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The neutral sphingomyelinase-2 is involved in angiogenic signaling triggered by oxidized LDL
- Source :
- Free Radical Biology and Medicine, Free Radical Biology and Medicine, Elsevier, 2016, 93, pp.204-216. ⟨10.1016/j.freeradbiomed.2016.02.006⟩
- Publication Year :
- 2016
- Publisher :
- HAL CCSD, 2016.
-
Abstract
- Capillaries of the external part of the normal arterial wall constitute the vasa vasorum network. In atherosclerotic lesions, neovascularization occurs in areas of intimal hyperplasia where it may promote plaque expansion, and intraplaque hemorrhage. Oxidized LDL that are present in atherosclerotic areas activate various angiogenic signaling pathways, including reactive oxygen species and the sphingosine kinase/sphingosine-1-phosphate pathway. We aimed to investigate whether oxidized LDL-induced angiogenesis requires neutral sphingomyelinase-2 activation and the neutral sphingomyelinase-2/sphingosine kinase-1 pathway. The role of neutral sphingomyelinase-2 in angiogenic signaling was investigated in Human Microvascular Endothelial Cells (HMEC-1) forming capillary tube on Matrigel and in vivo in the Matrigel plug assay in C57BL/6 mice and in the chicken chorioallantoic membrane model. Low concentration of human oxidized LDL elicits HMEC-1 capillary tube formation and neutral sphingomyelinase-2 activation, which were blocked by neutral sphingomyelinase-2 inhibitors, GW4869 and specific siRNA. This angiogenic effect was mimicked by low concentration of C6-Ceramide and was inhibited by sphingosine kinase-1 inhibitors. Upstream of neutral sphingomyelinase-2, oxidized LDL-induced activation required LOX-1, reactive oxygen species generation by NADPH oxidase and p38-MAPK activation. Inhibition of sphingosine kinase-1 blocked the angiogenic response and triggered HMEC-1 apoptosis. Low concentration of oxidized LDL was angiogenic in vivo, both in the Matrigel plug assay in mice and in the chorioallantoic membrane model, and was blocked by GW4869. In conclusion, low oxLDL concentration triggers sprouting angiogenesis that involves ROS-induced activation of the neutral sphingomyelinase-2/sphingosine kinase-1 pathway, and is effectively inhibited by GW4869.
- Subjects :
- 0301 basic medicine
Transcriptional Activation
Ceramide
Angiogenesis
[SDV]Life Sciences [q-bio]
Sphingosine kinase
Apoptosis
030204 cardiovascular system & hematology
Ceramides
Biochemistry
Benzylidene Compounds
p38 Mitogen-Activated Protein Kinases
Muscle, Smooth, Vascular
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Sphingosine
Physiology (medical)
Animals
Humans
ComputingMilieux_MISCELLANEOUS
Sprouting angiogenesis
Matrigel
NADPH oxidase
Aniline Compounds
biology
Neovascularization, Pathologic
Endothelial Cells
NADPH Oxidases
Cell biology
Lipoproteins, LDL
Chorioallantoic membrane
Oxidative Stress
Phosphotransferases (Alcohol Group Acceptor)
030104 developmental biology
Sphingomyelin Phosphodiesterase
chemistry
biology.protein
Lysophospholipids
Reactive Oxygen Species
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Subjects
Details
- Language :
- English
- ISSN :
- 08915849
- Database :
- OpenAIRE
- Journal :
- Free Radical Biology and Medicine, Free Radical Biology and Medicine, Elsevier, 2016, 93, pp.204-216. ⟨10.1016/j.freeradbiomed.2016.02.006⟩
- Accession number :
- edsair.doi.dedup.....bd322f6f206c1ca62cba00ce224fdfea