Mechanisms underlying unidirectional laminar shear stress-mediated Nrf2 activation in endothelial cells: Amplification of low shear stress signaling by primary cilia

TY - JOUR

T1 - Mechanisms underlying unidirectional laminar shear stress-mediated Nrf2 activation in endothelial cells

T2 - Amplification of low shear stress signaling by primary cilia

AU - Ishii, Tetsuro

AU - Warabi, Eiji

AU - Mann, Giovanni E.

N1 - Funding Information: We gratefully acknowledge The Great Britain SASAKAWA Foundation for a Butterfield Award supporting our UK-Japan collaboration between the University of Tsukuba (T.I., E.W.) and King's College London (G.E.M.), Japanese Society for Promotion of Science, KAKENHI ( E.W. JP19790178 ), British Heart Foundation (G.E.M.) and Heart Research UK (G.E.M.) . Publisher Copyright: © 2021 Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/10

Y1 - 2021/10

N2 - Endothelial cells are sensitive to mechanical stress and respond differently to oscillatory flow versus unidirectional flow. This review highlights the mechanisms by which a wide range of unidirectional laminar shear stress induces activation of the redox sensitive antioxidant transcription factor nuclear factor-E2-related factor 2 (Nrf2) in cultured endothelial cells. We propose that fibroblast growth factor-2 (FGF-2), brain-derived neurotrophic factor (BDNF) and 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) are potential Nrf2 activators induced by laminar shear stress. Shear stress-dependent secretion of FGF-2 and its receptor-mediated signaling is tightly controlled, requiring neutrophil elastase released by shear stress, αvβ3 integrin and the cell surface glycocalyx. We speculate that primary cilia respond to low laminar shear stress (<10 dyn/cm2), resulting in secretion of insulin-like growth factor 1 (IGF-1), which facilitates αvβ3 integrin-dependent FGF-2 secretion. Shear stress induces generation of heparan-binding epidermal growth factor-like growth factor (HB-EGF), which contributes to FGF-2 secretion and gene expression. Furthermore, HB-EGF signaling modulates FGF-2-mediated NADPH oxidase 1 activation that favors casein kinase 2 (CK2)-mediated phosphorylation/activation of Nrf2 associated with caveolin 1 in caveolae. Higher shear stress (>15 dyn/cm2) induces vesicular exocytosis of BDNF from endothelial cells, and we propose that BDNF via the p75NTR receptor could induce CK2-mediated Nrf2 activation. Unidirectional laminar shear stress upregulates gene expression of FGF-2 and BDNF and generation of 15d-PGJ2, which cooperate in sustaining Nrf2 activation to protect endothelial cells against oxidative damage.

AB - Endothelial cells are sensitive to mechanical stress and respond differently to oscillatory flow versus unidirectional flow. This review highlights the mechanisms by which a wide range of unidirectional laminar shear stress induces activation of the redox sensitive antioxidant transcription factor nuclear factor-E2-related factor 2 (Nrf2) in cultured endothelial cells. We propose that fibroblast growth factor-2 (FGF-2), brain-derived neurotrophic factor (BDNF) and 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) are potential Nrf2 activators induced by laminar shear stress. Shear stress-dependent secretion of FGF-2 and its receptor-mediated signaling is tightly controlled, requiring neutrophil elastase released by shear stress, αvβ3 integrin and the cell surface glycocalyx. We speculate that primary cilia respond to low laminar shear stress (<10 dyn/cm2), resulting in secretion of insulin-like growth factor 1 (IGF-1), which facilitates αvβ3 integrin-dependent FGF-2 secretion. Shear stress induces generation of heparan-binding epidermal growth factor-like growth factor (HB-EGF), which contributes to FGF-2 secretion and gene expression. Furthermore, HB-EGF signaling modulates FGF-2-mediated NADPH oxidase 1 activation that favors casein kinase 2 (CK2)-mediated phosphorylation/activation of Nrf2 associated with caveolin 1 in caveolae. Higher shear stress (>15 dyn/cm2) induces vesicular exocytosis of BDNF from endothelial cells, and we propose that BDNF via the p75NTR receptor could induce CK2-mediated Nrf2 activation. Unidirectional laminar shear stress upregulates gene expression of FGF-2 and BDNF and generation of 15d-PGJ2, which cooperate in sustaining Nrf2 activation to protect endothelial cells against oxidative damage.

KW - Cilium

KW - Elastase

KW - Endothelial cells

KW - FGF-2

KW - Nrf2

KW - Shear stress

UR - http://www.scopus.com/inward/record.url?scp=85114365503&partnerID=8YFLogxK

U2 - 10.1016/j.redox.2021.102103

DO - 10.1016/j.redox.2021.102103

M3 - Review article

AN - SCOPUS:85114365503

SN - 2213-2317

VL - 46

JO - Redox Biology

JF - Redox Biology

M1 - 102103

ER -