In epithelial cells, the protein Scrib (Scribble) controls apico-basal polarity whereas apico-lateral polarity is mainly controlled by the Par and Crumbs complexes. The positioning of proteins is achieved through a localized activation of kinases and small GTPases like Rac1 and CDC42. The function of polarity proteins in endothelial cells is less clear and we have previously reported that loss of Scrib disturbs endothelial directed migration. Shear stress-induced signaling and its impact on endothelial function depend on planar cell polarity. On this basis, we hypothesize that Scrib has an impact on mechanotransduction and anti-atherosclerotic functions.

Tamoxifen-induced Scrib knockout mice were crossed into ApoE background and atherosclerosis development was analyzed in response to high-fat diet or partial carotid artery ligation combined with high-fat diet. In both models, deletion of Scrib resulted in increased atherosclerosis development. Interestingly, flow- and acetylcholine-induced endothelium dependent relaxation together with AKT phosphorylation was reduced by Scrib-knockout. RNASeq gene expression analysis from murine carotid endothelial cells showed that loss of Scrib is associated with reduced expression of Rac1 and Cdc42. Coimmunoprecipitation/mass spectrometry identified the Actin Related Protein 2/3 Complex Subunit 2 (ARPC2) as a novel Scrib interacting protein. SiRNA-knockdown of Scrib led to significantly reduced protein level of Rac1, RhoA, Cdc42 and Arp2/3. In line, F-Actin protein level was reduced by Scrib siRNA. Moreover, endothelial specific Scrib deficiency was accompanied by an increased basal vascular permeability and leukocyte extravasation after LPS treatment.

Conclusion: By stabilizing the cytoskeleton, the polarity protein Scrib has anti-atherosclerotic functions.