タイトル； Dynamical Nuclear Factor for Activated T cells (NFAT) activation with shear stress in endothelium.
（熊本大学 生命資源研究・支援センター 分子血管制御分野）
Cancer malignancy is tightly correlated to the tumor vessel microenvironment involving hypoxia and adhesiveness due to the disorganized and destabilized blood flow in tumor vascular. Recently, we have identified that aerobic exercise promote the tumor vessel normalization following to the enhanced chemotherapy effect in mice. Combination of sunitinib and exercise suppress tumor growth compared with only the drug treatment. One of the main reason is considered as the stability of blood flow resulting to the laminar shear stress exerting on endothelial cell (EC)s by the exercise. ECs is known to stabilize with fluid share stress, which is initiated by the Calcium signaling. We have previously reported that Ca+-calcineurin-Nuclear Factor for Activated T cells (NFAT) signaling axis is indispensable for EC activation and the keeping the homeostasis. However, the relationship between shear stress and the exact NFAT localization is not well experienced. Thus in this study, we aimed to examine the effect of shear stress on NFAT signal in endothelium.
To that end, we have constructed dynamical shear stress experimental system using primary cultured ECs. Adenovirally-transfected GFP-tagged NFAT1 localization in ECs was observed under time-lapse fluorescence microscopy with shear stress. Exposure to laminar shear stress initiated the NFAT1 nuclear localization from cytoplasm within 30 min. Unexpectedly, not all expressed NFAT1 (~50%) translocated into the nucleus. Moreover, NFAT1 translocation with cytoplasm to nucleus and vice versa was repeated in subset (~10%) of ECs under the sustained share stress for 12 h. These results suggest that nuclear-translocation of NFAT1 in ECs via fluid shear stress might lead to the vessel normalization after the exercise training.
We believe the new theory as NFAT signal mediated vessel normalization is important and should be further evaluated by advanced single cell-seq analysis and lineage tracings with share-driven NFAT responsive heterogeneity and the resulting downstream gene set signature in ECs.