Abstract P140: Molecular Signatures Of The Delayed Healing Response To Arterial Injury In Diabetic Rats

Aim: Atherosclerosis is a major complication of diabetes mellitus and a leading cause of mortality in diabetic patients. Vascular interventions in diabetic patients can lead to complications attributed to defective vascular remodeling and impaired healing response. In this study, we aim to elucidate the physiological and molecular differences in the vascular healing response over time using a rat model of arterial injury applied in healthy and diabetic conditions. Methods: Wistar (healthy) and Goto-Kakizaki (GK, diabetic) rats (n = 40 per strain) were subjected to left common carotid artery (CCA) balloon injury and euthanized at different timepoints: 0 and 24 hours, 5 days, 2, 4 and 6 weeks. Non-invasive morphological and physiological assessment, and microarray profiling of the CCA was performed for each timepoint. Bioinformatic analyses were conducted using R software, DAVID bioinformatic tool, online STRING database and Cytoscape software. Results: Significant increase in the neointimal thickness (p<0.01; 2-way ANOVA) was observed after 2 weeks of injury in diabetic compared to heathy rats, which was confirmed by histological analyses. Moreover, a decrease in the reendothelialization rate was also detected in the diabetic rats at 4 and 6 weeks after injury. Bioinformatic analyses showed that expression of early response genes related to inflammation and proliferation were delayed in diabetic rats, coupled with the dysregulation of key pathways related to vascular healing. Defective expression patterns were observed for endothelial, macrophage and lymphocyte markers indicating potential faults on cell regulation level. TF-PPI analysis provided mechanistic evidence wherein an array of transcription factors was dysregulated in diabetic rats specifically from 2 weeks after injury. Conclusions: In this study, we investigated the effect of diabetes on vessel wall healing. We demonstrate that diabetic rats exhibit impaired arterial remodelling characterised by a delayed healing response. These results further corroborate the higher prevalence of restenosis in diabetic patients and provide vital molecular insights into the mechanisms contributing to the impaired arterial healing response in diabetes.