| First Author | Kobayashi K | Year | 2014 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 34 |
| Issue | 8 | Pages | 1716-22 |
| PubMed ID | 24925969 | Mgi Jnum | J:227101 |
| Mgi Id | MGI:5699669 | Doi | 10.1161/ATVBAHA.114.303890 |
| Citation | Kobayashi K, et al. (2014) Stromal cell-derived factor-1alpha/C-X-C chemokine receptor type 4 axis promotes endothelial cell barrier integrity via phosphoinositide 3-kinase and Rac1 activation. Arterioscler Thromb Vasc Biol 34(8):1716-22 |
| abstractText | OBJECTIVE: Although stromal cell-derived factor (SDF)-1alphais 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-1alphasignaling in endothelial barrier function. APPROACH AND RESULTS: Treatment with SDF-1alpha elevated transendothelial electrical resistance and inhibited the dextran hyperpermeability elicited by thrombin in bovine aortic endothelial cells, both indicating an increase in endothelial barrier function. SDF-1alpha 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 (siRNA) eliminated SDF-1alpha-induced endothelial barrier enhancement. In contrast, CXCR7 antagonist or CXCR7 gene depletion by siRNA did not influence SDF-1alpha-induced barrier enhancement. Pretreatment with a Gi-protein inhibitor, a phosphoinositide 3-kinase (PI3K) inhibitor, or PI3K p110gammasubunit gene depletion by siRNA also inhibited SDF-1alpha-induced barrier enhancement significantly. Western blot analysis revealed that SDF-1alpha phosphorylated Akt(Ser473) in endothelial cells, suggesting PI3K activation. Immunostaining showed that treatment with SDF-1alphaformed a cortical actin rim, which was accompanied by Rac1 activation. In vivo, SDF-1alphainhibited croton oil-induced vascular leakage indexed by dye extravasation, which is attenuated by a pretreatment with a CXCR4 antagonist. CONCLUSIONS: We have identified SDF-1alpha as a novel suppressor of endothelial permeability. Specifically, SDF-1alpha stimulates the CXCR4/PI3K/Rac1 signaling pathway and the subsequent cytoskeletal rearrangement. |
