Shear stress, exerted on endothelial cells by flowing blood, activates Akt which is known to phosphorylate Foxo1, thereby regulating the expression of its target genes. This study was done to investigate, whether shear stress regulates Foxo1 and its angiogenesis related target gene angiopoietin-2 (Ang-2). HUVEC were exposed to shear stress (cone-and-plate device) with or without inhibition of PI3K (using LY294,002) or Foxo1 (using siRNA) and analysed by fluorescence microscopy, RT- PCR, immunoblotting, and immunoprecipitation. Shear stress (6 dyn/cm2) increased phosphorylation of Akt and Foxo1 in a PI3K-dependent manner and Foxo1 was translocated out of the nucleus. Foxo1 protein and mRNA expression decreased accompanied by a decrease in Ang-2 which was similiarly be achieved by siRNA against Foxo1. Down-regulation of Foxo1-target gene p27Kip1 further verified the biological significance. Expression of Tie2 was increased by shear stress by a not yet identified mechanism, while Ang-1 remained unchanged.

In conclusion, endothelial cells adapt to flow via nuclear exclusion and transcriptional suppression of Foxo1 and its target gene Ang-2, thus stabilizing perfused blood vessels and priming non-perfused sprouts for angiogenic factors.