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Am J Hypertens. 2007 Sep;20(9):1007-15.

Renal versus extrarenal activation of vitamin D in relation to atherosclerosis, arterial stiffening, and hypertension.

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Studies Coordinating Center, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium.


Low dietary intake of calcium stimulates the activation of vitamin D3 precursors to calcitriol in the kidney. This circulating hormone raises blood and urinary calcium by increasing both gastrointestinal absorption of calcium and bone resorption. Renal activation of vitamin D3 is under tight feedback control. Macrophages also activate vitamin D3, but, unlike renal tubular cells, they lack feedback suppression of the activating 1alpha-hydroxylase. In large-scale epidemiologic studies, blood pressure correlated positively with serum and urinary calcium but inversely with the dietary intake of calcium. Several population-based reports, including the Framingham Study, noticed an association of carotid plaques, arterial calcification, and increased arterial stiffness with lower bone-mineral content. Randomized clinical trials of calcium supplementation did not demonstrate a consistent effect on blood pressure. Macrophages in atherosclerotic lesions can locally activate vitamin D3 to calcitriol, which might contribute to arterial stiffening and hypertension. Calcitriol acts as a vasoactive and pro-oxidative substance on vascular smooth muscle cells. In animal models, active vitamin D3 promotes arterial stiffening and the pathogenesis of systolic hypertension and perpetuates a self-sustaining cycle leading to arterial damage and calcification. On the other hand, active vitamin D3 inhibits renin activity, thereby decreasing blood pressure in short-term, randomized trials. This article assesses the potential role of active vitamin D3 in causing cardiovascular complications via its effects on the structure of the arterial wall and the pathogenesis of hypertension. To set the stage and open up new perspectives, our article also summarizes the pathways leading to the renal and extrarenal activation and metabolism of vitamin D3 and will propose some directions for further research in this complex field.

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