Positive Effects of Vitamin K on Arterial Calcification, Cerebral Blood Flow, and Cognition in a Murine Model of Arterial Calcification

Abstract

Abstract Objectives Investigate whether VK can attenuate cognitive impairment associated with arterial stiffness, and assess its effect on arterial calcification and resting cerebral blood flow (rCBF). Methods Ten to 12 wk-old male C57BL/6 mice (n = 12/diet gp) were fed diets containing either 0.1, 1 or 10 mg/kg of K1, or 10, 50 or 100 mg/kg of MK-4 for 4 wks. Arterial calcification was induced by the local application of CaCl2 (3 M), sham animals were treated with NaCl (0.9%). Learning abilities over 5 days and memory retention were assessed using the Morris water maze, 3 wks after surgery. rCBF was determined by quantitative autoradiography (iodoantipirine 4-N-Methyl-14C as a diffusible tracer) in key brain regions. Carotid Ca2+ content was determined by a colorimetric method, brain K1 and MK4 were assessed by HPLC and brain expression of carboxylated Gas6 and PS by Western blot. Results Learning performances did not differ between CaCl2 and NaCl-treated mice at any of the K1 and MK4 doses although when groups were combined, MK-4100 mg/kg fed mice had better cognitive abilities compared to K1 0.1 mg/kg group (P < 0.05). In contrast, memory retention was altered by arterial calcification in the lower VK diet groups (K1 0.1 and MK-4 10 mg/kg) (P < 0.05). MK-4 was the main form of VK in brain (at least 98.5%) irrespective of diet. Expression of carboxylated Gas6 and PS increased with dietary MK-4 but not dietary K1. Carotid Ca2 + content decreased as a function of dietary K1 and MK-4 in a dose dependent manner (P < 0.05). Ca2 + treatment significantly decreased rCBF in several brain regions of mice fed the K1 0.1 mg/kg diet including visual and somatosensory cortex, thalamus, hippocampus, dentate gyrus and corpus callosum (P < 0.05); negative effects were also observed in K1 1 mg/kg fed mice. Conclusions These results suggest that VK can oppose the detrimental effects of vascular calcification on cognition in part by limiting vascular calcification, restoring rCBF, and increasing Gas6 and PS carboxylation in brain. Funding Sources CIHR.