Mechano-transduction mechanisms are instrumental to embryogenesis, tissue homeostasis, and disease pathologies. This is especially important in the vasculature, where local disturbed blood flow activates vascular endothelial cells at arterial curvatures and bifurcations prone to atherosclerosis, the leading cause of human mortality and morbidity worldwide. In contrast, unidirectional blood flow associated with higher time-average shear stress in straight parts of blood vessels promotes endothelial quiescence and barrier integrity. Mechanical signals from hemodynamics are transduced in endothelial cells through their metabolic pathway and epigenetic landscapes, which collectively dictate transcriptome remodeling. But it remains unexplored how these processes are interconnected to achieve such high coordination, specifically (1) how the individual cis-regulatory elements work synergistically on gene regulation, and (2) how the glycolytic signal is translated into atherogenesis. Addressing these two questions will promote our understanding on how endothelial cells integrate and orchestrate individual modules from different layers to achieve flow-induced functional phenotypes. My studies in Chapter Two discovered that mechano-sensitive super-enhancers tend to collectively activate genes with prominent functions in mechano-transduction. It provides new molecular mechanism underlying the systematic transcriptome reprogramming in adaptation to hemodynamics. My studies in Chapter Three identified disturbed flow upregulates endothelial lactate dehydrogenase A to drive atherogenic gene transcription and leads to atherosclerosis, and proposed a novel epigenetic model through histone lactylation. Collectively, these studies demonstrate the effective crosstalk between metabolism and epigenome in mediating endothelial mechano-transduction, and emphasize the sophisticated molecular coordination in driving cardiovascular pathophysiology.