Response of endothelial cells to shear stress

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R-HSA-9860931
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Homo sapiens
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Response of endothelial cells to shear stress
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Vascular endothelial cells experience shear stress produced by the flow of blood across their apical surfaces. Different types of shear stress have been identified based on the type of flow and the response of the endothelial cells: low volume laminar flow, high volume laminar flow, and turbulent (disturbed, oscillatory) flow (reviewed in Davis et al. 2023, Rahaman et al. 2023, Lim and Harraz 2024). A key difference between the responses of cells to the different types of flow is the absence or presence of inflammation (reviewed in Davis et al. 2023, Wang et al. 2023). Whereas high volume laminar flow produces vasodilation and cytoskeletally based streamlining without inflammation, both turbulent flow and low volume laminar flow activate the inflammatory NF-kB and YAP1 pathways.
All types of flow activate the mechanosensitive cation channel PIEZO1, resulting in an influx of calcium ions (Li et al. 2014, reviewed in Fang et al. 2021, Davis et al. 2023, Xiao et al. 2023). Calcium binds and activates the Calpain2 protease complex which acts on cytoskeletal proteins near the inner face of the plasma membrane, causing alterations to the morphology of the cell (Miyazaki et al. 2020). In the case of high volume laminar flow, cells become ellipsoid with their long axes parallel with the flow of blood.
In addition to optimization of cell shape, high volume laminar flow activates AKT1 via ligand-independent KDR (VEGFR2) signaling, ATP-dependent P2RY2 signaling, and Adrenomedullin (ADM) signaling (Tzima et al. 2005, Wang et al. 2015, Iring et al. 2019, reviewed in Xiao et al. 2023). AKT1 and other kinases then phosphorylate NOS3 (eNOS), resulting in increased production of nitric oxide and vasodilation (Dimmeler et al. 1999, Jin et al. 2021). High volume laminar flow is thus atheroprotective.
In contrast, turbulent flow activates signaling by integrin alpha5:beta1 (ITGA5:ITGB1) that causes the phosphodiesterase PDE4D5 to hydrolyze cAMP (Yun et al. 2016) and the phosphatase PP2A to dephosphorylate and hence activate the transcription factor YAP1 (Jiang et al. 2021). YAP1 positively regulates expression of pro-inflammatory genes. Also during turbulent flow, Focal adhesion kinase (PTK2, FAK) is activated by phosphorylation and causes phosphorylation and nuclear translocation of the pro-inflammatory transcription factor complex NF-kB (Albarrán-Juárez et al. 2018).
Literature References
PubMed ID Title Journal Year
25119035 Piezo1 integration of vascular architecture with physiological force

Li, J, Hou, B, Tumova, S, Muraki, K, Bruns, A, Ludlow, MJ, Sedo, A, Hyman, AJ, McKeown, L, Young, RS, Yuldasheva, NY, Majeed, Y, Wilson, LA, Rode, B, Bailey, MA, Kim, HR, Fu, Z, Carter, DA, Bilton, J, Imrie, H, Ajuh, P, Dear, TN, Cubbon, RM, Kearney, MT, Prasad, RK, Evans, PC, Ainscough, JF, Beech, DJ

Nature 2014
37595342 Mechanosensitive GPCRs and ion channels in shear stress sensing

Xiao, R, Liu, J, Xu, XZS

Curr Opin Cell Biol 2023
34055807 Protein Phosphatase 2A Mediates YAP Activation in Endothelial Cells Upon VEGF Stimulation and Matrix Stiffness

Jiang, X, Hu, J, Wu, Z, Cafarello, ST, Di Matteo, M, Shen, Y, Dong, X, Adler, H, Mazzone, M, Ruiz de Almodóvar, C, Wang, X

Front Cell Dev Biol 2021
16163360 A mechanosensory complex that mediates the endothelial cell response to fluid shear stress

Tzima, E, Irani-Tehrani, M, Kiosses, WB, Dejana, E, Schultz, DA, Engelhardt, B, Cao, G, DeLisser, H, Schwartz, MA

Nature 2005
37615786 Mechanosensing and Mechanosignal Transduction in Atherosclerosis

Rahaman, SG, Mahanty, M, Mukherjee, P, Dutta, B, Rahaman, SO

Curr Atheroscler Rep 2023
33422128 Structure, kinetic properties and biological function of mechanosensitive Piezo channels

Fang, XZ, Zhou, T, Xu, JQ, Wang, YX, Sun, MM, He, YJ, Pan, SW, Xiong, W, Peng, ZK, Gao, XH, Shang, Y

Cell Biosci 2021
34499618 Protein kinase N2 mediates flow-induced endothelial NOS activation and vascular tone regulation

Jin, YJ, Chennupati, R, Li, R, Liang, G, Wang, S, Iring, A, Graumann, J, Wettschureck, N, Offermanns, S

J Clin Invest 2021
27595237 Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling

Yun, S, Budatha, M, Dahlman, JE, Coon, BG, Cameron, RT, Langer, R, Anderson, DG, Baillie, G, Schwartz, MA

Nat Cell Biol 2016
30194266 Piezo1 and Gq/G11 promote endothelial inflammation depending on flow pattern and integrin activation

Albarrán-Juárez, J, Iring, A, Wang, S, Joseph, S, Grimm, M, Strilic, B, Wettschureck, N, Althoff, TF, Offermanns, S

J Exp Med 2018
17596297 Requirement of Ca2+ influx- and phosphatidylinositol 3-kinase-mediated m-calpain activity for shear stress-induced endothelial cell polarity

Miyazaki, T, Honda, K, Ohata, H

Am J Physiol Cell Physiol 2007
37225873 Flow-induced reprogramming of endothelial cells in atherosclerosis

Tamargo, IA, Baek, KI, Kim, Y, Park, C, Jo, H

Nat Rev Cardiol 2023
37163659 Endothelial mechanobiology in atherosclerosis

Wang, X, Shen, Y, Shang, M, Liu, X, Munn, LL

Cardiovasc Res 2023
26168216 P2Y₂ and Gq/G₁₁ control blood pressure by mediating endothelial mechanotransduction

Wang, S, Iring, A, Strilic, B, Albarrán Juárez, J, Kaur, H, Troidl, K, Tonack, S, Burbiel, JC, Müller, CE, Fleming, I, Lundberg, JO, Wettschureck, N, Offermanns, S

J Clin Invest 2015
36603156 Vascular mechanotransduction

Davis, MJ, Earley, S, Li, YS, Chien, S

Physiol Rev 2023
31205027 Shear stress-induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure

Iring, A, Jin, YJ, Albarrán-Juárez, J, Siragusa, M, Wang, S, Dancs, PT, Nakayama, A, Tonack, S, Chen, M, Künne, C, Sokol, AM, Günther, S, Martínez, A, Fleming, I, Wettschureck, N, Graumann, J, Weinstein, LS, Offermanns, S

J Clin Invest 2019
10376603 Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation

Dimmeler, S, Fleming, I, Fisslthaler, B, Hermann, C, Busse, R, Zeiher, AM

Nature 1999
33543538 Early events in endothelial flow sensing

Tanaka, K, Joshi, D, Timalsina, S, Schwartz, MA

Cytoskeleton (Hoboken) 2021
37863105 Mechanosensing by Vascular Endothelium

Lim, XR, Harraz, OF

Annu Rev Physiol 2024
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cellular response to endogenous stimulus (0071495)
Orthologous Events
Response of endothelial cells to shear stress (Bos taurus)
Response of endothelial cells to shear stress (Caenorhabditis elegans)
Response of endothelial cells to shear stress (Canis familiaris)
Response of endothelial cells to shear stress (Danio rerio)
Response of endothelial cells to shear stress (Dictyostelium discoideum)
Response of endothelial cells to shear stress (Drosophila melanogaster)
Response of endothelial cells to shear stress (Gallus gallus)
Response of endothelial cells to shear stress (Mus musculus)
Response of endothelial cells to shear stress (Plasmodium falciparum)
Response of endothelial cells to shear stress (Rattus norvegicus)
Response of endothelial cells to shear stress (Saccharomyces cerevisiae)
Response of endothelial cells to shear stress (Schizosaccharomyces pombe)
Response of endothelial cells to shear stress (Sus scrofa)
Response of endothelial cells to shear stress (Xenopus tropicalis)
Authored
May, B  (2024-02-10)
Reviewed
Xiao, R  (2024-07-16)
Created
May, B  (2024-02-12)
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