Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells

In endothelial cells, fluid flow is sensed by mechanoresponsive membrane-localized PIEZO1 channels, which open and cause an influx of cations including calcium ions (Ca2+) (inferred from the mouse homolog in Conte et al. 2010). Intracellular Ca2+ activates the protease complex Calpain2, which cleaves Vinculin (VCL), a component of the peripheral cytoskeleton located between integrins and actin fibers (Miyazaki et al. 2007, 2010). Turbulent flow across endothelial cells also causes release of ATP by an uncharacterized mechanism.

Through an uncharacterized PIEZO1-dependent mechanism, the phosphatase PTPN1 (PTP1B) is activated to dephosphorylate Annexin-2 (ANXA2), which relocalizes with integrins (ITGA5:ITGB1) to lipid rafts in the cell membrane. The integrins recruit the phosphodiesterase PDE4D5 and the phosphatase PP2A, which activates PDE4D5 by dephosphorylating serine-715 and activates YAP1 by dephosphorylating serine-127 (inferred from mouse homologs in Yun et al. 2016). Activated PDE4D5 hydrolyzes cAMP and thereby increases inflammation. YAP1 is phosphorylated by ABL1 on tyrosine-407 and transits to the nucleus to activate pro-inflammatory genes.

The kinase PTK2 (focal adhesion kinase, FAK) is phosphorylated, likely through autophosphorylation, and then activates pro-inflammatory NF-κB signaling through phosphorylation of CHUK (IKKA) and RELA. IKBKE is phosphorylated by an uncharacterized mechanism and phosphorylates STAT1, which dimerizes and transits to the nucleus to activate pro-inflammatory genes such as NLRP3.