Stromal Cell–Derived Factor-1α/C-X-C Chemokine Receptor Type 4 Axis Promotes Endothelial Cell Barrier Integrity via Phosphoinositide 3-Kinase and Rac1 Activation
Objective—Although stromal cell–derived factor (SDF)-1α is well known to modulate the mobilization of hematopoietic stem cells and endothelial progenitor cells, its effects on some pre-existing vascular functions remain unknown. We have investigated here the role of SDF-1α signaling in endothelial barrier function.
Approach and Results—Treatment with SDF-1α elevated transendothelial electric resistance and inhibited the dextran hyperpermeability elicited by thrombin in bovine aortic endothelial cells, both indicating an increase in endothelial barrier function. SDF-1α binds to 2 receptors, C-X-C chemokine receptor types 4 and 7 (CXCR4 and CXCR7). Pretreatment with a CXCR4 antagonist or CXCR4 gene depletion by small interfering RNA eliminated SDF-1α–induced endothelial barrier enhancement. In contrast, CXCR7 antagonist or CXCR7 gene depletion by small interfering RNA did not influence SDF-1α–induced barrier enhancement. Pretreatment with a Gi-protein inhibitor, a phosphoinositide 3-kinase inhibitor, or phosphoinositide 3-kinase p110γ subunit gene depletion by small interfering RNA also inhibited SDF-1α–induced barrier enhancement significantly. Western blot analysis revealed that SDF-1α phosphorylated AktSer473 in endothelial cells, suggesting phosphoinositide 3-kinase activation. Immunostaining showed that treatment with SDF-1α formed a cortical actin rim, which was accompanied by Rac1 activation. In vivo, SDF-1α inhibited croton oil–induced vascular leakage indexed by dye extravasation, which is attenuated by a pretreatment with a CXCR4 antagonist.
Conclusions—We have identified SDF-1α as a novel suppressor of endothelial permeability. Specifically, SDF-1α stimulates the CXCR4/phosphoinositide 3-kinase/Rac1 signaling pathway and the subsequent cytoskeletal rearrangement.
- Received December 17, 2012.
- Accepted June 2, 2014.
- © 2014 American Heart Association, Inc.