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Laminar shear stress inhibits CXCR4 expression on endothelial cells: functional consequences for atherogenesis
Author(s) -
Melchionna Roberta,
Porcelli Daniele,
Mangoni Antonella,
Carlini Daniele,
Liuzzo Giovanna,
Spinetti Gaia,
Antonini Annalisa,
Capogrossi Maurizio C.,
Napolitano Monica
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-2219fje
Subject(s) - chemokine , umbilical vein , stromal cell derived factor 1 , chemokine receptor , endothelial stem cell , endothelium , microbiology and biotechnology , chemotaxis , receptor , cxcr4 , cxc chemokine receptors , chemistry , apoptosis , biology , immunology , endocrinology , in vitro , biochemistry
Laminar shear stress (LSS) represents a major athero‐protective stimulus. However, the mechanisms for this effect are poorly characterized. As chemokine receptors modulate endothelial cell functions, we hypothesized that at least some LSS effects on endothelial cells (ECs) may be due to LSS‐dependent changes in chemokine receptor expression and function. Exposure of Human umbilical vein endothelial cells (HUVECs) to 15 dynes/cm 2 /sec −1 LSS strongly inhibited CXC chemokine receptor 4 (CXCR4) expression at the transcriptional level and impaired stromal‐derived factor (SDF)‐1/CXCL12‐driven chemotaxis. On the contrary, low shear stress (SS; 4 dynes/cm 2 /sec −1 ) only marginally affected CXCR4 expression when compared with static control cells. Differently from CXCR4, the expression of SDF‐1 mRNA was not affected by LSS treatment. CXCR4 overexpression induced a dose‐dependent endothelial cell apoptosis that was enhanced by SDF‐1 treatment and was caspase‐dependent. CXCR4 overexpression inhibited the LSS‐mediated antiapoptotic effect on ECs and was associated to impairment of LSS‐induced ERK1/2 phosphorylation. These findings suggest that LSS‐induced CXCR4 down‐regulation may contribute to endothelial cell survival. Interestingly, the expression of the proatherogenic chemokines MCP‐1 and IL‐8 was induced by SDF‐1 treatment and by CXCR4 overexpression in HUVECs. Further, the known LSS‐induced inhibition of MCP‐1 expression was impaired in CXCR4 overexpressing ECs. Finally, CXCR4 was abundantly expressed by human atherosclerotic plaque endothelium that is exposed to low/absent shear stress, while it was poorly expressed by minimally diseased carotid artery endothelium. In conclusion, LSS‐dependent CXCR4 down‐regulation may contribute to atheroprotection by favoring the integrity of the endothelial barrier and by inhibiting MCP‐1 and IL‐8 expression.