Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, United States; Molecular and Systems Pharmacology Program, Emory University, Atlanta, United States
Marwa Mahmoud
Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, United States
Renfa Liu
Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, United States; Department of Biomedical Engineering, Peking University, Beijing, China
Aitor Andueza
Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, United States
Sandeep Kumar
Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, United States
Dong-Won Kang
Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, United States
Jiahui Zhang
Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, United States
Ian Tamargo
Molecular and Systems Pharmacology Program, Emory University, Atlanta, United States
Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, United States; Molecular and Systems Pharmacology Program, Emory University, Atlanta, United States; Department of Medicine, Emory University, Atlanta, United States
Atherosclerosis preferentially occurs in arterial regions exposed to disturbed blood flow (d-flow), while regions exposed to stable flow (s-flow) are protected. The proatherogenic and atheroprotective effects of d-flow and s-flow are mediated in part by the global changes in endothelial cell (EC) gene expression, which regulates endothelial dysfunction, inflammation, and atherosclerosis. Previously, we identified kallikrein-related peptidase 10 (Klk10, a secreted serine protease) as a flow-sensitive gene in mouse arterial ECs, but its role in endothelial biology and atherosclerosis was unknown. Here, we show that KLK10 is upregulated under s-flow conditions and downregulated under d-flow conditions using in vivo mouse models and in vitro studies with cultured ECs. Single-cell RNA sequencing (scRNAseq) and scATAC sequencing (scATACseq) study using the partial carotid ligation mouse model showed flow-regulated Klk10 expression at the epigenomic and transcription levels. Functionally, KLK10 protected against d-flow-induced permeability dysfunction and inflammation in human artery ECs, as determined by NFκB activation, expression of vascular cell adhesion molecule 1 and intracellular adhesion molecule 1, and monocyte adhesion. Furthermore, treatment of mice in vivo with rKLK10 decreased arterial endothelial inflammation in d-flow regions. Additionally, rKLK10 injection or ultrasound-mediated transfection of Klk10-expressing plasmids inhibited atherosclerosis in Apoe−/− mice. Moreover, KLK10 expression was significantly reduced in human coronary arteries with advanced atherosclerotic plaques compared to those with less severe plaques. KLK10 is a flow-sensitive endothelial protein that serves as an anti-inflammatory, barrier-protective, and anti-atherogenic factor.
