title: Inhibitory effects of sepiapterin on vascular endothelial growth factor-A-induced proliferation and adhesion in human umbilical vein endothelial cells.
abstract: Tetrahydrobiopterin (BH(4)) has been known to be an essential cofactor for the activities of nitric oxide (NO) synthase and aromatic amino acid hydroxylases, which are involved in physiological and pathological processes. In the present study, we report that sepiapterin, the more stable form of BH4 precursor, modulates vascular endothelial growth factor-A (VEGF-A)-induced cell proliferation and adhesion in human umbilical vein endothelial cells (HUVECs). The antiproliferative activity of sepiapterin in VEGF-A-treated HUVECs is associated with inhibition of the expression of cyclin-dependent kinases (Cdks) such as Cdk4 and Cdk2. Pretreatment with NO synthase inhibitor does not abrogate the ability of sepiapterin to inhibit VEGF-A-induced cell proliferation and adhesion, indicating that the suppressive effects of sepiapterin on VEGF-Ainduced responses are mediated by NO-independent mechanism. Finally, we show that sepiapterin modulates VEGF-A-induced cell proliferation and adhesion through down-regulation of VEGF receptor-2 downstream signaling pathways. Taken together, these findings represent a novel function of sepiapterin in the regulation of angiogenesis, supporting further development and evaluation of sepiapterin as an antiangiogenic agent.
authors: Department of Molecular Bioscience, Institute of Bioscience and Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon 200-701, Korea.
authors: Soo Hyeon
authors: SH
authors: Kim
authors: Young-Rak
authors: YR
authors: Cho
authors: Myoung-Dong
authors: MD
authors: Kim
authors: Hyun Ju
authors: HJ
authors: Kim
authors: Shin Wook
authors: SW
authors: Choi
authors: Dong-Wan
authors: DW
authors: Seo
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D009569:Nitric Oxide / Q000096:biosynthesis; D011622:Pterins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology* / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis
chemical_list: D020533:Angiogenesis Inhibitors; D011622:Pterins; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; C016727:sepiapterin; D040301:Vascular Endothelial Growth Factor Receptor-2