Vitamin D metabolites influence the expression of various genes involved in
calcium homeostasis, cell differentiation, and regulation of the immune system. Expression of these genes is mediated by the activation of the nuclear
vitamin D receptor (VDR). Previous studies have shown that a hormonally active form of
vitamin D, 1alpha,25-dihydroxyvitamin D3, exerts
anticoagulant effects in cultured monocytic cells. To clarify whether activation of VDR plays any antithrombotic actions in vivo,
hemostatic/thrombogenic systems were examined in normocalcemic VDR knock-out (KO) mice on a high
calcium diet and compared with wild type and hypocalcemic VDRKO mice that were fed a regular diet. Platelet aggregation was enhanced significantly in normocalcemic VDRKO mice compared with wild type and hypocalcemic VDRKO mice. Aortic endothelial
nitric-oxide (
NO) synthase expression and urinary NOx excretions were reduced in hypocalcemic VDRKO mice, but not in normocalcemic VDRKO mice. Northern blot and RT-PCR analyses revealed that the gene expression of
antithrombin in the liver as well as that of
thrombomodulin in the aorta, liver and kidney was down-regulated in hypo- and normocalcemic VDRKO mice. Whereas
tissue factor mRNA expression in the liver and kidney was up-regulated in VDRKO mice regardless of plasma
calcium level. Furthermore, VDRKO mice manifested an exacerbated multi-organ
thrombus formation after exogenous
lipopolysaccharide injection regardless of the calcemic conditions. These results demonstrate that activation of nuclear VDR elicits antithrombotic effects in vivo, and suggest that the VDR system may play a physiological role in the maintenance of antithrombotic homeostasis.