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.
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.
Benndorf
Ralf A
RA
Clinical Pharmacology Unit, Department of Pharmacology, University Hospital Hamburg, Hamburg, Germany. benndorf@uke.uni-hamburg.de
Schwedhelm
Edzard
E
Gnann
Anke
A
Taheri
Raihana
R
Kom
Ghainsom
G
Didié
Michael
M
Steenpass
Anna
A
Ergün
Süleyman
S
Böger
Rainer H
RH
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000199:Actins / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000378:metabolism; D004146:Dioxanes / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005231:Fatty Acids, Unsaturated; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D028421:Isoprostanes / Q000378:metabolism*; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D018384:Oxidative Stress; D010766:Phosphorylation; D011454:Prostaglandins A / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D022502:Stress Fibers / Q000378:metabolism; D013453:Sulfonylurea Compounds / Q000494:pharmacology; D046509:Tissue Culture Techniques; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
C117466:8-isoprostaglandin A2; D000199:Actins; D020533:Angiogenesis Inhibitors; C434802:BM 567; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004146:Dioxanes; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D028421:Isoprostanes; D011454:Prostaglandins A; D034741:RNA, Small Interfering; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013453:Sulfonylurea Compounds; D042461:Vascular Endothelial Growth Factor A; C057498:ICI 192605; C075750:8-epi-prostaglandin F2alpha; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; D015237:Dinoprost; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D015232:Dinoprostone; C011987:8-isoprostaglandin E2