PAR-1 is a novel mechano-sensor transducing laminar flow-mediated endothelial signaling

• Published in: Scientific reports Vol. 8; no. 1; pp. 15172 - 14
• Main Authors: Kim, Suji, Han, Jung-Hwa, Nam, Dae-Hwan, Kim, Geun-Young, Lim, Jae Hyang, Kim, Jae-Ryong, Woo, Chang-Hoon
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 11.10.2018; Nature Publishing Group UK
• Subjects: Acetylcholine; Actin; Aorta; Apoptosis; Arteriosclerosis; Cell surface; Endosomes; Endothelial cells; Flow cytometry; Inflammation; Mechanotransduction; Monocytes; Phosphorylation; Proteinase-activated receptor 1; Rodents; siRNA; Tumor necrosis factor-α; Vascular cell adhesion molecule 1; Vascular diseases; Vasodilation
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-33222-3

Recent studies have indicated that protease-activated receptor-1 (PAR-1) is involved in cytoprotective and anti-inflammatory responses in endothelial cells (ECs). However, the role of PAR-1 in laminar flow-mediated atheroprotective responses remains unknown. Herein, we investigated whether PAR-1 regulates laminar flow-mediated mechanotransduction in ECs. Confocal analysis showed that PAR-1 was internalized into early endosomes in response to laminar flow. In addition, flow cytometry analysis showed that cell surface expression of PAR-1 was reduced by laminar flow, suggesting that PAR-1 was activated in response to laminar flow. Depletion of PAR-1 using human PAR-1 siRNA inhibited unidirectional laminar flow-mediated actin stress fiber formation and cellular alignment as well as atheroprotective gene expressions in HUVECs. Moreover, PAR-1 knockdown inhibited laminar flow-stimulated eNOS phosphorylation, and inhibited the phosphorylations of Src, AMPK, ERK5 and HDAC5. Furthermore, PAR-1 depletion inhibited laminar flow-mediated anti-inflammatory responses as demonstrated by reduced TNFα-induced VCAM-1 expression and by monocyte adhesion to HUVECs, and prevented laminar flow-mediated anti-apoptotic response. An investigation of the role of PAR-1 in vasomotor modulation using mouse aortic rings revealed that acetylcholine-induced vasorelaxation was diminished in PAR-1 deficient mice compared to littermate controls. Taken together, these findings suggest that PAR-1 be viewed as a novel pharmacologic target for the treatment of vascular diseases, including atherosclerosis.