title: MicroRNA-24 suppression of N-deacetylase/N-sulfotransferase-1 (NDST1) reduces endothelial cell responsiveness to vascular endothelial growth factor A (VEGFA).
abstract: Heparan sulfate (HS) proteoglycans, present at the plasma membrane of vascular endothelial cells, bind to the angiogenic growth factor VEGFA to modulate its signaling through VEGFR2. The interactions between VEGFA and proteoglycan co-receptors require sulfated domains in the HS chains. To date, it is essentially unknown how the formation of sulfated protein-binding domains in HS can be regulated by microRNAs. In the present study, we show that microRNA-24 (miR-24) targets NDST1 to reduce HS sulfation and thereby the binding affinity of HS for VEGFA. Elevated levels of miR-24 also resulted in reduced levels of VEGFR2 and blunted VEGFA signaling. Similarly, suppression of NDST1 using siRNA led to a reduction in VEGFR2 expression. Consequently, not only VEGFA binding, but also VEGFR2 protein expression is dependent on NDST1 function. Furthermore, overexpression of miR-24, or siRNA-mediated reduction of NDST1, reduced endothelial cell chemotaxis in response to VEGFA. These findings establish NDST1 as a target of miR-24 and demonstrate how such NDST1 suppression in endothelial cells results in reduced responsiveness to VEGFA.
authors.affiliation: From the Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Husargatan 3, P. O. Box 582, SE-751 23 Uppsala.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Kasza
authors.affiliation: From the Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Husargatan 3, P. O. Box 582, SE-751 23 Uppsala.
authors.forename: Peder
authors.initials: P
authors.lastname: Fredlund Fuchs
authors.affiliation: From the Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Husargatan 3, P. O. Box 582, SE-751 23 Uppsala.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Tamm
authors.affiliation: From the Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Husargatan 3, P. O. Box 582, SE-751 23 Uppsala.
authors.forename: Anna S
authors.initials: AS
authors.lastname: Eriksson
authors.affiliation: From the Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Husargatan 3, P. O. Box 582, SE-751 23 Uppsala.
authors.forename: Paul
authors.initials: P
authors.lastname: O'Callaghan
authors.affiliation: From the Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Husargatan 3, P. O. Box 582, SE-751 23 Uppsala.
authors.forename: Femke
authors.initials: F
authors.lastname: Heindryckx
authors.affiliation: From the Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Husargatan 3, P. O. Box 582, SE-751 23 Uppsala.
authors.forename: Dorothe
authors.initials: D
authors.lastname: Spillmann
authors.affiliation: the Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-405 30 Göteborg, and.
authors.forename: Erik
authors.initials: E
authors.lastname: Larsson
authors.affiliation: From the Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Husargatan 3, P. O. Box 582, SE-751 23 Uppsala.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Le Jan
authors.affiliation: From the Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Husargatan 3, P. O. Box 582, SE-751 23 Uppsala.
authors.forename: Inger
authors.initials: I
authors.lastname: Eriksson
authors.affiliation: From the Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Husargatan 3, P. O. Box 582, SE-751 23 Uppsala,; the Department of Radiology, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.
authors.forename: Pär
authors.initials: P
authors.lastname: Gerwins
authors.affiliation: From the Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Husargatan 3, P. O. Box 582, SE-751 23 Uppsala.
authors.forename: Lena
authors.initials: L
authors.lastname: Kjellén
authors.affiliation: From the Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Husargatan 3, P. O. Box 582, SE-751 23 Uppsala,. Electronic address: Johan.Kreuger@imbim.uu.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Kreuger
mesh_terms: D002633:Chemotaxis / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006497:Heparan Sulfate / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D015238:Sulfotransferases / Q000096:biosynthesis* / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D006497:Heparan Sulfate; D035683:MicroRNAs; D015238:Sulfotransferases; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; C543845:MIRN24 microRNA, human; C467484:VEGFA protein, human; C021350:heparitin sulfotransferase
keywords: Angiogenesis; Biosynthesis; Heparan Sulfate; MicroRNA; NDST1; Vascular Endothelial Growth Factor (VEGF); miR-24