Elevated levels of
cholesterol in the blood can induce endothelial dysfunction, a condition characterized by impaired
nitric oxide production and decreased vasodilatory capacity. Endothelial dysfunction can promote
vascular disease, such as
atherosclerosis, where macrophages accumulate in the vascular intima and fatty plaques form that impair normal blood flow in conduit arteries. Current pharmacological strategies to treat
atherosclerosis mostly focus on
lipid lowering to prevent high levels of plasma
cholesterol that induce endothelial dysfunction and
atherosclerosis. While this approach is effective for most patients with
atherosclerosis, for some,
lipid lowering is not enough to reduce their cardiovascular risk factors associated with
atherosclerosis (e.g.,
hypertension, cardiac dysfunction,
stroke, etc.). For such patients, additional strategies targeted at reducing endothelial dysfunction may be beneficial. One novel strategy to restore endothelial function and mitigate
atherosclerosis risk is to enhance the activity of Ca2+-activated K+ (KCa) channels in the endothelium with positive gating modulator drugs. Here, we review the mechanism of action of these small molecules and discuss their ability to improve endothelial function. We then explore how this strategy could mitigate endothelial dysfunction in the context of
atherosclerosis by examining how KCa modulators can improve cardiovascular function in other settings, such as aging and
type 2 diabetes. Finally, we consider questions that will need to be addressed to determine whether KCa channel activation could be used as a long-term add-on to
lipid lowering to augment
atherosclerosis treatment, particularly in patients where
lipid-lowering is not adequate to improve their cardiovascular health.