ADAM17 cleaves the hyaluronan receptor CD44 from the endothelial surface, leading to impaired mechanotransduction of shear stress

Hyaluronan is a primary component of the endothelial glycocalyx and participates in mechanotransduction of shear stress which results in vasodilation. However, extracellular hyaluronan interacts indirectly with endothelial cells via its cell surface receptor CD44, which has recently been demonstrated to be mechanosensitive. CD44 is also a substrate for A Disintegrin And Metalloprotease-17 (ADAM17) , a sheddase that is elevated in the vasculature of individuals with type 2 diabetes (T2D). Of note, T2D is characterized by reduced flow-mediated dilation (FMD), indicative of impaired shear stress mechanotransduction. Thus, we hypothesized that increased endothelial ADAM17 activity causes cleavage of CD44 leading to impaired shear stress mechanotransduction. In support of this hypothesis, we demonstrate that ADAM17 overexpression in endothelial cells sheds CD44 from the cell surface and reduces the cellular responses to flow-induced shear stress (15 dynes/cm 2 ; 24hrs). We also demonstrate the specificity of ADAM17 for CD44 using a cell-free assay in which co-incubation of recombinant human active ADAM17 (rh-ADAM17; 5ug) with recombinant human CD44 (rh-CD44; 500ng), for 8 hours, results in the generation of cleaved fragments of CD44. This cleavage is prevented with co-incubation of TAPI-0 (50uM; 8hrs), an ADAM17 inhibitor. Furthermore, pharmacological activation of ADAM17, via a phorbol 12-myristate 13-acetate (PMA; 1uM, 2hrs/24hrs), cleaves CD44 and impairs mechanotransduction of shear stress in endothelial cells. Notably, these effects of PMA are prevented by TAPI-0 (50uM; 2hrs/24hrs). To further establish the consequences of ADAM17-mediated cleavage of CD44, and likely other mechanosensors, we corroborate that endothelial exposure to rh-ADAM17 (1ug/mL, 1hr) reduces FMD in isolated mouse mesenteric arteries, without effecting endothelium-independent vasodilation. Taken together, these data suggest that ADAM17-mediated cleavage of CD44 may represent a novel mechanism contributing to endothelial dysfunction in T2D. Funding: R01HL151384, R01HL153264, and AHA23PRE1020897. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.