Abstract 18448: Laminar Flow and Klf2 Regulate the Paracrine Activity of Endothelial Cells by Modulating the Balance of Cxcr4 versus Cxcr7 Expression
Recent studies suggest that endothelial cells are not only important for oxygen delivery but act as paracrine source for signals that determine tissue regeneration versus fibrosis. The paracrine regulation of liver regeneration by endothelial cells was shown to be critically controlled by the SDF-1 receptors CXCR4, which was shown to control the release of pro-fibrotic cytokines, whereas signaling via the CXCR7 receptor was shown to provide a pro-regenerative niche. The regulation of the endothelial CXCR4 versus CXCR7 expression and their role in heart regeneration is unclear. Here we show that laminar flow as well as the expression of the flow-induced transcription factor Krüppel-like factor 2 (KLF2) reduced mRNA expression of CXCR4 by (0.34±0.01 fold; p<0.005) and (0.22±0.05 fold; p<0.0005), respectively, whereas CXCR7 expression was significantly increased (flow: 6.59±0.52 fold; p<0.005, KLF2: 36±12.3 fold; p<0.05). Western blots confirmed that flow and KLF2 critically modulate the CXCR4 / CXCR7 protein expression. Interestingly, shear stress and KLF2 induce the expression of the CXCR7-downstream inhibitor of DNA binding 1 (Id1), a transcription factor known to induce pro-regenerative angiocrine factors. Cytokine arrays further demonstrate that flow and KLF2 overexpression change the paracrine release of important growth factors. For example, Activin A (1.7±0.69 fold) and IGF-binding proteins were increased (1.7±0.87 fold), whereas the release of pro-inflammatory cytokines IL-8 (0.16±0.02 fold) and MCP1 (0.43±0.01 fold) and growth factors VEGF-C (0.16±0.01 fold), PlGF (0.09±0.01 fold) and Endoglin (0.27±0.09 fold) were reduced. The changes in the release of these paracrine growth factors were partially reduced by siRNA-mediated silencing of CXCR7. In summary these data suggest that flow and KLF2 critically regulate the paracrine secretion of endothelial growth factors by modulating the balance of CXCR4 versus CXCR7 expression. Ongoing studies address the contribution of endothelial KLF2 in liver and heart regeneration in vivo.
Author Disclosures: Y. Manavski: None. A. Doddaballapur: None. J. Hu: None. H. Augustin: None. R. Boon: None. S. Dimmeler: None.
- © 2014 by American Heart Association, Inc.