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Prepublished online as a Blood First Edition Paper on June 5, 2003; DOI 10.1182/blood-2002-11-3400. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-11-3400v1 102/6/1966    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Salcedo, R. Articles by Oppenheim, J. J. Search for Related Content PubMed PubMed Citation Articles by Salcedo, R. Articles by Oppenheim, J. J. Related Collections Chemokines, Cytokines, and Interleukins Gene Therapy Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 September 2003, Vol. 102, No. 6, pp. 1966-1977 CHEMOKINES Angiogenic effects of prostaglandin E2 are mediated by up-regulation of CXCR4 on human microvascular endothelial cells Rosalba Salcedo, Xia Zhang, Howard A. Young, Nelson Michael, Ken Wasserman, Wei-Hong Ma, Manuela Martins-Green, William J. Murphy, and Joost J. Oppenheim From the Laboratory of Molecular Immunoregulation, Laboratory of Experimental Immunology, Cancer Center Research, National Cancer Institute (NCI), Intramural Research Support Program, Science Applications International Corporation (SAIC), Frederick, MD; Division of Retrovirology, Walter Reed Army Institute of Research, Rockville, MD; and the Department of Cell Biology and Neuroscience, University of California, Riverside. Stimulation of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) increases the expression of CXCR4 on endothelial cells, rendering these cells more responsive to stromal-derived factor 1 (SDF-1), an angiogenic CXC chemokine and unique ligand for CXCR4. Here, we show that prostaglandin E2 (PGE2) mediates the effects of bFGF and VEGF in up-regulating CXCR4 expression on human microvascular endothelial cells (HMECs). Forskolin or 3-isobutyl-1-methyl xanthine (IBMX), 2 inducers of adenylate cyclase, markedly enhanced, whereas cyclooxygenase (COX) inhibitors including aspirin, piroxicam, and NS398 markedly inhibited CXCR4 expression on HMECs. Furthermore, the ability of PGE2 to augment in vitro tubular formation in SDF-1 containing matrigel was inhibited completely by blocking CXCR4. Treatment of bFGF- or VEGF-stimulated HMECs with COX inhibitors blocked tubular formation by about 50% to 70%. Prostaglandin-induced human endothelial cell organization and subsequent vascularization can be inhibited to a greater extent by a neutralizing antibody to human CXCR4 in severe combined immunodeficient mice. Additionally, VEGF- and bFGF-induced angiogenesis in vivo was also inhibited by about 50% by NS-398 or piroxicam, and this inhibitory effect was accompanied by decreased expression of CXCR4 on murine endothelial cells. Consequently, by inducing CXCR4 expression, prostaglandin accounts for about 50% of the tubular formation in vitro and in vivo angiogenic effects of VEGF and bFGF. Moreover, augmentation of CXCR4 expression by VEGF, bFGF, and PGE2 involves stimulation of transcription factors binding to the Sp1-binding sites within the promoter region of the CXCR4 gene. These findings indicate that PGE2 is a mediator of VEGF- and bFGF-induced CXCR4-dependent neovessel assembly in vivo and show that angiogenic effects of PGE2 require CXCR4 expression. 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