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ADAM17 impairs arterial fluid shear stress mechanosensing in aged mice
Author(s) -
Tian Yanna,
Davila Alec,
Clermont Andrew,
Balogh Marta Bagine,
Czikora Istvan,
Bagi Zsolt
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06412
Subject(s) - mechanotransduction , downregulation and upregulation , endothelium , shear stress , microbiology and biotechnology , gene silencing , chemistry , medicine , endocrinology , biology , materials science , biochemistry , composite material , gene
Junctional Adhesion Molecule A (F11R/JAM‐A), which can be shed by a disintegrin and metalloproteinase ADAM17, has been implicated in arterial mechanotransduction. We hypothesized that in aging ADAM17 activation impairs wall shear stress mechanosensing via an augmented F11R/JAM‐A shedding. Using videomicroscopy we found a reduced wall shear stress (WSS)‐induced dilation in isolated, pressurized gracilis muscle arteries in 30‐month old (aged) mice, when compared to 12‐week old (young) controls. Dilations to acetylcholine or to the NO donor, sodium nitroprusside were not different between the two groups. We found that ADAM17 expression was significantly upregulated in arteries in aged mice, which was associated with reduced endothelial cell junction localized F11R/JAM‐A. After activation of ADAM17 with phorbol‐myristat‐acetate, WSS‐induced dilation was reduced in young mice, whereas ADAM17 inhibition by TIMP3 augmented WSS‐induced dilation in aged mice. Cultured HUVECs exposed to increasing levels of WSS (0 to 16 dyne/cm2) progressively changed their orientation to the direction of flow. In the presence of recombinant ADAM17 or after siRNA‐mediated silencing of F11R/JAM‐A, endothelial cells failed to efficiently orient with the direction of flow. Gene transfer of ADAM17 cleavage resistant, mutated JAM‐A(V227Y) resulted in a normal endothelial orientation to flow even after ADAM17 activation. Collectively, our results uncover a novel role for ADAM17 in impairing F11R/JAM‐A‐dependent WSS mechanosensing in arteries of aged mice. Support or Funding Information National Institute of Aging (R01AG054651)