Sulodexide inhibits angiogenesis via decreasing Dll4 and Notch1 expression in mouse proepicardial explant cultures

• Published in: Fundamental & clinical pharmacology 2019-04, Vol.33 (2), p.159-169
• Main Authors: Niderla‐Bielińska, Justyna, Bartkowiak, Krzysztof, Ciszek, Bogdan, Jankowska‐Steifer, Ewa, Krejner, Alicja, Ratajska, Anna
• Format: Article
• Language: English
• Subjects: Angiogenesis; Angiogenesis Inhibitors - pharmacology; Animals; Cardiovascular diseases; Cell adhesion; Cell adhesion & migration; Cell Line; Cell Proliferation - drug effects; Coronary Vessels - drug effects; Coronary Vessels - embryology; Coronary Vessels - metabolism; Dll4; Down-Regulation; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Explants; Fibroblast growth factor 2; Gene expression; Gestational Age; Glycosaminoglycans - pharmacology; Growth factors; Heart diseases; Heparin; Inflammation; Insulin-like growth factors; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Leukocytes; Low molecular weights; Macrophages; Medical treatment; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice, Inbred C57BL; Mice, Inbred CBA; Morphology; Neovascularization, Physiologic - drug effects; Notch1 protein; Pericardium - drug effects; Pericardium - embryology; Pericardium - metabolism; Pharmacology; proepicardium; Proteins; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; Signal Transduction - drug effects; Sulfates; Sulodexide; Tissue Culture Techniques; Tubules; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0767-3981; 1472-8206
• DOI: 10.1111/fcp.12418

Sulodexide (SDX) is a mixed drug containing low‐molecular‐weight heparin sulfate and dermatan sulfate. It exerts mild anticoagulant action but can also affect leukocytes, macrophages, and cell–cell adhesion and may interact with growth factors although its direct influence on endothelial cells is not well described. Clinically, SDX is used for the treatment of cardiovascular diseases, where it exerts anti‐inflammatory and endothelial protective effects. The aim of this study was to determine the influence of SDX on tubule formation and angiogenesis‐related proteins’ mRNA expression in endothelial cell line C166 and mouse proepicardial explants. C166 cells and explants were stimulated with a proangiogenic cocktail containing bFGF/VEGF‐A120/VEGF‐A164 enriched with SDX. After stimulation, the number and morphology of tubules stained with anti‐CD31 antibody were examined under confocal microscope and expression of mRNA for VEGF‐A, VEGF‐B, VEGF‐C, bFGF, IGF‐1, Dll4, and Notch1 was measured with real‐time PCR. In C166 cell line, there was no difference in tubule formation and mRNA expression, but in proepicardial explants, we observed reduction in tubule number and in mRNA level for DLL4 and Notch1 after SDX administration. In conclusion, SDX indirectly inhibits angiogenesis in mouse proepicardial explant cultures but has no direct effect on the C166 endothelial cell line.