Shear stress is uncoupled from atheroprotective KLK10 in atherosclerotic plaques

Ziqi Zhou; Suze-Anne Korteland; Blanca Tardajos-Ayllon; Junxi Wu; Emily Chambers; Julia Weninck; Michael Simons; Mark Dunning; Torsten Schenkel; Mannekomba Diagbouga; Jolanda Wentzel; Maria Fragiadaki; Paul C Evans

doi:10.1016/j.atherosclerosis.2024.118622

Shear stress is uncoupled from atheroprotective KLK10 in atherosclerotic plaques

Atherosclerosis. 2024 Oct 4:398:118622. doi: 10.1016/j.atherosclerosis.2024.118622. Online ahead of print.

Authors

Affiliations

¹ Department of Infection, Immunity and Cardiovascular Disease, INSIGNEO Institute, and the Bateson Centre, University of Sheffield, Sheffield, UK.
² Department of Cardiology, Erasmus Medical Center, University Medical Center Rotterdam, 3015 GD, Rotterdam, the Netherlands.
³ Department of Infection, Immunity and Cardiovascular Disease, INSIGNEO Institute, and the Bateson Centre, University of Sheffield, Sheffield, UK; Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁴ Department of Biomedical Engineering, University of Strathclyde, Glasgow, G1 1QE, UK.
⁵ Department of Internal Medicine, Yale Cardiovascular Research Center, New Haven, CT, United States.
⁶ Sheffield Bioinformatics Core, The Medical School, University of Sheffield, Sheffield, UK.
⁷ Department of Engineering and Mathematics, Sheffield Hallam University, Sheffield, UK.
⁸ Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁹ Department of Infection, Immunity and Cardiovascular Disease, INSIGNEO Institute, and the Bateson Centre, University of Sheffield, Sheffield, UK; Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. Electronic address: [email protected].

PMID: 39413592
DOI: 10.1016/j.atherosclerosis.2024.118622

Abstract

Background and aims: Physiological shear stress promotes vascular homeostasis by inducing protective molecules in endothelial cells (EC). However, physiological shear stress has been linked to atherosclerosis progression in some individuals with heightened cardiovascular risk. To address this apparent paradox, we hypothesized that diseased arteries may exhibit reduced responsiveness to the protective effects of physiological shear stress. Consequently, we compared the transcriptome of EC exposed to physiological shear stress in healthy arteries versus atherosclerotic conditions.

Methods: Employing 3D light sheet imaging and computational fluid dynamics, we identified NOS3 as a marker of physiological shear stress in both healthy and atherosclerotic murine arteries. Single-cell RNA sequencing was performed on EC from healthy (C57BL/6) mice, mildly diseased (Apoe^-/- normal diet) mice, and highly diseased (Apoe^-/- high fat diet) mice. The transcriptomes of Nos3^high cells (exposed to physiological shear stress) were compared among the groups.

Results: Nos3^high EC were associated with several markers of physiological shear stress in healthy arteries. Clustering of Nos3^high EC revealed 8 different EC subsets that varied in proportion between healthy and diseased arteries. Cluster-specific nested functional enrichment of gene ontology terms revealed that Nos3^high EC in diseased arteries were enriched for inflammatory and apoptotic gene expression. These alterations were accompanied by changes in several mechanoreceptors, including the atheroprotective factor KLK10, which was enriched in Nos3^high EC in healthy arteries but markedly reduced in severely diseased arteries.

Conclusions: Physiological shear stress is uncoupled from atheroprotective KLK10 within atherosclerotic plaques. This sheds light on the complex interplay between shear stress, endothelial function, and the progression of atherosclerosis in individuals at risk of cardiovascular complications.

Grants and funding

R01 HL152197/HL/NHLBI NIH HHS/United States