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Updated: Jun 4, 2025
A New Murine Model of Endovascular Aortic Aneurysm Repair
Published on: July 7, 2013
Big data analytics and scRNA-seq in human aortic aneurysms and dissections: role of endothelial MerTK
Shijie Liu1, Jinzi Wu1, Oishani Banerjee1
1Department of Biology, Georgia State University, Atlanta, GA, 30303, USA.
Insights
Endothelial MER proto-oncogene tyrosine kinase (MerTK) deficiency impairs efferocytosis, leading to endothelial dysfunction and promoting ascending aortic aneurysms and dissections (AAAD). This highlights MerTK as a potential therapeutic target for AAAD prevention.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Cellular Biology
Background:
- Aortic aneurysms and dissections (AAD) are a significant cause of mortality in the US, with no current preventative medications.
- MER proto-oncogene tyrosine kinase (MerTK) is crucial for efferocytosis, the clearance of apoptotic cells.
- The role of endothelial MerTK in ascending aortic aneurysms and dissections (AAAD) progression requires further investigation.
Purpose of the Study:
- To investigate the role of endothelial MerTK in the pathogenesis of ascending aortic aneurysms and dissections (AAAD).
- To determine the impact of MerTK deficiency in endothelial cells (ECs) on AAAD development.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) analysis of human AAAD samples.
- RNA-seq big data analytics.
- Utilized a MerTK conditional knockout mouse model (MerTKflox/flox/Tie2Cre) to study MerTK deficiency in ECs.
Main Results:
- Endothelial MerTK expression is significantly reduced in human AAAD, impairing EC efferocytosis capabilities.
- MerTK deficiency in ECs led to a 100% incidence of AAAD in the knockout mice, versus 11.1% in controls.
- Endothelial MerTK deficiency caused endothelial dysfunction and smooth muscle cell (SMC) phenotypic alterations, driving AAAD development.
Conclusions:
- Impaired endothelial MerTK function is a novel mechanism contributing to AAAD pathogenesis.
- Endothelial dysfunction and altered SMC phenotype resulting from MerTK deficiency promote AAAD.
- Targeting endothelial MerTK may offer a new strategy for preventing AAAD.
Abstract:
Rationale: Aortic aneurysms and dissections (AAD) cause more than 10,000 deaths in the United States each year. However, there are no medications that can effectively prevent the pathogenesis of AAD. MER proto-oncogene tyrosine kinase (MerTK) is a key receptor for efferocytosis, a process for the clearance of apoptotic cells. Here, we mainly focused on ascending aortic aneurysms and dissections (AAAD) and investigated the role of endothelial MerTK in AAAD progression. Methods: Single-cell RNA sequencing (scRNA-seq) analysis in human AAAD samples and RNA-seq big data analytics, combined with our unique MerTKflox/flox/Tie2Cre mouse model with MerTK deficiency in endothelial cells (ECs), were applied to define the role of endothelial MerTK in AAAD. Results: Through comparative analyses of scRNA-seq in human AAAD (communications of ECs with other cells) and comprehensive big data analytics including about 600,000 cross analyses, we found that the expression of endothelial MerTK is significantly inhibited in human AAAD, resulting in decreased ability of ECs to engulf antigen presenting cells, phagocytes, leukocytes, blood cells and myeloid cells. Our in vivo data showed a significantly higher incidence of AAAD in MerTK flox/flox/Tie2Cre mice compared to that of their littermate controls of MerTK flox/flox mice (100% vs. 11.1%). MerTK deficiency in ECs induces both endothelial dysfunction and SMC phenotypic alterations, subsequently promoting AAAD development. Conclusions: Our findings indicate that endothelial MerTK impairment and subsequent endothelial dysfunction and SMC phenotypic alterations represent novel mechanisms promoting AAAD.
