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Objective Endovascular interventions cause arterial injury and induce a healing response to restore vessel wall homeostasis. Complications of defective or excessive healing are common and result in increased morbidity and repeated interventions. Experimental models of intimal hyperplasia are vital for understanding the vascular healing mechanisms and resolving the clinical problems of restenosis, vein graft stenosis, and dialysis access failure. Our aim was to systematically investigate the transcriptional, histologic, and systemic reaction to vascular injury during a prolonged time. Methods Balloon injury of the left common carotid artery was performed in male rats. Animals (n = 69) were euthanized before or after injury, either directly or after 2 hours, 20 hours, 2 days, 5 days, 2 weeks, 6 weeks, and 12 weeks. Both injured and contralateral arteries were subjected to microarray profiling, followed by bioinformatic exploration, histologic characterization of the biopsy specimens, and plasma lipid analyses. Results Immune activation and coagulation were key mechanisms in the early response, followed by cytokine release, tissue remodeling, and smooth muscle cell modulation several days after injury, with reacquisition of contractile features in later phases. Novel pathways related to clonal expansion, inflammatory transformation, and chondro-osteogenic differentiation were identified and immunolocalized to neointimal smooth muscle cells. Analysis of uninjured arteries revealed a systemic component of the reaction after local injury, underlined by altered endothelial signaling, changes in overall tissue bioenergy metabolism, and plasma high-density lipoprotein levels. Conclusions We demonstrate that vascular injury induces dynamic transcriptional landscape and metabolic changes identifiable as early, intermediate, and late response phases, reaching homeostasis after several weeks. This study provides a temporal “roadmap” of vascular healing as a publicly available resource for the research community., Clinical Relevance Endovascular intervention causes an injury to the arterial wall that subsequently induces a healing response to restore the vessel wall homeostasis. Complications after vascular interventions related to defective or excessive healing response, such as thrombosis or restenosis, are common and result in increased morbidity, suffering of the patient, need for repeated interventions, and possibly death. Thus, there is a need for better understanding of the underlying molecular mechanisms during vascular injury and healing response to identify and to assess the risk of complications in patients. Using an experimental model of vascular injury, this study demonstrates the full landscape of dynamic transcriptional changes in the resolution of vascular injury, accompanied also by systemic variations in plasma lipid levels and reaching homeostasis several weeks after injury. These results can guide the development of new strategies and molecular targets for modulation of the intimal response on endovascular interventions.