Mechanisms and Clinical Consequences of Vascular Calcification

Zhu, Dongxing; Mackenzie, Neil E.; Farquharson, Colin; MacRae, Vicky

doi:10.3389/fendo.2012.00095

Cited by 99 publications

(114 citation statements)

References 196 publications

(246 reference statements)

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“…[36][37][38] In contrast, increased levels of PP i are known to inhibit vascular calcification. 39 The ENPP1 K173Q mutation identified in this study has previously been shown to affect intracellular ENPP1 activity and serum ENPP1 enzyme levels. 40,41 In both our discovery and validation studies, we found that the ENPP1 K variant was associated with a significantly decreased stroke risk, which suggests that decreased ENPP1 activity may protect against stroke via PP i levels.…”

Section: Discussionmentioning

confidence: 63%

Genetic mapping and exome sequencing identify 2 mutations associated with stroke protection in pediatric patients with sickle cell anemia

Flanagan

Sheehan

Linder

et al. 2013

Blood

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• The complication of stroke is common in patients with SCA, and there is a genetic component.• We have performed a largeassociation study to identify 2 genetic variants that protect patients with SCA from stroke.Stroke is a devastating complication of sickle cell anemia (SCA), occurring in 11% of patients before age 20 years. Previous studies of sibling pairs have demonstrated a genetic component to the development of cerebrovascular disease in SCA, but few candidate genetic modifiers have been validated as having a substantial effect on stroke risk. We performed an unbiased whole-genome search for genetic modifiers of stroke risk in SCA. Genome-wide association studies were performed using genotype data from single-nucleotide polymorphism arrays, whereas a pooled DNA approach was used to perform whole-exome sequencing. In combination, 22 nonsynonymous variants were identified and represent key candidates for further in-depth study. To validate the association of these mutations with the risk for stroke, the 22 candidate variants were genotyped in an independent cohort of control patients (n 5 231) and patients with stroke (n 5 57) with SCA. One mutation in GOLGB1 (Y1212C) and another mutation in ENPP1 (K173Q) were confirmed as having significant associations with a decreased risk for stroke. These mutations were discovered and validated by an unbiased whole-genome approach, and future studies will focus on how these functional mutations may lead to protection from stroke in the context of SCA. (Blood. 2013;121(16):3237-3245)

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Section: Discussionmentioning

confidence: 63%

Genetic mapping and exome sequencing identify 2 mutations associated with stroke protection in pediatric patients with sickle cell anemia

Flanagan

Sheehan

Linder

et al. 2013

Blood

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“…Consequently, no effective therapies are available. Increasing body of recent evidence has challenged the traditional consideration of vascular calcification as a passive aging-related process and points to specific mechanisms of its regulation depending on diseaserelated environmental cues [32,33]. A role of circulating calcifying cells in this process is emerging [34].…”

Section: Discussionmentioning

confidence: 99%

Urokinase Receptor Mediates Osteogenic Differentiation of Mesenchymal Stem Cells and Vascular Calcification via the Complement C5a Receptor

Anaraki

Patecki²,

Larmann³

et al. 2014

Stem Cells and Development

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Vascular calcification is a severe consequence of several pathological processes with a lack of effective therapy. Recent studies suggest that circulating and resident mesenchymal stem cells (MSC) contribute to the osteogenic program of vascular calcification. Molecular mechanisms underlying MSC osteogenic potential and differentiation remain, however, sparsely explored. We investigated a role for the complement receptor C5aR in these processes. We found that expression of C5aR was upregulated upon differentiation of human MSC to osteoblasts. C5aR inhibition by silencing and specific antagonist impaired osteogenic differentiation. We demonstrate that C5aR expression upon MSC differentiation was regulated by the multifunctional urokinase receptor (uPAR). uPAR targeting by siRNA resulted in complete abrogation of C5aR expression and consequently in the inhibition of MSC-osteoblast differentiation. We elucidated the NFkB pathway as the mechanism utilized by the uPAR-C5aR axis. MSC treatment with the NFkB inhibitor completely blocked the differentiation process. Nuclear translocation of the p65 RelA component of the NFkB complex was induced under osteogenic conditions and impaired by the inhibition of uPAR or C5aR. Dual-luciferase reporter assays demonstrated enhanced NFkB signaling upon MSC differentiation, whereas uPAR and C5aR downregulation lead to inhibition of the NFkB activity. We show involvement of the Erk1/2 kinase in this cascade. In vivo studies in a uPAR/LDLR double knockout mouse model of diet-induced atherosclerosis revealed impaired C5aR expression and calcification in aortic sinus plaques in uPAR -/ -/LDLR -/ -versus uPAR + / + /LDLR -/ -control animals. These results suggest that uPAR-C5aR axis via the underlying NFkB transcriptional program controls osteogenic differentiation with functional impact on vascular calcification in vivo.

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“…It shares some outward similarities with bone mineralisation and is associated with a phenotypic transdifferentiation of vascular smooth muscle cells (VSMCs) towards a more osteoblast-like phenotype [80].…”

Section: Pyrophosphate and Vascular Calcificationmentioning

confidence: 99%