Vitamin D has been shown to play critical activities in several physiological pathways not involving the calcium/phosphorus homeostasis. The ubiquitous distribution of the vitamin D receptor that is expressed in a variety of human and mouse tissues has strongly supported research on these “nonclassical” activities of vitamin D. On the other hand, the recent discovery of the expression also for vitamin D-related enzymes (such as 25-hydroxyvitamin D-1α-hydroxylase and the catabolic enzyme 1,25-dihydroxyvitamin D-24-hydroxylase) in several tissues suggested that the vitamin D system is more complex than previously shown and it may act within tissues through autocrine and paracrine pathways. This updated model of vitamin D axis within peripheral tissues has been particularly investigated in atherosclerotic pathophysiology. This review aims at updating the role of the local vitamin D within atherosclerotic plaques, providing an overview of both intracellular mechanisms and cell-to-cell interactions. In addition, clinical findings about the potential causal relationship between vitamin D deficiency and atherogenesis will be analysed and discussed. 1. Introduction Since its discovery in the early 1900s, the role of vitamin D has been limited to calcium/phosphate homeostasis through a predominant action on the kidney, intestine, and bone [1]. On the contrary, evidence in recent decades has suggested that vitamin D might play a critical role in many other metabolic pathways, referred as “nonclassical effects” [2]. Thus, vitamin D is currently under investigation in cancer [3], autoimmune disorders [4], infections [5], and neurological [6] and cardiovascular (CV) diseases. A large amount of observational studies has shown that vitamin D deficiency is associated with a wide range of CV risk factors [7], as well as poor CV outcome [8], but more recent findings from interventional trial have weakened this initial enthusiasm with a more sceptical view. Ultimately, Brandenburg correctly stated: “there should be less persuasive observational associative data, but more convincing interventional results in the field of vitamin D” [9]. Certainly, a critical analysis of literature has revealed several limitations especially in study design, but also the newer insights about the local activity of vitamin D within peripheral tissues might explain the conflicting results between interventional and observational studies. In this new research approach, 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) is emerging as a main regulator of the extrarenal vitamin D system along with the
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