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Isoprostanes inhibit vascular endothelial growth factor-induced endothelial cell migration, tube formation, and cardiac vessel sprouting in vitro, as well as angiogenesis in vivo via activation of the thromboxane A(2) receptor: a potential link between oxidative stress and impaired angiogenesis
- Source :
- Circulation research. 103(9)
- Publication Year :
- 2008
-
Abstract
- Isoprostanes are endogenously formed end products of lipid peroxidation. Furthermore, they are markers of oxidative stress and independent risk markers of coronary heart disease. In patients experiencing coronary heart disease, impaired angiogenesis may exacerbate insufficient blood supply of ischemic myocardium. We therefore hypothesized that isoprostanes may exert detrimental cardiovascular effects by inhibiting angiogenesis. We studied the effect of isoprostanes on vascular endothelial growth factor (VEGF)-induced migration and tube formation of human endothelial cells (ECs), and cardiac angiogenesis in vitro as well as on VEGF-induced angiogenesis in the chorioallantoic membrane assay in vivo. The isoprostanes 8-iso-PGF(2alpha), 8-iso-PGE(2), and 8-iso-PGA(2) inhibited VEGF-induced migration, tube formation of ECs, and cardiac angiogenesis in vitro, as well as VEGF-induced angiogenesis in vivo via activation of the thromboxane A(2) receptor (TBXA2R): the specific TBXA2R antagonists SQ-29548, BM 567, and ICI 192,605 but not the thromboxane A(2) synthase inhibitor ozagrel blocked the effect of isoprostanes. The isoprostane 8-iso-PGA(2) degraded into 2 biologically active derivatives in vitro, which also inhibited EC tube formation via the TBXA2R. Moreover, short hairpin RNA-mediated knockdown of the TBXA2R antagonized isoprostane-induced effects. In addition, Rho kinase inhibitor Y-27632 reversed the inhibitory effect of isoprostanes and the thromboxane A(2) mimetic U-46619 on EC migration and tube formation. Finally, the various isoprostanes exerted a synergistic inhibitory effect on EC tube formation. We demonstrate for the first time that isoprostanes inhibit angiogenesis via activation of the TBXA2R. By this mechanism, isoprostanes may contribute directly to exacerbation of coronary heart disease and to capillary rarefaction in disease states of increased oxidative stress.
- Subjects :
- Vascular Endothelial Growth Factor A
Neovascularization, Physiologic
Angiogenesis Inhibitors
Apoptosis
Chick Embryo
Isoprostanes
Dinoprost
Chorioallantoic Membrane
Dinoprostone
Receptors, Thromboxane A2, Prostaglandin H2
Dioxanes
Tissue Culture Techniques
Mice
Cell Movement
Stress Fibers
Animals
Humans
Phosphorylation
RNA, Small Interfering
Extracellular Signal-Regulated MAP Kinases
Cells, Cultured
Prostaglandins A
Endothelial Cells
Bridged Bicyclo Compounds, Heterocyclic
Coronary Vessels
Actins
Oxidative Stress
Hydrazines
Sulfonylurea Compounds
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
Focal Adhesion Kinase 1
Fatty Acids, Unsaturated
RNA Interference
Proto-Oncogene Proteins c-akt
Subjects
Details
- ISSN :
- 15244571
- Volume :
- 103
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Circulation research
- Accession number :
- edsair.pmid..........c454f82d567aee28d058660998cb21f5