Ljubica Matic, Sweden
Karolinska Institute Department of Molecular Medicine and SurgeryPresenter of 1 Presentation
Transcriptomic profiling of experimental arterial injury reveals new mechanisms and temporal dynamics in vascular healing response
Abstract
Background and Aims
Endovascular interventions cause arterial injury and induce a healing response to restore vessel wall homeostasis. Complications of defective or excessive healing are common, resulting in increased morbidity and repeated interventions. Experimental intimal hyperplasia models are vital for understanding vascular healing mechanisms and resolving clinical problems of restenosis, vein graft stenosis and dialysis access failure. Our aim was to systematically investigate the transcriptional, histological and systemic reaction to vascular injury over a prolonged period of time.
Methods
Balloon injury of the left common carotid artery was performed in male rats. Animals (n=69) were euthanized prior to or post-injury, either directly or after 2h, 20h, 2 days, 5 days and 2, 6, 12 weeks. Injured and contralateral arteries were microarray profiled, followed by bioinformatic exploration, histological biopsy characterization 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 (SMC) modulation several days after injury, with re-acquisition of contractile features in later phases. Clonal expansion, inflammatory transformation and chondro-osteogenic differentiation were novel pathways identified and immunolocalized to neointimal SMCs. Analysis of uninjured arteries revealed a systemic component of the reaction following local injury, underlined by altered endothelial signaling, changes in tissue bioenergy metabolism and plasma HDL 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 public resource for the research community.