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Sortilin mediates vascular calcification via its recruitment into extracellular vesicles
Claudia Goettsch, … , Sasha A. Singh, Elena Aikawa
Claudia Goettsch, … , Sasha A. Singh, Elena Aikawa
Published March 7, 2016
Citation Information: J Clin Invest. 2016;126(4):1323-1336. https://doi.org/10.1172/JCI80851.
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Research Article Vascular biology Article has an altmetric score of 13

Sortilin mediates vascular calcification via its recruitment into extracellular vesicles

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Abstract

Vascular calcification is a common feature of major cardiovascular diseases. Extracellular vesicles participate in the formation of microcalcifications that are implicated in atherosclerotic plaque rupture; however, the mechanisms that regulate formation of calcifying extracellular vesicles remain obscure. Here, we have demonstrated that sortilin is a key regulator of smooth muscle cell (SMC) calcification via its recruitment to extracellular vesicles. Sortilin localized to calcifying vessels in human and mouse atheromata and participated in formation of microcalcifications in SMC culture. Sortilin regulated the loading of the calcification protein tissue nonspecific alkaline phosphatase (TNAP) into extracellular vesicles, thereby conferring its calcification potential. Furthermore, SMC calcification required Rab11-dependent trafficking and FAM20C/casein kinase 2–dependent C-terminal phosphorylation of sortilin. In a murine model, Sort1-deficiency reduced arterial calcification but did not affect bone mineralization. Additionally, transfer of sortilin-deficient BM cells to irradiated atherosclerotic mice did not affect vascular calcification, indicating a primary role of SMC-derived sortilin. Together, the results of this study identify sortilin phosphorylation as a potential therapeutic target for ectopic calcification/microcalcification and may clarify the mechanism that underlies the genetic association between the SORT1 gene locus and coronary artery calcification.

Authors

Claudia Goettsch, Joshua D. Hutcheson, Masanori Aikawa, Hiroshi Iwata, Tan Pham, Anders Nykjaer, Mads Kjolby, Maximillian Rogers, Thomas Michel, Manabu Shibasaki, Sumihiko Hagita, Rafael Kramann, Daniel J. Rader, Peter Libby, Sasha A. Singh, Elena Aikawa

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Figure 2

Sortilin is necessary for vascular calcification in vivo.

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Sortilin is necessary for vascular calcification in vivo.
(A) TNAP activ...
(A) TNAP activity (arrows) after ex vivo aortic ring culture of Sort1+/+ littermates and Sort1–/– mice in osteogenic medium (OM). n = 4. L, lumen. Scale bars: 20 μm. Inset scale bars: 200 μm. (B–F) Sort1+/+Ldlr–/– (littermates) and Sort1–/–Ldlr–/– mice (10-week-old, sex-mixed) consumed a high-fat, high-cholesterol (1.25% cholesterol) diet for 15 weeks. (B) Ex vivo FRI analysis. Representative images of the fluorescence intensity in the aorta. Scale bars: 2 mm. (C) Quantification of FRI signal–positive area (dashed red line indicates signal cut-off for quantification). Sort1+/+Ldlr–/–, n = 9; Sort1–/–Ldlr–/–, n = 10. ***P < 0.005, t test. (D) Aortic calcium content. Sort1+/+Ldlr–/–, n = 7; Sort1–/–Ldlr–/–, n = 9. *P < 0.05, t test. (E) Representative images of TNAP activity in the aortic arch (lesser curvature). Scale bars: 20 μm. (F) Quantitative assessment of TNAP by percent-positive lesion area. Sort1+/+Ldlr–/–, n = 7; Sort1–/–Ldlr–/–, n = 9. *P < 0.05, t test. (G–I) BM transplantation. Sort+/+Ldlr–/– (10-week-old males) received BM cells from age- and sex-matched Sort+/+ and Sort–/– mice and consumed a high-fat, high-cholesterol (1.25% cholesterol) diet for 24 weeks. (G) Ex vivo FRI analysis. Representative images of the fluorescence intensity in the aorta. Scale bar: 2 mm. (H) Quantification of FRI signal–positive area. Donor: Sort1+/+, n = 7; Sort1–/–, n = 6. (I) Aortic calcium content. Donor: Sort1+/+, n = 7; Sort1–/–, n = 5. Each dot depicts one mouse. Error bars indicate ±SD.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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