Abstract
Aims: In-stent restenosis (ISR) remains an Achilles heel of drug-eluting stents despite technical advances in devices and procedural techniques. Neointimal hyperplasia (NIH) is the most important pathophysiological process of ISR. The present study mapped normal arteries and stenotic arteries to uncover potential cellular targets of neointimal hyperplasia.Methods and Results: By comparing the left (control) and right (balloon injury) carotid arteries of rats, we mapped 11 clusters in normal arteries and 11 mutual clusters in both the control and experimental groups. Different clusters were categorized into 6 cell types, including vascular smooth muscle cells (VSMCs), fibroblasts, endothelial cells (ECs), macrophages, unknown cells and others. An abnormal cell type expressing both VSMC and fibroblast markers at the same time was termed a transitional cell via pseudotime analysis. Due to the high proportion of VSMCs, we divided them into 6 clusters and analyzed their relationship with VSMC phenotype switching. Moreover, N-myristoyltransferase 1 (NMT1) was verified as a credible VSMC synthetic phenotype marker. Finally, we proposed several novel target genes by disease susceptibility gene analysis, such as Cyp7a1 and Cdk4, which should be validated in future studies.Conclusion: Maps of the heterogeneous cellular landscape in the carotid artery were defined by single-cell RNA sequencing and revealed several cell types with their internal relations in the ISR model. This study highlights the crucial role of VSMC phenotype switching in the progression of neointimal hyperplasia and provides clues regarding the underlying mechanism of NIH.
Highlights
It has been more than 30 years since the first stent implantation, and currently, percutaneous coronary intervention (PCI) has been widely adopted for most ischemic heart diseases
The present study was designed to map the full view of normal arteries and stenotic arteries with an established rat carotid artery balloon injury model to further explore the underlying mechanism of neointimal hyperplasia (NIH) by using advanced single-cell technologies
The rat carotid artery balloon injury model is the most common in vivo model widely used to study in-stent restenosis (ISR). This approach consists of isolating a segment from the right common carotid artery in SD rats under general anesthesia, creating an arteriotomy incision in the external carotid branch followed by inserting a balloon catheter (Fogarty, 12A0602F, 0.67 mm, Edwards Lifesciences) into the common carotid artery, repeated balloon inflation and pulling back five times to imitate percutaneous transluminal coronary angioplasty (PTCA), and removal of the catheter with external carotid ligation [10]
Summary
It has been more than 30 years since the first stent implantation, and currently, percutaneous coronary intervention (PCI) has been widely adopted for most ischemic heart diseases. The proportion of cell types inside the coronary artery changes after the development of atherosclerotic plaque and stent implantation due to the adaptive defense of blood vessels in response to internal and external stimuli. It is important to determine the changes in the proportion and status of these cells in the coronary artery after ISR, which could help us understand the underlying mechanisms of ISR. Neointimal hyperplasia (NIH) with VSMC migration and proliferation remains the most essential pathophysiological mechanism of ISR [7,8,9]. The present study was designed to map the full view of normal arteries and stenotic arteries with an established rat carotid artery balloon injury model to further explore the underlying mechanism of NIH by using advanced single-cell technologies
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