Endothelial CD44 cleavage by ADAM17 impairs shear stress mechanotransduction

In individuals with type 2 diabetes (T2D), blood flow-mediated increases in endothelial shear stress fail to elicit a robust vasodilatory response. This defective flow-mediated dilation (FMD) is associated with loss of the endothelial glycocalyx, a mechanosensitive extracellular structure that lines the luminal side of blood vessels. Hyaluronan (HA), a polysaccharide constituent of the glycocalyx, is anchored to the plasma membrane by its primary cell-surface receptor, CD44, which is implicated in mechanotransduction of shear stress. Critically, CD44 is also a substrate of a disintegrin and metalloproteinase 17 (ADAM17), a sheddase that is elevated in T2D. However, it is currently unknown whether elevated ADAM17 activity enhances CD44 cleavage from the endothelium and whether this contributes to impaired mechanotransduction and reduced FMD in T2D. Herein, we report elevated plasma HA and ADAM17 activity in a cohort of women and men with T2D and impaired FMD. Moreover, reduced endothelial CD44 is coupled with impaired FMD in arteries isolated from diabetic (db/db) mice. We also provide support for CD44 as a mechanotransducer of HA-associated shear stress mechanosensation and ADAM17-mediated cleavage of CD44 attenuating shear stress mechanotransduction. Finally, using an in-vitro assay and surface plasmon resonance, we show that active recombinant human ADAM17 (ADAM17-r) cleaves recombinant human CD44 and that intraluminal incubation of isolated arteries with ADAM17-r reduces FMD. Collectively, this work supports the role of ADAM17-mediated cleavage of CD44 in impairing endothelial shear stress mechanotransduction.NEW & NOTEWORTHY Impaired flow-mediated dilation (FMD) is an indicator of endothelial dysfunction in type 2 diabetes (T2D). However, the exact cellular and molecular mechanisms contributing to impaired mechanotransduction of shear stress in T2D are incompletely understood. This work supports the novel concept that increased endothelial activity of a disintegrin and metalloproteinase 17 (ADAM17) causes cleavage of cell-surface CD44, leading to loss of hyaluronan (HA)-associated shear stress mechanotransduction.