Endothelial Collagen Type VIII in Atherosclerotic Plaque Vulnerability

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY / ABSTRACT Atherosclerosis, the leading cause of heart disease, results in arterial plaque formation that can lead to life- threatening events like myocardial infarction and stroke. Collagen type VIII, particularly its COL8A1 component, is highly expressed in atherosclerotic lesions and may play a crucial role in plaque stability by influencing smooth muscle cell recruitment and endothelial-to-mesenchymal transition (EndMT). Accumulating data also support a role for COL8A1 in the progression of a variety of cancers, such as breast cancer, pancreatic adenocarcinoma, and glioma, and it is increasingly being considered as a therapeutic target in these conditions. Our preliminary data suggest that COL8A1 expression is modulated by inflammatory cytokines and may promote atherosclerotic plaque stabilization by guiding EndMT toward myofibroblast-like and osteogenic lineages. This study aims to investigate the role of collagen VIII in atherosclerotic plaque vulnerability. In Aim 1, we use endothelial lineage-tracing (Cdh5CreERT2;RosatdTomato) methods to evaluate EndMT in a hyperlipidemic COL8A1 knockout (Col8a1-/-;Apoe-/-) mouse model. Single-cell RNA sequencing analysis of endothelial-derived cells and quantitative histomorphometry of atherosclerotic lesions will be used to characterize EndMT and atherosclerotic plaque vulnerability. In Aim 2, we will employ a hyperlipidemic, inducible endothelial-specific Col8a1 knockout mouse model (Cdh5-CreERT2;Col8a1fl/fl;Apoe-/-) to determine whether endothelial COL8A1 promotes atherosclerotic plaque stability. Radiolabeled 18F-NaF µPET/µCT imaging will be used to evaluate the effects of endothelial Col8a1 on calcified plaque morphology in vivo, as well as quantitative histomorphometry to assess EndMT and plaque features of vulnerability. Findings from this project will bridge the work of our K08 award to strengthen our R01 proposal by providing valuable in vivo data on the effects of endothelial COL8A1 on EndMT and atherosclerotic calcification.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Collagen type VIII is an extracellular matrix protein that is highly expressed in atherosclerotic plaques and may influence their vulnerability to rupture, leading to heart attack and stroke. This study will determine whether endothelial collagen VIII reduces plaque vulnerability by regulating endothelial-to-mesenchymal transition (EndMT). Using lineage-tracing and endothelial-specific knockout mouse models, combined with in vivo molecular imaging of calcification morphology and single-cell RNA sequencing, we will define how endothelial collagen VIII affects EndMT and plaque stability in atherosclerosis.