From inflammation to remodelling: A novel BASP1+ monocyte subset as a catalyst for acute aortic dissection

Abstract

Role and Molecular Mechanism of the BASP1+ Monocyte Subset in Acute Aortic Dissection (AAD) Initiation and Progression. During AAD, a distinct subpopulation of BASP1-positive monocytes (BASP1+ monocytes) with elevated inflammatory gene expression occurs in both the peripheral blood and aortic wall. These BASP1+ monocytes infiltrate aortic tissues, triggering early vascular remodelling. BASP1 modulates the ACTN1 and GSN signalling pathways, which influence monocyte motility and recruitment. As a result, BASP1+ monocytes differentiate into tissue macrophages that release matrix metalloproteinases (MMPs) and inflammatory cytokines. Furthermore, BASP1+ monocytes enhance apoptosis in healthy vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), promote the emergence of a novel inflammatory VSMC subset via a glutamate-mGluR5 mechanism, and generate a reactive oxygen species (ROS)-rich EC subset. These processes lead to matrix degradation, VSMC apoptosis, disruption of myoendothelial gap junctions, and EC apoptosis. Collectively, these changes contribute to vascular remodelling, aortic wall weakening, and the progression of AAD. • For the first time, this study identifies a novel BASP1 + monocyte subset that acts as a catalyst for acute aortic dissection (AAD) by orchestrating inflammation and vascular remodeling. • BASP1 activates VAV3 and GSN signaling pathways, suggesting a key mechanism in the immune response mediated by BASP1+ monocyte in AAD. • BASP1+ monocyte as the first line immune cells infiltrate aortic tissues, amplifying inflammation and inducing an inflammatory phenotype in vascular smooth muscle cells (VSMCs) and a reactive oxygen species (ROS)-enriched endothelial cell (EC) subset, contributing to vascular remodeling in the pathogenesis of AAD. • The identification of the BASP1+ monocyte subset and its regulatory network provides deep insights into AAD pathogenesis, offering a novel and promising target for early intervention in AAD formation. Monocytes comprise heterogeneous cell populations. However, beyond traditionally considered as precursors of tissue macrophages, heterogeneity and detailed effects of monocytes in acute aortic dissection (AAD) are largely unknown. To investigate the role of brain soluble acid protein 1 positive (BASP1 + ) monocyte subset in promoting AAD development as well as the underlying mechanism. Monocyte/macrophage heterogeneity in both human peripheral blood and aortic tissues were assayed by scRNA-seq. Monocyte trafficking and lineage tracing were detected by immunofluorescence and using BASP1-CreER/Lyz2-DreER-tdT reporter mice with AAD. The effects and underlying mechanism were investigated by laser speckle image, ultrasound imaging, Co-IP, ChIP-sequencing. Conditional knockout of BASP1 on monocyte and BASP1 siRNA were used to observe BASP1 + monocyte subset-targeted AAD intervention. “PIP2-SP1-ACTN1/VAV3” and “ITGB1-Rac1-GSN” signalling mediated BASP1 + monocyte subset as the first line immune cells infiltrating aortic tissues in AAD induction and partial of them transformed to BASP1 + macrophages to amplify the inflammation. Meanwhile, BASP1 + monocyte subset induced an inflammatory phenotype vascular smooth muscle cell (VSMC) subset and a ROS-enriched endothelial cell (EC) subset accompanied with promoting the apoptosis of normal VSMC and EC, contributing to vascular remodelling and dampening the myo-endothelial gap junction. Selective deletion of BASP1 + monocyte subset and interference with BASP1 expression in monocytes both inhibited the development of AAD in mice. Interpretation BASP1 + monocyte subset and its regulatory network provides deep insight into AAD pathogenesis and a novel potential target for early intervention in AAD formation

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