The Contribution of Osteoprogenitor Cells to Arterial Stiffness and Hypertension

Pikilidou, Maria; Yavropoulou, Maria P; Αντωνίου, Μαρία; Yovos, John G.

doi:10.1159/000381098

Cited by 14 publications

(6 citation statements)

References 63 publications

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“…Osteogenic differentiation of vSMCs follows a distinct change in phenotype, firstly switching from a contractile phenotype to one with an increased senescent capacity, before manifesting as an increase in arterial stiffness and a decrease in arterial compliance 58 . Therefore, whilst this study demonstrates the correlation between calcification and a reduction in SIRT1, it was important to establish whether this was dependant on a senescence pathway.…”

Section: Discussionmentioning

confidence: 99%

Suppression of SIRT1 in Diabetic Conditions Induces Osteogenic Differentiation of Human Vascular Smooth Muscle Cells via RUNX2 Signalling

Bartoli-Leonard

Wilkinson

Schiro

et al. 2019

Sci Rep

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Vascular calcification is associated with significant morbidity and mortality within diabetes, involving activation of osteogenic regulators and transcription factors. Recent evidence demonstrates the beneficial role of Sirtuin 1 (SIRT1), an NAD+ dependant deacetylase, in improved insulin sensitivity and glucose homeostasis, linking hyperglycaemia and SIRT1 downregulation. This study aimed to determine the role of SIRT1 in vascular smooth muscle cell (vSMC) calcification within the diabetic environment. An 80% reduction in SIRT1 levels was observed in patients with diabetes, both in serum and the arterial smooth muscle layer, whilst both RUNX2 and Osteocalcin levels were elevated. Human vSMCs exposed to hyperglycaemic conditions in vitro demonstrated enhanced calcification, which was positively associated with the induction of cellular senescence, verified by senescence-associated β-galactosidase activity and cell cycle markers p16 and p21. Activation of SIRT1 by SRT1720 reduced Alizarin red staining by a third, via inhibition of the RUNX2 pathway and prevention of senescence. Conversely, inhibition of SIRT1 via Sirtinol and siRNA increased RUNX2 by over 50%. These findings demonstrate the key role that SIRT1 plays in preventing calcification in a diabetic environment, through the inhibition of RUNX2 and senescence pathways, suggesting a downregulation of SIRT1 may be responsible for perpetuating vascular calcification in diabetes.

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Section: Discussionmentioning

confidence: 99%

Suppression of SIRT1 in Diabetic Conditions Induces Osteogenic Differentiation of Human Vascular Smooth Muscle Cells via RUNX2 Signalling

Bartoli-Leonard

Wilkinson

Schiro

et al. 2019

Sci Rep

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“…Vascular calcification is associated with arterial stiffness and osteoprogenitor cells play an important role in the bone–vascular axis which regulates calcium metabolism around the arterial wall [ 36 , 37 ]. Many factors can modulate vascular calcification, such as osteoblastic differentiation, vitamin D status, matrix Gla protein or even oxidative stress [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

“…Sclerostin is a signaling pathway inhibitor of the Wnt/β-catenin pathway that contributes to reduced bone turnover and upregulates the calcification induced by vascular smooth muscle cells [ 15 , 16 , 38 , 39 ]. After vascular calcification has progressed, serum sclerostin is elevated to decrease β-catenin stability in the cells and suppress the proliferation and differentiation of osteoprogenitor cells [ 15 , 16 , 37 ]. Clinical studies have reported that serum sclerostin levels are positively correlated with carotid intima-media thickness in hemodialysis patients, and positively associated with coronary artery or abdominal aortic calcification in non-dialysis CKD patients [ 40 – 42 ].…”

Section: Discussionmentioning

confidence: 99%

Serum levels of sclerostin as a potential biomarker in central arterial stiffness among hypertensive patients

Chang

Hsu

Liou

et al. 2018

BMC Cardiovasc Disord

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BackgroundSclerostin is known to be a canonical Wnt/β-catenin signaling pathway inhibitor, while the Wnt/β-catenin signaling pathway is proposed to be involved in the development of arterial stiffness. This study aims to investigate the relationship between serum sclerostin levels and carotid–femoral pulse wave velocity (cfPWV) among hypertensive patients.MethodsFasting blood samples were obtained from 105 hypertensive patients. Patients with cfPWV values of > 10 m/s were classified in the high arterial stiffness group, whereas those with cfPWV values of ≤10 m/s were assigned to the low arterial stiffness group. Serum sclerostin and Dickkopf-1 (DKK1) levels were quantified using commercially available enzyme-linked immunosorbent assays.ResultsThirty-six hypertensive patients (34.3%) who belonged to the high arterial stiffness group were generally older (p < 0.001), presented with lower estimated glomerular filtration rates (eGFR, p = 0.014), higher incidence of diabetes mellitus (p = 0.030), average systolic blood pressures (SBP, p = 0.013), pulse pressure (p = 0.026), serum creatinine levels (p = 0.013), intact parathyroid hormone levels (iPTH, p = 0.003), and sclerostin levels (p < 0.001) than their counterparts in the low arterial stiffness group. A multivariable logistic regression analysis identified sclerostin as an independent predictor of arterial stiffness in hypertensive patients (odds ratio, 1.042; 95% confidence interval (CI), 1.017–1.068; p = 0.001). Multivariable forward stepwise linear regression analysis also showed that serum sclerostin level (β = 0.255, adjusted R2 change: 0.146, p = 0.003) was positively associated with cfPWV values in patients with hypertension.ConclusionsIn this study, serum sclerostin level, but not DKK1, is found to be positively correlated with cfPWV values and is identified as an independent predictor of arterial stiffness in hypertensive patients after adjusting for significant confounders.

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“…Additionally, VSMC may also undergo a phenotypic switching from a quiescent contractile phenotype to a proliferative secretory phenotype. Recently, it has been suggested that VSMC may also dedifferentiate to a more osteogenic phenotype, and thereby may play a role in increasing stiffness through vascular calcification (Pikilidou et al, 2015 ). It is plausible that VSMC may play a larger role in contributing to vascular wall stiffness and arterial wall mechanics than previously considered.…”

Section: Major Mechanisms Mediating Causes Of Increased Vascular Stifmentioning

confidence: 99%

“Smooth Muscle Cell Stiffness Syndrome”—Revisiting the Structural Basis of Arterial Stiffness

2015

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In recent decades, the pervasiveness of increased arterial stiffness in patients with cardiovascular disease has become increasingly apparent. Though, this phenomenon has been well documented in humans and animal models of disease for well over a century, there has been surprisingly limited development in a deeper mechanistic understanding of arterial stiffness. Much of the historical literature has focused on changes in extracellular matrix proteins—collagen and elastin. However, extracellular matrix changes alone appear insufficient to consistently account for observed changes in vascular stiffness, which we observed in our studies of aortic stiffness in aging monkeys. This led us to examine novel mechanisms operating at the level of the vascular smooth muscle cell (VSMC)—that include increased cell stiffness and adhesion to extracellular matrix—which that may be interrelated with other mechanisms contributing to arterial stiffness. We introduce these observations as a new concept—the Smooth Muscle Cell Stiffness Syndrome (SMCSS)—within the field of arterial stiffness and posit that stiffening of vascular cells impairs vascular function and may contribute stiffening to the vasculature with aging and cardiovascular disease. Importantly, this review article revisits the structural basis of arterial stiffness in light of these novel findings. Such classification of SMCSS and its contextualization into our current understanding of vascular mechanics may be useful in the development of strategic therapeutics to directly target arterial stiffness.

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The Contribution of Osteoprogenitor Cells to Arterial Stiffness and Hypertension

Cited by 14 publications

References 63 publications

Suppression of SIRT1 in Diabetic Conditions Induces Osteogenic Differentiation of Human Vascular Smooth Muscle Cells via RUNX2 Signalling

Suppression of SIRT1 in Diabetic Conditions Induces Osteogenic Differentiation of Human Vascular Smooth Muscle Cells via RUNX2 Signalling

Serum levels of sclerostin as a potential biomarker in central arterial stiffness among hypertensive patients

“Smooth Muscle Cell Stiffness Syndrome”—Revisiting the Structural Basis of Arterial Stiffness

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