MicroRNA-24 Suppression of N-Deacetylase/N-Sulfotransferase-1 (NDST1) Reduces Endothelial Cell Responsiveness to Vascular Endothelial Growth Factor A (VEGFA) |
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Authors: | Zsolt Kasza Peder Fredlund Fuchs Christoffer Tamm Anna S Eriksson Paul O'Callaghan Femke Heindryckx Dorothe Spillmann Erik Larsson Sébastien Le Jan Inger Eriksson P?r Gerwins Lena Kjellén Johan Kreuger |
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Institution: | 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 Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-405 30 Göteborg, and ;the ¶Department of Radiology, Uppsala University Hospital, SE-751 85 Uppsala, Sweden |
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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. |
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Keywords: | Angiogenesis Biosynthesis Heparan Sulfate MicroRNA Vascular Endothelial Growth Factor (VEGF) NDST1 miR-24 |
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