Vascular endothelial growth factor mediates ceramide 1-phosphate-stimulated macrophage proliferation

• Published in: Experimental cell research 2017-12, Vol.361 (2), p.277-283
• Main Authors: Ouro, Alberto, Arana, Lide, Riazy, Maziar, Zhang, Peng, Gomez-Larrauri, Ana, Steinbrecher, Urs, Duronio, Vincent, Gomez-Muñoz, Antonio
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; ANTIBODIES; Antibodies, Neutralizing - pharmacology; CELL DIVISION; Cell Division - drug effects; Cell Line; Cell Membrane - drug effects; Cell Membrane - metabolism; CELL PROLIFERATION; Cell Proliferation - drug effects; Ceramide 1-phosphate; Ceramides - antagonists & inhibitors; Ceramides - pharmacology; GENES; GROWTH FACTORS; INHIBITION; MACROPHAGES; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Mice; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - genetics; Mitogen-Activated Protein Kinases - metabolism; PHOSPHATES; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; PHOSPHOTRANSFERASES; PLANT GROWTH; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Pyrimidines - pharmacology; RECEPTORS; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; SECRETION; Sphingolipids; STIMULATION; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - genetics; Vascular Endothelial Growth Factor Receptor-2 - metabolism; VEGF
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2017.10.027

The bioactive sphingolipid ceramide 1-phosphate (C1P) regulates cell division in a variety of cell types including macrophages. However, the mechanisms involved in this action are not completely understood. In the present work we show that C1P stimulates the release of vascular endothelial growth factor (VEGF) in RAW264.7 macrophages, and that this growth factor is essential for stimulation of cell proliferation by C1P. The stimulation of VEGF release was dependent upon activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB-1 also known as Akt-1), and mitogen-activated protein kinase-kinase (MEK)/extracellularly regulated kinase-2 (ERK-2) pathways, as inhibition of these kinases with selective pharmacological inhibitors or with specific gene silencing siRNA, abrogated VEGF release. A key observation was that sequestration of VEGF with a neutralizing antibody, or treatment with VEGF siRNA abolished C1P-stimulated macrophage growth. Also, inhibition of the pathways involved in C1P-stimulated VEGF release inhibited the stimulation of macrophage growth by C1P. Moreover, blockade of VEGF receptor-2 (VEGFR-2), which is the primary receptor for VEGF, with the pharmacological inhibitor DMH4, or with specific VEGFR-2 siRNA, substantially inhibited C1P-stimulated cell growth. It can be concluded that stimulation of VEGF release is a key factor in the promotion of macrophage proliferation by C1P. [Display omitted] •C1P promotes macrophage proliferation through stimulation of VEGF secretion.•C1P-stimulated VEGF secretion is mediated by the PI3K/Akt-1 and MEK/ERK-2 pathways.•Blockade of VEGF receptor-2 inhibited C1P-stimulated macrophage proliferation.