期刊
CARDIOVASCULAR RESEARCH
卷 92, 期 3, 页码 456-465出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvr240
关键词
Vascular endothelial cadherin; Myosin light chain; Transendothelial migration of monocytes; Adherens junctions; ERK
资金
- American Heart Association South Central Affiliate [0865174F]
- MacDonald General Research Fund [09RDM002]
- US Army [W81XWH-04-2-0035]
Aims Transendothelial migration (TEM) of monocytes is a crucial step in inflammatory processes such as atherogenesis. Tyrosine phosphorylation of vascular endothelial cadherin (VE-cad) has been implicated in the dissociation of adherens junctions and the increased paracellular permeability of endothelial cells (ECs) that occur during TEM of monocytes. However, the underlying molecular mechanism has not been determined. We tested the hypothesis that the phosphorylation of myosin light chain (MLC) in ECs is crucial for the dissociation of adherens junctions during TEM of monocytes. Methods and results Using a combination of biochemical and cellular techniques, we provide evidence for the signal transduction pathways that regulate tyrosine phosphorylation of VE-cad in ECs after the attachment of monocytes. Our findings indicate that after interaction of integrins on THP-1 cells with adhesion molecules on ECs, the induction of the HRas\Raf\MEK\ERK signalling cascade leads to the phosphorylation of MLC. This results in the recruitment of Src to the VE-cad complex and tyrosine phosphorylation of VE-cad, which leads to dissociation of beta-catenin from the VE-cad complex, formation of gaps between ECs, and enhancement of THP-1 cell TEM. Conclusion Our studies suggest that monocyte-induced phosphorylation of MLC in ECs enhances TEM of monocytes through dissociation of EC adherens junctions.
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