The Vicious Cycle of Arterial Stiffness and Arterial Media Calcification

Bergh, Geoffrey Van den; Opdebeeck, Britt; D’Haese, Patrick C.; Verhulst, Anja

doi:10.1016/j.molmed.2019.08.006

Cited by 72 publications

(61 citation statements)

References 97 publications

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“…Arterial stiffness and medial calcification are independent predictors of cardiovascular mortality, and have been strongly and reciprocally correlated in many clinical studies. Each process intensifies each other, to create a vicious cycle [19]. Here, hypertension plays a critical role in this vicious cycle [20].…”

Section: Classification Of Vascular Calcification Depending On Site mentioning

confidence: 99%

Vascular Calcification—New Insights into Its Mechanism

Lee

Jeon

2020

IJMS

281

254

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Vascular calcification (VC), which is categorized by intimal and medial calcification, depending on the site(s) involved within the vessel, is closely related to cardiovascular disease. Specifically, medial calcification is prevalent in certain medical situations, including chronic kidney disease and diabetes. The past few decades have seen extensive research into VC, revealing that the mechanism of VC is not merely a consequence of a high-phosphorous and -calcium milieu, but also occurs via delicate and well-organized biologic processes, including an imbalance between osteochondrogenic signaling and anticalcific events. In addition to traditionally established osteogenic signaling, dysfunctional calcium homeostasis is prerequisite in the development of VC. Moreover, loss of defensive mechanisms, by microorganelle dysfunction, including hyper-fragmented mitochondria, mitochondrial oxidative stress, defective autophagy or mitophagy, and endoplasmic reticulum (ER) stress, may all contribute to VC. To facilitate the understanding of vascular calcification, across any number of bioscientific disciplines, we provide this review of a detailed updated molecular mechanism of VC. This encompasses a vascular smooth muscle phenotypic of osteogenic differentiation, and multiple signaling pathways of VC induction, including the roles of inflammation and cellular microorganelle genesis.

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Section: Classification Of Vascular Calcification Depending On Site mentioning

confidence: 99%

Vascular Calcification—New Insights into Its Mechanism

Lee

Jeon

2020

IJMS

281

254

View full text Add to dashboard Cite

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“…It would be interesting to investigate whether IS and PCS are involved in the EndMT process, as (i) IS and PCS are known to promote arterial media calcification, and (ii) IS and PCS stimulate the EMT process in proximal tubular cells. Moreover, research so far predominantly focused on the transdifferentiation of VSMCs into bone-like cells, whilst the phenotypic transition of endothelial cells (EndMT) is often neglected and might be more important than generally thought [76]. Subsequently, in vitro experiments have demonstrated that both IS and PCS induce endothelial dysfunction, underlining even more that the endothelium plays a crucial role during uremic-toxin-induced arterial media calcification.…”

Section: Protein-bound Uremic Toxins Influence Phenotypic Switch Of Mmentioning

confidence: 99%

Molecular and Cellular Mechanisms that Induce Arterial Calcification by Indoxyl Sulfate and P-Cresyl Sulfate

Opdebeeck

D’Haese

Verhulst

2020

Toxins

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The protein-bound uremic toxins, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), are considered to be harmful vascular toxins. Arterial media calcification, or the deposition of calcium phosphate crystals in the arteries, contributes significantly to cardiovascular complications, including left ventricular hypertrophy, hypertension, and impaired coronary perfusion in the elderly and patients with chronic kidney disease (CKD) and diabetes. Recently, we reported that both IS and PCS trigger moderate to severe calcification in the aorta and peripheral vessels of CKD rats. This review describes the molecular and cellular mechanisms by which these uremic toxins induce arterial media calcification. A complex interplay between inflammation, coagulation, and lipid metabolism pathways, influenced by epigenetic factors, is crucial in IS/PCS-induced arterial media calcification. High levels of glucose are linked to these events, suggesting that a good balance between glucose and lipid levels might be important. On the cellular level, effects on endothelial cells, which act as the primary sensors of circulating pathological triggers, might be as important as those on vascular smooth muscle cells. Endothelial dysfunction, provoked by IS and PCS triggered oxidative stress, may be considered a key event in the onset and development of arterial media calcification. In this review a number of important outstanding questions such as the role of miRNA’s, phenotypic switching of both endothelial and vascular smooth muscle cells and new types of programmed cell death in arterial media calcification related to protein-bound uremic toxins are put forward and discussed.

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“…Results from in vitro and in vivo studies form an argument for the fact that NO inhibits VSMC calcification and osteo/chondrogenic transdifferentiation. Endothelial to mesenchymal transition contributes to arterial calcification by the generation of mesenchymal stem-like cells that can eventually migrate to the medial layer and differentiate further into multiple cell lineages: fibroblasts/myofibroblasts, osteoblasts/osteocytes and chondrocytes [ 17 ].…”

Section: Arterial Calcificationmentioning

confidence: 99%

“…Arterial media calcification is associated with arterial stiffening. A vicious cycle of arterial stiffness and arterial media calcification is described in which mechano-sensing plays an important role as VSMCs sense matrix stiffness, which in turn induces alterations in gene expression and thus, stimulates the phenotypic conversion of VSMCs [ 17 ]. Interestingly, activation of the P2Y 2 receptor has been associated with mechano-sensing in osteoblasts and chondrocytes [ 86 , 87 , 88 ].…”

Section: Purinergic Receptor Dependent Pathwaymentioning

confidence: 99%

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

Opdebeeck

Orriss

Neven

et al. 2020

IJMS

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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.

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The Vicious Cycle of Arterial Stiffness and Arterial Media Calcification

Cited by 72 publications

References 97 publications

Vascular Calcification—New Insights into Its Mechanism

Vascular Calcification—New Insights into Its Mechanism

Molecular and Cellular Mechanisms that Induce Arterial Calcification by Indoxyl Sulfate and P-Cresyl Sulfate

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

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