Abstract
We sought to determine if lumen narrowing inward arterial remodeling is mediated by impaired endothelial mechanosensing of wall shear stress (WSS) in aging. Previously we have shown that aging upregulates A disintegrin and metalloproteinase ADAM17 in the vascular endothelium. ADAM17 sheds F11R/JAM‐A, an important tight junction‐located endothelial cell (EC) adhesion molecule. Here we tested if ADAM17 activation promotes aging‐related inward artery remodeling by shedding F11R/JAM‐A. Human arteries were obtained from fat biopsies in 40 consecutive patients. We found that vascular ADAM17 enzyme activity increases significantly with age, whereas F11R/JAM‐A expression was reduced in older (>64 yo) subjects, which was associated with reduced luminal diameter and increased wall thickness. Cultured human ECs exposed to increasing levels of flow (0 to 8 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, ECs failed to efficiently orient with the direction of flow. Gene transfer of ADAM17 cleavage resistant, mutated JAM‐A(V227Y) resulted in a normal EC orientation to flow. Collectively, our results uncover a novel regulatory role for vascular ADAM17 in reducing F11R/JAM‐A‐dependent WSS mechanosensing, which can lead to lumen narrowing inward arterial remodeling in aging.Support or Funding InformationNIH R01AG054651This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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