Neuraminidase-3 Inhibition Improves Vascular Function in Diabetic Mice

In type 2 diabetes (T2D), endothelial dysfunction and arterial stiffening play a significant role in the development of cardiovascular disease. A central mediator of vascular dysfunction is degradation of the endothelial glycocalyx, a semipermeable mechanosensitive structure that separates the endothelium from the flow of blood and shear forces associated with it. Neuraminidase, a sialidase that cleaves sialic acid from the terminal branches of glycoproteins and glycolipids, is implicated in glycocalyx degradation. However, its role in mediating vascular dysfunction in the setting of T2D remains relatively unexplored. Herein, we tested the hypothesis that pharmacological inhibition of neuraminidase-3 (Neu3i) improves glycocalyx integrity, ameliorates endothelial dysfunction, and reduces arterial stiffness in diabetes. In support of this hypothesis, we report that, relative to vehicle-treated cells, endothelial cells exposed to Neu3i for 24hr have increased glycocalyx components including sialic acid and N-acetylglucosamine (GlcNAc), one of the amino sugars comprising the N-acetyllactosaminoglycans chains within the glycocalyx, as assessed with fluorescent lectin staining using MAA/Mal I+2 and WGA, respectively. We further show that treatment of diabetic ( i.e., db/db) mice with Neu3i for 28 days reduced aortic pulse wave velocity, with no change in blood pressure, when compared to vehicle-treated mice. Neu3i also reduced the stiffness of aortic explants, as assessed via atomic force microscopy. Excised arteries were also assessed for flow-mediated dilation and vascular stiffness using pressure myography. Diabetic mice treated with Neu3i had increased flow-mediated dilation and reduced incremental modulus of elasticity, indicative of improved endothelial function and reduced arterial stiffness. Collectively, these data support the hypothesis that Neu3 is a potential therapeutic target for the amelioration of vascular dysfunction in T2D. National Institutes of Health grant: R01HL153264 to LM-L and JP. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.