Thioridazine protects against disturbed flow-induced atherosclerosis by inhibiting RhoA/YAP-mediated endothelial inflammation

Jiang, Minchun; Ding, Huanyu; Huang, Yühong; Cheng, Chak Kwong; Lau, Chi Wai; Xia, Yin; Yao, Xiaoqiang; Wang, Li; Huang, Yü

doi:10.1038/s41401-023-01102-w

Cited by 8 publications

(1 citation statement)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For instance, research involving lipopolysaccharide (LPS)-based stimulation has shown that RhoA signaling operates upstream of NF-kB phosphorylation 75 . Furthermore, the Yap/Taz pathway, activated under low, oscillatory FSS 76 via α5β1 integrin and tyrosine protein kinase ABL1 activation 77 , is known to be regulated by RhoA signaling 78 , potentially through cytoskeletal tension-mediated nuclear pore complex opening, facilitating Yap nuclear translocation 79 . Consequently, the rise in traction induced by low FSS may be attributed to molecular sensors activating pathways like Notch1 or TNF-α, which, in turn, activate RhoA, ultimately influencing NF-kB or Yap signaling.…”

Section: Discussionmentioning

confidence: 99%

Low Shear in Short-Term Impacts Endothelial Cell Traction and Alignment in Long-Term

Chandurkar,

Mittal,

Royer-Weeden

et al. 2023

Preprint

View full text Add to dashboard Cite

Fluid shear stress (FSS) plays a vital role in endothelial cell (EC) function, impacting vascular health. Low FSS triggers an inflammatory, atheroprone EC phenotype, while high FSS promotes atheroprotective responses. Yet, the adaptation of ECs to high FSS following low FSS exposure remains poorly understood. We explored this process's influence on vascular tension by measuring traction in human umbilical vein endothelial cells (HUVECs) subjected to high FSS (1 Pa) after prior low FSS exposure (0.1 Pa). We discovered that HUVECs experienced an immediate traction increase after low FSS exposure. Intriguingly, the transition to high FSS did not further enhance traction; instead, a secondary traction rise emerged after 2 hours under high FSS, lasting over 10 hours before gradually diminishing. Conversely, HUVECs exposed directly to high FSS displayed an initial traction surge within 30 minutes, followed by a rapid decline within an hour, falling below initial levels. Notably, even after more than 20 hours of exposure to high FSS, HUVECs previously preconditioned with 1-hour of low FSS exhibited traction alignment perpendicular to the flow direction, whereas those directly exposed to high FSS displayed alignment with the flow direction, both in the short and long terms. Collectively, these results suggest that even brief exposure to low FSS can initiate a low-shear-sensitive response in ECs, which requires a much-extended period to recover towards tension relaxation under laminar high shear flow conditions.

show abstract