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

Although, vitamin K-2 displays vasoprotective effects, it is still not known whether K-2 treatment improves endothelial function. In ApoE/LDLR-/- mice at the stage prior to atherosclerosis development, four-week treatment with K-2-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 K-2-MK-7 (0.5; 5 mg/kg) resulted in a dose-dependent increase in plasma K-2-MK-7 and K-2-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 K-2-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 K-2-MK-7 also reduced media thickness in the brachiocephalic artery, but did not modify atherosclerotic plaque size. In conclusion, K-2-MK-7 improves NO-dependent endothelial function in ApoE/LDLR-/- mice. This study, identifies the endothelial profile of the pharmacological activity of vitamin K-2, which has not been previously described.