Novel Aortic Dissection Model Links Endothelial Dysfunction and Immune Infiltration.

Area of Science:

• Cardiovascular Biology
• Connective Tissue Diseases
• Genetics and Genomics

Background:

• Aortic dissection (AD) is a life-threatening condition, particularly in patients with connective tissue disorders like Marfan syndrome.
• The molecular triggers, progression, and cellular interactions in AD remain poorly understood.
• A spontaneous mouse model was developed to investigate the underlying molecular mechanisms of AD.

Purpose of the Study:

• To elucidate the molecular mechanisms and cellular interactions driving aortic dissection.
• To characterize the pathological progression of AD in a novel mouse model.
• To identify potential therapeutic targets for aortic dissection.

Main Methods:

• A novel mouse model was created using CRISPR/Cas9 to incorporate a pathogenic FBN1 variant (p.G234D).
• Comprehensive analyses included histology, immunofluorescence, electron microscopy, synchrotron imaging, and single-cell RNA sequencing.
• Biochemical assays assessed mutant FBN1 protein binding to LTBP and TGFβ signaling pathways.

Main Results:

• Mutant mice (Fbn1G234D/G234D) exhibited high mortality due to aortic rupture with significant immune cell infiltration.
• Endothelial cells showed altered mechanosensing and increased adhesion molecules (VCAM-1, ICAM-1) prior to dissection.
• Single-cell RNA sequencing identified distinct monocyte/macrophage populations in the intima, correlating with disease progression and matrix metalloproteinase (MMP2/9) upregulation.
• Mutant FBN1 protein lost binding to LTBPs, leading to reduced TGFβ signaling.

Conclusions:

• Endothelial cell and macrophage/monocyte interactions within the intima, coupled with reduced TGFβ signaling in the extracellular matrix, initiate AD.
• This novel AD mouse model is a valuable tool for identifying therapeutic targets.
• Findings pave the way for developing new treatment strategies for aortic dissection.