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

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

Stable Identifier

R-HSA-9860927

DOI

10.3180/R-HSA-9860927.1

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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

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Both turbulent (disturbed) flow and low laminar flow across epithelial cells initiate an inflammatory response that causes atherosclerosis (reviewed in Rahaman et al. 2023, Tamargo et al. 2023, Wang et al. 2023). In vivo, this process makes curved and branched regions of arteries especially prone to atherosclerosis.
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 (Albarrán-Juárez et al. 2018).
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 (Zhang et al. 2020). 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 (Li et al. 2019).
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) (Dwyer et al. 2015) and RELA (Albarrán-Juárez et al. 2018). 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 (Lv et al. 2024).

Literature References

PubMed ID	Title	Journal	Year
30194266	Piezo1 and G_q/G₁₁ promote endothelial inflammation depending on flow pattern and integrin activation Offermanns, S, Althoff, TF, Wettschureck, N, Strilic, B, Albarrán-Juárez, J, Grimm, M, Joseph, S, Iring, A, Wang, S	J Exp Med	2018
27595237	Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling Yun, S, Anderson, DG, Dahlman, JE, Cameron, RT, Coon, BG, Langer, R, Baillie, G, Schwartz, MA, Budatha, M	Nat Cell Biol	2016
20813920	Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels Earley, TJ, Dubin, AE, Coste, B, Petrus, MJ, Patapoutian, A, Ranade, S, Schmidt, M, Mathur, J	Science	2010
38315275	Low-Shear Stress Promotes Atherosclerosis via Inducing Endothelial Cell Pyroptosis Mediated by IKKε/STAT1/NLRP3 Pathway Gu, Y, Lv, Y, Wang, D, Yang, H, Zhu, L, Kong, C, Jiang, Z, Chen, S, Qian, Z, Zhou, W, Jin, G	Inflammation	2024
37615786	Mechanosensing and Mechanosignal Transduction in Atherosclerosis Rahaman, SG, Dutta, B, Rahaman, SO, Mukherjee, P, Mahanty, M	Curr Atheroscler Rep	2023
32673515	Coupling of Integrin α5 to Annexin A2 by Flow Drives Endothelial Activation Li, B, Yan, M, Ai, D, Zhu, Y, Shi, L, Wang, C, Zhou, T, Lv, H, Xiang, S, Zhang, C, Chen, Z	Circ Res	2020
25798060	Identification of novel focal adhesion kinase substrates: role for FAK in NFκB signaling Gao, L, Gelman, IH, Dwyer, SF	Int J Biol Sci	2015
30629551	c-Abl regulates YAPY357 phosphorylation to activate endothelial atherogenic responses to disturbed flow Lv, X, Li, B, Ai, D, He, J, Zhu, Y, Liu, Y, Lv, H, Zhang, C	J Clin Invest	2019
37225873	Flow-induced reprogramming of endothelial cells in atherosclerosis Jo, H, Tamargo, IA, Park, C, Kim, Y, Baek, KI	Nat Rev Cardiol	2023
37163659	Endothelial mechanobiology in atherosclerosis Munn, LL, Shang, M, Wang, X, Shen, Y, Liu, X	Cardiovasc Res	2023
17596297	Requirement of Ca2+ influx- and phosphatidylinositol 3-kinase-mediated m-calpain activity for shear stress-induced endothelial cell polarity Ohata, H, Honda, K, Miyazaki, T	Am J Physiol Cell Physiol	2007
19752040	m-Calpain antagonizes RhoA overactivation and endothelial barrier dysfunction under disturbed shear conditions Ohata, H, Honda, K, Miyazaki, T	Cardiovasc Res	2010