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J. Biol. Chem., Vol. 279, Issue 13, 12171-12180, March 26, 2004

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Hypoxic Regulation of Angiopoietin-2 Expression in Endothelial Cells^*

Paola Pichiule, Juan C. Chavez, and Joseph C. LaManna

From the Department of Anatomy, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106

Exposure of endothelial cells to hypoxia-induced angiopoietin-2 (Ang2) expression. The increase in Ang2 mRNA levels occurred by transcriptional regulation and by post-transcriptional increase in mRNA stability. Induction of Ang2 mRNA resulted in an increase of intracellular and secreted Ang2 protein levels. Since the transcriptional regulation of several genes involved in angiogenesis during hypoxia is mediated by hypoxia-inducible factor-1 (HIF-1), it was conceivable that Ang2 expression might be regulated by the same oxygen-dependent mechanism. However, our data showed that pharmacological HIF inducers, CoCl₂ and DFO, did not affect Ang2 expression. Moreover, HIF-1-deficient hepatoma cell (Hepa1 c4) and its wild-type counterpart (Hepa1 c1c4) up-regulates Ang2 during hypoxia. These results indicated that hypoxia-driven Ang2 expression may be independent of the HIF pathway. Using neutralizing VEGF antibody or pharmacological inhibitors of VEGF receptors, we showed that hypoxia-induced VEGF participates but could not account completely for Ang2 expression during hypoxia. In addition, hypoxia elicited an increase of cyclooxygenase-2 (COX-2) expression and a parallel increase in prostanglandin E₂ (PGE₂) and prostacyclin (PGI₂) production. COX-2 inhibitors decreased the hypoxic induction of Ang2 and the hypoxic induction of PGE₂ and PGI₂ in a dose-dependent manner. Similarly, COX-2 but not COX-1 antisense treatment decreased hypoxic induction of Ang2 expression, and this effect was reversed by exogenous PGE₂. Finally, exogenous PGE₂ and PGI₂ were able to stimulate Ang2 under normoxic conditions. These findings suggest that COX-2-dependent prostanoids may play an important role in the regulation of hypoxia-induced Ang2 expression.

Received for publication, May 16, 2003 , and in revised form, December 12, 2003.

^* This work was supported by NINDS, National Institutes of Health Grants NS-38632 and NS-37111. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence may be addressed: Burke Medical Research Institute, White Plains, NY 10605. E-mail: jchavez{at}burke.org. To whom correspondence may be addressed: Dept. of Anatomy, Case Western Reserve University, School of Medicine, 10900 Euclid Ave., Cleveland OH 44106-4938. Tel.: 216-368-1112; Fax: 216-368-1144; E-mail: JCL4{at}po.cwru.edu.

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