title: Sortilin mediates vascular calcification via its recruitment into extracellular vesicles.
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.forename: Claudia
authors.initials: C
authors.lastname: Goettsch
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Hutcheson
authors.forename: Masanori
authors.initials: M
authors.lastname: Aikawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwata
authors.forename: Tan
authors.initials: T
authors.lastname: Pham
authors.forename: Anders
authors.initials: A
authors.lastname: Nykjaer
authors.forename: Mads
authors.initials: M
authors.lastname: Kjolby
authors.forename: Maximillian
authors.initials: M
authors.lastname: Rogers
authors.forename: Thomas
authors.initials: T
authors.lastname: Michel
authors.forename: Manabu
authors.initials: M
authors.lastname: Shibasaki
authors.forename: Sumihiko
authors.initials: S
authors.lastname: Hagita
authors.forename: Rafael
authors.initials: R
authors.lastname: Kramann
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Sasha A
authors.initials: SA
authors.lastname: Singh
authors.forename: Elena
authors.initials: E
authors.lastname: Aikawa
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000469:Alkaline Phosphatase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D047389:Casein Kinase I / Q000235:genetics / Q000378:metabolism; D047390:Casein Kinase II / Q000378:metabolism; D055252:Cell-Derived Microparticles / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D061205:Vascular Calcification / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000469:Alkaline Phosphatase; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D047389:Casein Kinase I; D047390:Casein Kinase II; D016326:Extracellular Matrix Proteins; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; D000099183:Sortilin; C509696:FAM20C protein, mouse; C524449:FAM20C protein, human; C548267:ALPL protein, human; C510878:ALPL protein, mouse