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(Circulation Research. 2000;87:739.)
© 2000 American Heart Association, Inc.

Molecular Medicine

Reversal of Angiogenesis In Vitro, Induction of Apoptosis, and Inhibition of Akt Phosphorylation in Endothelial Cells by Thromboxane A₂

Yunling Gao¹, Ryoji Yokota¹, Shaoqing Tang, Anthony W. Ashton, J. Anthony Ware

From the Departments of Medicine (Cardiovascular Division) (Y.G., R.Y., S.T., A.W.A., J.A.W.) and Molecular Pharmacology (J.A.W.), Albert Einstein College of Medicine of Yeshiva University, Bronx, NY. Current address for R.Y. is Department of Cardiology, Nara Hospital, Kinki University School of Medicine, Ikoma City, Nara, Japan.

Correspondence to J. Anthony Ware, MD, Cardiovascular Division, Department of Medicine, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Ave, Bronx, NY 10461. E-mail jaware{at}aecom.yu.edu\\ © 2000 American Heart Association, Inc.

Abstract—Thromboxane A₂ (TxA₂) causes platelet aggregation, vasoconstriction, and inhibition of endothelial cell (EC) migration and prevents vascular tube formation via its specific receptors (TP), of which there are two isoforms (TP and TPß), both expressed in human ECs. In this study, we demonstrate that the TxA₂ mimetic IBOP increases apoptosis of human ECs and inhibits the phosphorylation of Akt kinase, an intracellular mediator required for cell survival. Treatment with IBOP destroyed EC networks formed on a basement membrane matrix in vitro. To distinguish the role of the TP isoforms, each isoform was expressed in TP-null ECs to create TP and TPß ECs. IBOP induced apoptosis and inhibited phosphorylation of Akt kinase in both TP and TPß. IBOP increased cAMP levels in TP but not in TPß. Apoptosis induced by IBOP in TP was not affected by either the adenylyl cyclase activator forskolin or the protein kinase A inhibitor 14-22 amide or H-89, whereas that in TPß was suppressed by forskolin and enhanced by the protein kinase A inhibitor 14-22 amide or H-89, suggesting that the TP isoforms differ in their signal pathways in mediating apoptosis. In conclusion, apoptosis may be the mechanism by which TxA₂-mediated destruction of vascular structures in ECs occurs; although both TP isoforms induce apoptosis, possibly via inhibiting Akt phosphorylation, the signaling differs in each isoform, in that activation of the adenylyl cyclase pathway prevents apoptosis caused by TPß, but not by TP, stimulation.

Key Words: thromboxane A₂ • endothelial cells • apoptosis • Akt kinase • cAMP

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