Vitamin K₂-MK-7 improves nitric oxide-dependent endothelial function in ApoE/LDLR^-/- mice

Although, vitamin K₂ displays vasoprotective effects, it is still not known whether K₂ treatment improves endothelial function. In ApoE/LDLR^-/- mice at the stage prior to atherosclerosis development, four-week treatment with K₂-MK-7, given at a low dose (0.05 mg/kg), improved acetylcholine- and flow-induced, endothelium-dependent vasodilation in aorta or in femoral artery, as assessed by MRI in vivo. This effect was associated with an increased NO production, as evidenced by EPR measurements in ex vivo aorta. Treatment with higher doses of K₂-MK-7 (0.5; 5 mg/kg) resulted in a dose-dependent increase in plasma K₂-MK-7 and K₂-MK-4 concentration, without further improvement in endothelial function. In ApoE/LDLR^-/- mice with developed atherosclerotic plaques, treatment with a low (0.03 mg/kg) or high (10 mg/kg) dose of K₂-MK-7 resulted in a similar degree of endothelium-dependent vasodilation improvement and increase in plasma nitrate concentration, what was not associated with changes in thrombin generation as measured by CAT. Both doses of K₂-MK-7 also reduced media thickness in the brachiocephalic artery, but did not modify atherosclerotic plaque size. In conclusion, K₂-MK-7 improves NO-dependent endothelial function in ApoE/LDLR^-/- mice. This study, identifies the endothelial profile of the pharmacological activity of vitamin K₂, which has not been previously described.