Extracellular Nucleotides Regulate Arterial Calcification by Activating Both Independent and Dependent Purinergic Receptor Signaling Pathways

Abstract

Arterial calcification, the deposition of calcium-phosphate crystals in the extracellular matrix, resembles physiological bone mineralization. It is well-known that extracellular nucleotides regulate bone homeostasis raising an emerging interest in the role of these molecules on arterial calcification. The purinergic independent pathway involves the enzymes ecto-nucleotide pyrophosphatase/phosphodiesterases (NPPs), ecto-nucleoside triphosphate diphosphohydrolases (NTPDases), 5′-nucleotidase and alkaline phosphatase. These regulate the production and breakdown of the calcification inhibitor—pyrophosphate and the calcification stimulator—inorganic phosphate, from extracellular nucleotides. Maintaining ecto-nucleotidase activities in a well-defined range is indispensable as enzymatic hyper- and hypo-expression has been linked to arterial calcification. The purinergic signaling dependent pathway focusses on the activation of purinergic receptors (P1, P2X and P2Y) by extracellular nucleotides. These receptors influence arterial calcification by interfering with the key molecular mechanisms underlying this pathology, including the osteogenic switch and apoptosis of vascular cells and possibly, by favoring the phenotypic switch of vascular cells towards an adipogenic phenotype, a recent, novel hypothesis explaining the systemic prevention of arterial calcification. Selective compounds influencing the activity of ecto-nucleotidases and purinergic receptors, have recently been developed to treat arterial calcification. However, adverse side-effects on bone mineralization are possible as these compounds reasonably could interfere with physiological bone mineralization.

Deletion of the P2Y 2 receptor aggravates internal elastic lamina calcification in chronic kidney disease mice through upregulation of alkaline phosphatase and lipocalin‐2

“…2 Cardiovascular calcification or the deposition of calcium-phosphate crystals (often as hydroxyapatite) has been found at four distinct sites throughout the vasculature being (i) the intima layer in the arterial wall (atherosclerotic plaque calcification), (ii) the medial layer in the arterial wall (arterial media calcification), (iii) aortic valve, and (iv) the cutaneous blood vessels (calciphylaxis). 3 Arterial media calcification also called Mönckeberg's arteriosclerosis, introduces a degree of vascular stiffness favoring cardiovascular events such as left ventricular hypertrophy and hypertension. 4 Arterial media calcification can be found in 50% of the CKD patients, 5 which most probably is even an underestimation as no effective treatment is available and therefore CKD patients are not routinely screened for arterial media calcifications.…”

“…Moreover, the cardiovascular mortality of young end‐stage CKD patients (25–34 years) equals that of the ≈85‐year ‐old general population 2 . Cardiovascular calcification or the deposition of calcium‐phosphate crystals (often as hydroxyapatite) has been found at four distinct sites throughout the vasculature being (i) the intima layer in the arterial wall (atherosclerotic plaque calcification), (ii) the medial layer in the arterial wall (arterial media calcification), (iii) aortic valve, and (iv) the cutaneous blood vessels (calciphylaxis) 3 …”

In Search of a Role for Extracellular Purine Enzymes in Bone Function

“…Indeed, the enzymes NPPs, CD39, CD73, and TNAP regulate the production and breakdown of the calcification inhibitor, PP i , and the calcification stimulator, P i , from extracellular nucleotides. This contribution, when balanced, is obviously beneficial for building/repairing bone, while it becomes detrimental to bone and also to vessels or cardiac valves and, thereby, to all the organs of the body, when there is an alteration in the purine enzyme function [ 103 ]. In particular, TNAP has very recently been indicated as a therapeutic target for cardiovascular calcification [ 104 ].…”

Apoptosis in the Extraosseous Calcification Process

“…There are several patho-mechanisms responsible for ectopic calcification, as altered hormonal homeostasis [ 47 ], dysregulated angiogenesis and/or vascular repair mechanisms [ 48 ], and abnormal extracellular nucleotide metabolism [ 49 , 50 ]. More recently, a number of investigations have focused on the release of membrane vesicles, on the role of modified mitochondria-related pathways, and on the influence of oxidative stress on the occurrence and progression of soft connective tissue mineralization, as detailed in the following sections of the present review.…”