ADAM17 via F11R/JAM‐A Shedding Regulates Flow/Wall Shear Stress Mechanosensing in Endothelial Cells

Abstract

Reduced or increased blood flow induces arterial remodeling and is critically mediated by proper endothelial cell (EC) mechanosensing of flow/wall shear stress (WSS). A disintegrin and metalloproteinase ADAM17 sheds F11R/JAM‐A, an important tight junction‐located endothelial cell adhesion molecule. Consequently, both ADAM17 and F11/JAM‐A have been previously implicated in arterial remodeling. Therefore, we tested the hypothesis that ADAM17 regulates EC mechanosensing via F11R/JAM‐A shedding. We found that compared to static/zero flow (WSS=0 dyne/cm2), cultured ECs exposed to increasing levels of flow (4 to 8 dyne/cm2) progressively changed their orientation in the direction of the flow. Ultimately, the ECs reaching maximum alignment at the physiologic, 8 dyne/cm2 WSS levels during the first 72 hours of culture. After siRNA‐mediated silencing of F11R/JAM‐A, ECs failed to efficiently orient with the direction of flow, whereas overexpression of F11R/JAM‐A facilitated enhanced EC alignment. In the presence of recombinant ADAM17 or through stimulation of ADAM17 by phorbol myristate acetate, ECs failed to orient to flow. Whereas gene transfer of the ADAM17 cleavage resistant, mutated JAM‐A(V227Y) resulted in a normal flow orientation. Our results uncover a novel regulatory role for ADAM17 in modulating F11R/JAM‐A‐dependent flow/WSS mechanosensing in ECs.Support or Funding InformationNIH‐NIA R01AG054651This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.