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A role for the endothelium in vascular calcification.

ABSTRACT: Vascular calcification is a regulated process that involves osteoprogenitor cells and frequently complicates common vascular disease, such as atherosclerosis and diabetic vasculopathy. However, it is not clear whether the vascular endothelium has a role in contributing osteoprogenitor cells to the calcific lesions.To determine whether the vascular endothelium contributes osteoprogenitor cells to vascular calcification.In this study, we use 2 mouse models of vascular calcification, mice with gene deletion of matrix Gla protein, a bone morphogenetic protein (BMP)-inhibitor, and Ins2Akita/+ mice, a diabetes model. We show that enhanced BMP signaling in both types of mice stimulates the vascular endothelium to contribute osteoprogenitor cells to the vascular calcification. The enhanced BMP signaling results in endothelial-mesenchymal transitions and the emergence of multipotent cells, followed by osteoinduction. Endothelial markers colocalize with multipotent and osteogenic markers in calcified arteries by immunostaining and fluorescence-activated cell sorting. Lineage tracing using Tie2-Gfp transgenic mice supports an endothelial origin of the osteogenic cells. Enhancement of matrix Gla protein expression in Ins2Akita/+ mice, as mediated by an Mgp transgene, limits the generation of multipotent cells. Moreover, matrix Gla protein-depleted human aortic endothelial cells in vitro acquire multipotency rendering the cells susceptible to osteoinduction by BMP and high glucose.Our data suggest that the endothelium is a source of osteoprogenitor cells in vascular calcification that occurs in disorders with high BMP activation, such as deficiency of BMP-inhibitors and diabetes mellitus.

SUBMITTER: Yao Y

PROVIDER: S-EPMC3851028 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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A role for the endothelium in vascular calcification.

Yao Yucheng Y Jumabay Medet M Ly Albert A Radparvar Melina M Cubberly Mark R MR Boström Kristina I KI

Circulation research 20130712 5

<h4>Rationale</h4>Vascular calcification is a regulated process that involves osteoprogenitor cells and frequently complicates common vascular disease, such as atherosclerosis and diabetic vasculopathy. However, it is not clear whether the vascular endothelium has a role in contributing osteoprogenitor cells to the calcific lesions.<h4>Objective</h4>To determine whether the vascular endothelium contributes osteoprogenitor cells to vascular calcification.<h4>Methods and results</h4>In this study, ...[more]

PMID: 23852538

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Project description:The present study aimed to determine the isoform-specific role of the NADPH oxidases (NOX) in the endothelium-mediated vascular dysfunction associated with ageing. Endothelium-dependent [intraluminal flow- and acetylcholine (ACh)-induced] vasodilatation in human skeletal muscle feed arteries (SMFAs) of young (24 ± 1 years, n = 16), middle aged (45 ± 1 years, n = 18) and old (76 ± 2 years, n = 21) subjects was assessed in vitro with and without the inhibition of NOX1 (ML090), NOX2 (gp91) and NOX4 (plumbagin). To identify the role of nitric oxide (NO) bioavailability in these responses, NO synthase blockade (l-NG -monomethyl arginine citrate) was utilized. SMFA NOX1, NOX2 and NOX4 protein expression was determined by western blotting. Age related endothelium-dependent vasodilatory dysfunction was evident in response to flow (young: 69 ± 3; middle aged: 51 ± 3; old: 27 ± 3%, P < 0.05) and ACh (young: 89 ± 2; middle aged: 72 ± 3; old: 45 ± 4%, P < 0.05). NOX1 inhibition had no effect on SMFA vasodilatation, whereas NOX2 inhibition restored flow- and ACh-induced vasodilatation in the middle aged and the old SMFAs (middle aged + gp91: 69 ± 3; 86 ± 3, old + gp91: 65 ± 5; 83 ± 2%, P < 0.05) and NOX4 inhibition tended to restore these vasodilatory responses in these two groups, but neither achieved statistical significance (P ≈ 0.06). l-NG -monomethyl arginine citrate negated the restorative effects of NOX2 and NOX4 blockade. Only NOX2 and NOX4 protein expression was significantly greater in the two older groups and inversely related to vascular function (r = 0.48 to 0.93, P < 0.05). NOX2 and, to a lesser extent, NOX4 appear to play an important, probably NO-mediated, role in age-related endothelial dysfunction. KEY POINTS: The present study aimed to determine the isoform-specific role of the NADPH oxidases (NOX) in the endothelium-mediated vascular dysfunction associated with ageing. Age related endothelium-dependent vasodilatory dysfunction was evident in skeletal muscle feed arteries in response to both flow and acetylcholine. NOX2 inhibition (gp91) restored endothelium-dependent vasodilatation in the middle aged and the old skeletal muscle feed arteries, and NOX4 inhibition (plumbagin) tended to restore these vasodilatory responses in these two groups. Nitric oxide synthase inhibition negated the restorative effects of NOX2 and NOX4 blockade. NOX2 and NOX4 protein expression was significantly greater in the two older groups and inversely related to vascular function. NOX2 and, to a lesser extent, NOX4 appear to play an important, probably nitric oxide-mediated, role in age-related endothelial dysfunction and could be important therapeutic targets to maintain vascular health with ageing.

Project description:Vascular calcification, which is common in the elderly and in patients with atherosclerosis, diabetes and chronic renal disease, increases the risk of cardiovascular morbidity and mortality. It is a complex, active and highly regulated cellular process that resembles physiological bone formation. It has previously been established that pharmacological doses of glucocorticoids facilitate arterial calcification. However, the consequences for vascular calcification of endogenous glucocorticoid elevation have yet to be established. Glucocorticoids (cortisol, corticosterone) are released from the adrenal gland, but can also be generated within cells from 11-keto metabolites of glucocorticoids (cortisone, 11-dehydrocorticosterone [11-DHC]) by the enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). In the current study we hypothesized that endogenous glucocorticoids facilitate vascular smooth muscle cell (VSMC) calcification and investigated the receptor-mediated mechanism underpinning this process. In vitro studies revealed increased phosphate-induced calcification in mouse VSMCs following treatment for 7days with corticosterone (100nM; 7.98 fold; P<0.01), 11-DHC (100nM; 7.14 fold; P<0.05) and dexamethasone (10nM; 7.16 fold; P<0.05), a synthetic glucocorticoid used as a positive control. Inhibition of 11β-HSD isoenzymes by 10μM carbenoxolone reduced the calcification induced by 11-DHC (0.37 fold compared to treatment with 11-DHC alone; P<0.05). The glucocorticoid receptor (GR) antagonist mifepristone (10μM) had no effect on VSMC calcification in response to corticosterone or 11-DHC. In contrast, the mineralocorticoid receptor (MR) antagonist eplerenone (10μM) significantly decreased corticosterone- (0.81 fold compared to treatment with corticosterone alone; P<0.01) and 11-DHC-driven (0.64 fold compared to treatment with 11-DHC alone; P<0.01) VSMC calcification, suggesting this glucocorticoid effect is MR-driven and not GR-driven. Neither corticosterone nor 11-DHC altered the mRNA levels of the osteogenic markers PiT-1, Osx and Bmp2. However, DAPI staining of pyknotic nuclei and flow cytometry analysis of surface Annexin V expression showed that corticosterone induced apoptosis in VSMCs. This study suggests that in mouse VSMCs, corticosterone acts through the MR to induce pro-calcification effects, and identifies 11β-HSD-inhibition as a novel potential treatment for vascular calcification.

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A role for the endothelium in vascular calcification.

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A role for the endothelium in vascular calcification.

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