSS)调节糖酵解和脂代谢 影响血管再生和保护的途径，导致动脉代谢变化 这可以通过三维EIS映射来检测到。为了检验我们的假设，我们有三个目标。在目标1中，我们将 确定流动介导的蛋白激酶Cε信号是否调节糖酵解代谢产物以促进血管再生。我们 假设PSs和Oss通过差异调控PKCε-PFKFB3信号通路来调节产物 糖酵解代谢物。在目标2中，我们将确定流动敏感的PPAR信号是否调节血脂 用于血管保护的代谢物。我们假设Pss和Oss对PPAR-Scd-1有差异的调制 调节脂肪酸代谢物产生的信号。在目标3中，我们将演示剪切力-ppar- 三维EIS标测介导动脉代谢改变。我们假设PPAR-scd1介导的 代谢变化可以通过三维EIS图进行查询。总体而言，血管生物学的整合， 血流动力和代谢组谱将为糖酵解的血流调节提供代谢洞察力 和脂质代谢发现新的生物标记物，对我们有心脏病风险的退伍军人具有治疗意义 疾病和代谢综合征。

Exercise-Induced Shear Stress Modulates Metabolic Pathways for Vascular Repair and Protection Cardiovascular and metabolic diseases are on the rise in our veterans returning from battlefields in Afghanistan and the Middle East, and exercise intervention remains an effective lifestyle modification. Hemodynamic stress forces modulate both metabolic and mechanical effects on vascular endothelial cells, mediating the focal and eccentric nature of atherosclerotic lesions. The advent in metabolomics and metabolic profiling has led to the discovery of new metabolic biomarkers and therapeutic targets. We established that bidirectional oscillatory flow impairs autophagic flux, perturbing mitochondrial homeostasis. In contrast, unidirectional pulsatile flow attenuated mitochondrial DNA damage to maintain endothelial homeostasis. In parallel, we developed flexible micro-electrochemical impedance sensors for detection of metabolically active atherosclerotic lesions in the New Zealand White (NZW) rabbit model. We demonstrated that oxidized Low- Density Lipoprotein (oxLDL) in atherosclerotic lesions display distinct frequency-dependent electrical and dielectrical properties. Our preliminary studies revealed that pulsatile and oscillatory flow differentially modulated metabolic pathways to promote vascular regeneration and athero-protection. We demonstrated that flow-sensitive arterial metabolic changes were detected by electrochemical impedance spectroscopy (EIS). Furthermore, our metabolomics analyses revealed that PSS vs. OSS differentially activates PKCɛ-6- phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) signaling to increase glycolytic metabolites, but to decrease gluconeogenic metabolites, for vascular repair and regeneration. Metabolomics analyses further uncovered flow-sensitive nuclear hormone receptor peroxisome proliferator-activated receptor  (PPAR)-dependent fatty acid metabolites to mitigate monocyte recruitment. In this context, we hypothesize that exercise-augmented pulsatile shear stress (PSS) modulates glycolytic and lipid metabolic pathways to influence vascular regeneration and protection, leading to the arterial metabolic changes that can be detected by 3-D EIS mapping. To test our hypothesis, we have three aims. In Aim 1, we will determine if flow-mediated PKCε signaling modulates glycolytic metabolites for vascular regeneration. We hypothesize that PSS and OSS differentially modulate PKCε-PFKFB3 signaling pathway to regulate production of glycolytic metabolites. In Aim 2, we will determine if flow-sensitive PPAR signaling modulates lipid metabolites for vascular protection. We hypothesize that PSS and OSS differentially modulate PPAR-SCD-1 signaling to regulate production of fatty acid metabolites. In Aim 3, we will demonstrate shear stress-PPAR- mediated arterial metabolic changes by 3-D EIS mapping. We hypothesize that PPAR-SCD1-mediated metabolic changes can be interrogated by 3-D EIS mapping. Overall, the integration of vascular biology, hemodynamic forces and metabolomic profiling will provide metabolic insights into flow modulation of glycolytic and lipid metabolisms to discover new biomarkers with therapeutic implications for our veterans at risk for heart disease and metabolic syndromes.