Elevated glucose impairs endothelial Kir2.1 via disruption of the glycocalyx in vitro

Hyperglycemia contributes to endothelial dysfunction and cardiovascular disease, although the mechanisms are not well understood. Kir2.1 is an inwardly-rectifying potassium channel that contributes to endothelial function and is dependent on the glycocalyx, an extracellular matrix previously shown to be sensitive to hyperglycemia. We hypothesized that hyperglycemia would result in Kir2.1 impairment through degradation of the glycocalyx. To examine the effects of hyperglycemia on Kir2.1 function, we exposed human adipose microvascular endothelial cells in culture to elevated glucose and examined Kir2.1 function with patch-clamp electrophysiology. We demonstrate that Kir2.1 function is impaired in hyperglycemia independent of osmotic stress or changes in channel expression. We subsequently show that hyperglycemia reduces the expression of syndecan-1 and heparan sulfate in the glycocalyx, and that restoring the glycocalyx recovers Kir2.1 function. Our work identifies a mechanism by which hyperglycemia contributes to endothelial dysfunction and suggests that protection or restoration of the glycocalyx is a potential therapeutic target for cardiovascular disease in hyperglycemia. This abstract was presented at the American Physiology Summit 2026 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.