TY - JOUR
T1 - Piezo1 and Gq/G11 promote endothelial inflammation depending on flow pattern and integrin activation
AU - Albarrán-Juárez, Julián
AU - Iring, Andras
AU - Wang, ShengPeng
AU - Joseph, Sayali
AU - Grimm, Myriam
AU - Strilic, Boris
AU - Wettschureck, Nina
AU - Althoff, Till F
AU - Offermanns, Stefan
N1 - © 2018 Albarrán-Juárez et al.
PY - 2018/10/1
Y1 - 2018/10/1
N2 - The vascular endothelium is constantly exposed to mechanical forces, including fluid shear stress exerted by the flowing blood. Endothelial cells can sense different flow patterns and convert the mechanical signal of laminar flow into atheroprotective signals, including eNOS activation, whereas disturbed flow in atheroprone areas induces inflammatory signaling, including NF-κB activation. How endothelial cells distinguish different flow patterns is poorly understood. Here we show that both laminar and disturbed flow activate the same initial pathway involving the mechanosensitive cation channel Piezo1, the purinergic P2Y2 receptor, and Gq/G11-mediated signaling. However, only disturbed flow leads to Piezo1- and Gq/G11-mediated integrin activation resulting in focal adhesion kinase-dependent NF-κB activation. Mice with induced endothelium-specific deficiency of Piezo1 or Gαq/Gα11 show reduced integrin activation, inflammatory signaling, and progression of atherosclerosis in atheroprone areas. Our data identify critical steps in endothelial mechanotransduction, which distinguish flow pattern-dependent activation of atheroprotective and atherogenic endothelial signaling and suggest novel therapeutic strategies to treat inflammatory vascular disorders such as atherosclerosis.
AB - The vascular endothelium is constantly exposed to mechanical forces, including fluid shear stress exerted by the flowing blood. Endothelial cells can sense different flow patterns and convert the mechanical signal of laminar flow into atheroprotective signals, including eNOS activation, whereas disturbed flow in atheroprone areas induces inflammatory signaling, including NF-κB activation. How endothelial cells distinguish different flow patterns is poorly understood. Here we show that both laminar and disturbed flow activate the same initial pathway involving the mechanosensitive cation channel Piezo1, the purinergic P2Y2 receptor, and Gq/G11-mediated signaling. However, only disturbed flow leads to Piezo1- and Gq/G11-mediated integrin activation resulting in focal adhesion kinase-dependent NF-κB activation. Mice with induced endothelium-specific deficiency of Piezo1 or Gαq/Gα11 show reduced integrin activation, inflammatory signaling, and progression of atherosclerosis in atheroprone areas. Our data identify critical steps in endothelial mechanotransduction, which distinguish flow pattern-dependent activation of atheroprotective and atherogenic endothelial signaling and suggest novel therapeutic strategies to treat inflammatory vascular disorders such as atherosclerosis.
UR - http://www.scopus.com/inward/record.url?scp=85054095377&partnerID=8YFLogxK
U2 - 10.1084/jem.20180483
DO - 10.1084/jem.20180483
M3 - Journal article
C2 - 30194266
SN - 0022-1007
VL - 215
SP - 2655
EP - 2672
JO - The Journal of Experimental Medicine
JF - The Journal of Experimental Medicine
IS - 10
ER -