Laminar shear stress inhibits endothelial-mesenchymal transition and improves atherosclerosis through SRXN1
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Bin Liu
PROVIDER: PXD075827 | iProX | Thu Mar 19 00:00:00 GMT 2026
REPOSITORIES: iProX
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Project description:Background: Protein-tyrosine-phosphatase CD45 is expressed in all nucleated cells of the hematopoietic system but has also been detected in mitral valve endothelial cells (ECs) undergoing endothelial-to-mesenchymal transition (EndoMT). Interestingly, our recent study indicated that activation of the endogenous CD45 promoter in human endothelial colony-forming cells (ECFCs) also induced expression of multiple EndoMT marker genes. We hypothesize that CD45 may contribute to atherosclerosis, a prevalent cardiovascular disease dependent on EndoMT. However, the detailed molecular mechanisms underlying how CD45 contributes to EndoMT and the impact of therapeutic manipulation of CD45 expression in atherosclerosis are entirely unknown. Method: We generated a tamoxifen-inducible EC-specific CD45-deficient mouse strain (EC-iCD45KO) on an ApoE-deficient (ApoE-/-/C57BL/6) background and fed them a Western diet to produce atherosclerosis. We enriched mouse aortic ECs with anti-CD31 beads to perform single-cell RNA sequencing. Cellular, biochemical, and molecular approaches were used to investigate the effect of endothelial CD45-specific deletion on EndoMT and lesion development in ApoE-/- model of atherosclerosis. Results: Endothelial ApoE-/- CD45-deficient mice showed reduced lesion development, plaque macrophages, and expression of cell adhesion molecules when compared to ApoE-/- controls. Single-cell RNA sequencing revealed that loss of endothelial CD45 reduces EndoMT marker expression and TGF-β signaling in atherosclerotic mice, which is associated with the reduction of lesions in the ApoE-/- mouse model. Mechanistically, the loss of CD45 results in increased FGFR2 in mouse aortic ECs and KLF2 expression in the aortic root. Consistently, endothelial CD45-deficiency inhibits EndoMT and TGF-β signaling. Conclusions: These findings demonstrate that genetic depletion of endothelial CD45 protects against EndoMT-driven atherosclerosis by promoting FGFR2 and KLF2 expression while inhibiting TGFβ signaling and EndoMT. Thus, targeting endothelial CD45 may be a novel therapeutic strategy to reduce EndoMT and treat atherosclerosis.
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Project description:While much progress has been made in identifying the mechanisms that trigger endothelial activation and inflammatory cell recruitment during atherosclerosis, less is known about the intrinsic pathways that counteract these events. Here we identified NOTCH1 as an antagonist of endothelial cell activation. NOTCH1 was constitutively expressed by adult arterial endothelium, but levels were significantly reduced by high fat diet. Furthermore, treatment of human aortic endothelial cells (HAEC) with inflammatory lipids (Ox-PAPC) and pro-inflammatory cytokines (TNFalpha and IL1beta) decreased Notch1 expression and signaling in vitro through a mechanism that requires STAT3 activation. Reduction of NOTCH1 in HAEC by siRNA, in the absence of inflammatory lipids or cytokines, increased inflammatory molecules and binding of monocytes. Conversely, some of the effects mediated by Ox-PAPC were reversed by increased NOTCH1 signaling; suggesting a link between lipid-mediated inflammation and Notch1. Interestingly, reduction of NOTCH1 by Ox-PAPC in HAEC was associated with a genetic variant previously correlated to HDL in a human GWAS. Finally endothelial Notch1 heterozygous mice showed higher diet-induced atherosclerosis. Based on these findings, we propose that reduction of endothelial NOTCH1 is a predisposing factor in the onset of vascular inflammation and initiation of atherosclerosis. Transcript profile from Human Aortic Endothelial Cells (HAEC) transfected with siRNA targeting NOTCH1 (n=3) or treated with Ox-PAPC (Oxidized 1-Palmitoyl-2-Arachidonoyl-sn-glycero-3-PhosphoCholine) for 6 hours (n=3) were compared to control HAEC (transfected with control siRNA and control media; n=3).
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