Molecular mechanisms of restenosis in Ossabaw pig obesity model

• Applicant: Dr. Olga Bondareva
• Subject Area: Cardiology, Angiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 559857009

In recent years it has become clear that restenosis is morphologically and chronologically different from primary atherosclerosis. Restenosis is characterized by hyperplasia of intima and thinning of the media layers of vessel wall. However, what causes such different phenotypes of primary and secondary blood vessel occlusion is unknown. Moreover, there is no clear indication as to why some patients develop restenosis, while others do not, and how different angioplasty interventions and drug treatments affect patient outcomes. We hypothesize that the molecular changes in restenosis will be different from those in primary atherosclerosis development. Moreover, we hypothesize that the efficacy of angioplasty treatments in treating atherosclerosis, and the molecular risk factors promoting restenosis following initial treatment, are therefore also different. Thus, in this proposal, we aim to characterize atherosclerotic and restenotic lesions in the Ossabaw pig model, assess effects of various angioplasty treatments, and perform direct comparison of transcriptional and cell composition changes using single cell RNA sequencing paired with immunofluorescence, histochemical, and immunological assays. Specific aims: 1. Baseline characterization of atherosclerotic and restenotic vessels in Ossabaw pig (WP1). Single cell transcriptomic analyses and quantitative histology will be used to map the molecular and morphological changes that occur in response to angioplasty at primary lesion sites. 2. Systematic analysis of vascular response to various endovascular interventions (WP2). We will perform analysis of tissue composition and cell type heterogeneity in response to endovascular intervention, including balloon angioplasty, stenting, and atherectomy in presence or absence of drugs (Sirolimus, Paclitaxel). We will compare the grade of restenosis between treatments and provide unbiased characterization of current endovascular intervention approaches in human. 3. Comparison to human restenosis and validation of findings in vitro (WP3). Comparison of molecular networks driving atherosclerosis and restenosis development in pig and human will be undertaken based on scRNA-seq data. Identified mechanisms will be further tested in in vitro models using primary human endothelial cell cultures for possible prevention of human restenosis. The role of predicted mediators of restenosis and recovery after endovascular interventions will be functionally investigated to provide mechanistic insights. Together, this project promises to (I) identify molecular mechanisms underlying the difference in restenosis and atherosclerosis, and (II) perform and thoroughly characterize angioplasty treatments and identify molecular risk factors promoting restenosis for further improvement of patient treatment strategies.

• DFG Programme: Research Grants