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, Joost J. Oppenheim

Research output: Contribution to journalArticle

144 Scopus citations

Abstract

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-1α 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 PGE 2 is a mediator of VEGF- and bFGF-induced CXCR4-dependent neovessel assembly in vivo and show that angiogenic effects of PGE2 require CXCR4 expression.

Original languageEnglish (US)
Pages (from-to)1966-1977
Number of pages12
JournalBlood
Volume102
Issue number6
DOIs
StatePublished - Sep 15 2003
Externally publishedYes

ASJC Scopus subject areas

  • Hematology

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    Salcedo, R., Zhang, X., Young, H. A., Michael, N., Wasserman, K., Ma, W. H., Martins-Green, M., Murphy, W. J., & Oppenheim, J. J. (2003). Angiogenic effects of prostaglandin E2 are mediated by up-regulation of CXCR4 on human microvascular endothelial cells. Blood, 102(6), 1966-1977. https://doi.org/10.1182/blood-2002-11-3400