Sortilin mediates vascular calcification via its recruitment into extracellular vesicles

Research output: Contribution to journalArticle

Authors

External Institution(s)

  • Harvard University
  • Aarhus University
  • Division of Cardiovascular Medicine
  • RWTH Aachen University

Details

Original languageEnglish (US)
Pages (from-to)1323-1336
Number of pages14
JournalJournal of Clinical Investigation
Volume126
Issue number4
StatusPublished - Apr 1 2016
Peer-reviewedYes

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.

Citation formats

APA

Goettsch, C., Hutcheson, J. D., Aikawa, M., Iwata, H., Pham, T., Nykjaer, A., ... Aikawa, E. (2016). Sortilin mediates vascular calcification via its recruitment into extracellular vesicles. Journal of Clinical Investigation, 126(4), 1323-1336. https://doi.org/10.1172/JCI80851

Harvard

Goettsch, C, Hutcheson, JD, Aikawa, M, Iwata, H, Pham, T, Nykjaer, A, Kjolby, M, Rogers, M, Michel, T, Shibasaki, M, Hagita, S, Kramann, R, Rader, DJ, Libby, P, Singh, SA & Aikawa, E 2016, 'Sortilin mediates vascular calcification via its recruitment into extracellular vesicles', Journal of Clinical Investigation, vol. 126, no. 4, pp. 1323-1336. https://doi.org/10.1172/JCI80851