MicroRNA-24 Suppression of N-Deacetylase/N-Sulfotransferase-1 (NDST1) Reduces Endothelial Cell Responsiveness to Vascular Endothelial Growth Factor A (VEGFA)

• Published in: The Journal of biological chemistry 2013-09, Vol.288 (36), p.25956-25963
• Main Authors: Kasza, Zsolt, Fredlund Fuchs, Peder, Tamm, Christoffer, Eriksson, Anna S., O'Callaghan, Paul, Heindryckx, Femke, Spillmann, Dorothe, Larsson, Erik, Le Jan, Sébastien, Eriksson, Inger, Gerwins, Pär, Kjellén, Lena, Kreuger, Johan
• Format: Article
• Language: English
• Subjects: ANGIOGENESIS; Biochemistry and Molecular Biology; Biokemi och molekylärbiologi; BIOSYNTHESIS; Cell and Molecular Biology; Cell- och molekylärbiologi; Chemotaxis - physiology; CHONDROITIN; DEACETYLASE/N-SULFOTRANSFERASE 1; EXPRESSION; Gene Expression Regulation, Enzymologic - physiology; Glycobiology and Extracellular Matrices; Heparan Sulfate; HEPARAN-SULFATE PROTEOGLYCANS; Heparitin Sulfate - genetics; Heparitin Sulfate - metabolism; Human Umbilical Vein Endothelial Cells - cytology; Human Umbilical Vein Endothelial Cells - metabolism; Humans; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; MIGRATION; miR-24; N-SULFATION; NDST1; PROTEINS; Sulfotransferases - biosynthesis; Sulfotransferases - genetics; TARGETS; Vascular Endothelial Growth Factor (VEGF); Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - genetics; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M113.484360

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. Background: Heparan sulfate proteoglycan (HSPG) co-receptors modulate VEGFA signaling. Results: MicroRNA-24 targets NDST1 to reduce HS sulfation and HS affinity for VEGFA, suppressing VEGFA signaling and endothelial cell migration. Conclusion: MicroRNAs targeting HS biosynthesis can regulate VEGFA-induced chemotaxis, essential during angiogenesis. Significance: HSPG-dependent signaling of pathophysiological importance can be targeted via microRNA interference with HS biosynthesis.