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(Circulation Research. 2008;103:1037.)
© 2008 American Heart Association, Inc.

Integrative Physiology

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 A₂ Receptor

A Potential Link Between Oxidative Stress and Impaired Angiogenesis

Ralf A. Benndorf^*, Edzard Schwedhelm^*, Anke Gnann, Raihana Taheri, Ghainsom Kom, Michael Didié, Anna Steenpass, Süleyman Ergün, Rainer H. Böger

From the Clinical Pharmacology Unit (R.A.B., E.S., A.G., R.T., G.K., M.D., A.S., R.H.B.), Institute of Experimental and Clinical Toxicology and Pharmacology, University Hospital Hamburg-Eppendorf; and Institute of Anatomy (S.E.), University Hospital Essen, Germany.

Correspondence to Ralf Benndorf, Clinical Pharmacology Unit, Department of Pharmacology, University Hospital Hamburg, Martinistrasse 52, Hamburg 20246, Germany. E-mail benndorf{at}uke.uni-hamburg.de

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-PGF₂, 8-iso-PGE₂, and 8-iso-PGA₂ 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 A₂ receptor (TBXA2R): the specific TBXA2R antagonists SQ-29548, BM 567, and ICI 192,605 but not the thromboxane A₂ synthase inhibitor ozagrel blocked the effect of isoprostanes. The isoprostane 8-iso-PGA₂ 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 A₂ 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.

Key Words: angiogenesis • migration • isoprostanes • thromboxane A₂ receptor • Rho kinase

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