Prostaglandin E2-EP4 Receptor Promotes Endothelial Cell Migration via ERK Activation and Angiogenesis in Vivo

Prostaglandin E2 (PGE2), a major product of cyclooxygenase, exerts its functions by binding to four G protein-coupled receptors (EP1–4) and has been implicated in modulating angiogenesis. The present study examined the role of the EP4 receptor in regulating endothelial cell proliferation, migration,...

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Published inThe Journal of biological chemistry Vol. 282; no. 23; pp. 16959 - 16968
Main Authors Rao, Reena, Redha, Reyadh, Macias-Perez, Ines, Su, Yan, Hao, Chuanming, Zent, Roy, Breyer, Matthew D., Pozzi, Ambra
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 08.06.2007
American Society for Biochemistry and Molecular Biology
Subjects
Animals
Base Sequence
Blotting, Western
Cell Movement - physiology
Cell Proliferation
Cells, Cultured
Dinoprostone - physiology
DNA Primers
Enzyme Activation
Extracellular Signal-Regulated MAP Kinases - metabolism
Mice
Neovascularization, Physiologic
Receptors, Prostaglandin E - metabolism
Receptors, Prostaglandin E - physiology
Receptors, Prostaglandin E, EP4 Subtype
Reverse Transcriptase Polymerase Chain Reaction
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Summary:Prostaglandin E2 (PGE2), a major product of cyclooxygenase, exerts its functions by binding to four G protein-coupled receptors (EP1–4) and has been implicated in modulating angiogenesis. The present study examined the role of the EP4 receptor in regulating endothelial cell proliferation, migration, and tubulogenesis. Primary pulmonary microvascular endothelial cells were isolated from EP4flox/flox mice and were rendered null for the EP4 receptor with adenoCre virus. Whereas treatment with PGE2 or the EP4 selective agonists PGE1-OH and ONO-AE1–329 induced migration, tubulogenesis, ERK activation and cAMP production in control adenovirus-transduced endothelial EP4flox/flox cells, no effects were seen in adenoCre-transduced EP4flox/flox cells. The EP4 agonist-induced endothelial cell migration was inhibited by ERK, but not PKA inhibitors, defining a functional link between PGE2-induced endothelial cell migration and EP4-mediated ERK signaling. Finally, PGE2, as well as PGE1-OH and ONO-AE1–329, also promoted angiogenesis in an in vivo sponge assay providing evidence that the EP4 receptor mediates de novo vascularization in vivo.
Bibliography:ObjectType-Article-1
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content type line 23
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M701214200