Arterial and Venous Endothelia Display Differential Functional Fractalkine (CX3CL1) Expression by Angiotensin-II
Objective—Angiotensin-II (Ang-II) promotes the interaction of mononuclear cells with arterioles and neutrophils with postcapillary venules. To investigate the mechanisms underlying this dissimilar response, the involvement of fractalkine (CX3CL1) was explored.
Methods and Results—Enhanced CX3CL1 expression was detected in both cremasteric arterioles and postcapillary venules 24 hours after Ang-II intrascrotal injection. Arteriolar leukocyte adhesion was the unique parameter significantly reduced (83%) in animals lacking CX3CL1 receptor (CX3CR1). Human umbilical arterial and venous endothelial cell stimulation with 1 μmol/L Ang-II increased CX3CL1 expression, yet neutralization of CX3CL1 activity only significantly inhibited Ang-II–induced mononuclear cell–human umbilical arterial endothelial cell interactions (73%) but not with human umbilical venous endothelial cells. The use of small interfering RNA revealed the involvement of tumor necrosis factor-α in Ang-II–induced CX3CL1 upregulation and mononuclear cell arrest. Nox5 knockdown with small interfering RNA or pharmacological inhibition of extracellular signal-regulated kinases1/2, p38 mitogen-activated protein kinase, and nuclear factor-κB also abolished these responses. Finally, when human umbilical arterial endothelial cells were costimulated with Ang-II, tumor necrosis factor-α, and interferon-γ, CX3CL1 expression and mononuclear cell adhesiveness were more pronounced than when each stimulus was provided alone.
Conclusion—These results suggest that Ang-II induces functional CX3CL1 expression in arterial but not in venous endothelia. Thus, targeting endothelial CX3CL1–mononuclear leukocyte CX3CR1 interactions may constitute a new therapeutic strategy in the treatment of Ang-II–associated cardiovascular diseases.
- Received June 8, 2012.
- Accepted October 24, 2012.
- © 2012 American Heart Association, Inc.