Abstract 15833: Shear Stress Modulates the Expression of the Vasoprotective Protein Cx37 in Endothelial Cells
Connexin37 (Cx37) is a gap junction protein essential for cell-cell communication in the vasculature. Endothelial cells (ECs) of healthy arteries express high levels of Cx37, but this expression is lost in ECs overlying atherosclerotic plaques. The deletion of Cx37 in ApoE−/− mice increases their susceptibility to atherosclerosis, which suggests that Cx37 has anti-atherogenic properties. High laminar shear stress is known to be vasculoprotective partly through the induction of KLF2. As the promoter region of the Cx37 gene contains KLF consensus binding sites, we hypothesize that shear stress, through the modulation of KLF2, may affect Cx37 expression in ECs. We observed that Cx37 is highly expressed in the straight region of the common carotid artery of ApoE−/− mice, whereas it was reduced at carotid bifurcation. Shear stress-modifying vascular casts were placed around the right common carotid artery of ApoE−/− mice and Cx37 expression in response to flow was assessed by en face immunofluorescence. We found that Cx37 expression is downregulated in regions of altered flow (either low laminar or oscillatory shear stress), but is conserved in regions of high laminar flow. To further study the mechanisms involved, the mouse endothelial cell line bEnd.3 was exposed to shear stress in vitro. After 24hrs of high laminar shear stress (30 dynes/cm2) Cx37 and KLF2 expression were increased when compared to static condition. Alternatively, bEnd.3 cells were exposed to simvastatin, which is known to mimic the effects of high laminar flow on KLF2. Simvastatin simultaneously increased the expression of Cx37 and KLF2. Interestingly, Cx37 expression was reduced after effective silencing of KLF2 by transfection with siRNA, suggesting that KLF2 acts as a transcription factor for this gap junction protein. In conclusion, high laminar shear stress in vivo or in vitro as well as exposure to simvastatin, upregulate the expression of KLF2 and of the anti-atherogenic protein Cx37. Therefore, this effect of shear stress on Cx37 expression may participate in the overall protective effect of high laminar flow on the endothelium.
- © 2010 by American Heart Association, Inc.