title: The syndecan-4/protein kinase Cα pathway mediates prostaglandin E2-induced extracellular regulated kinase (ERK) activation in endothelial cells and angiogenesis in vivo.
abstract: Prostaglandin E2 (PGE2) is regarded as the main mediator of inflammatory symptoms. In addition, it also plays an important role in tumor growth and angiogenesis. In this study, we examined the mechanism of PGE2-induced angiogenic response. We show that in the absence of proteoglycan syndecan-4 (Sdc4), PGE2-induced ERK activation is decreased significantly, as is endothelial cell migration and cord formation in a two-dimensional Matrigel assay. In vivo, PGE2-induced angiogenesis is reduced dramatically in Sdc4(-/-) mice. The mechanism was traced to Sdc4-dependent activation of protein kinase Cα (PKCα). Transduction of an Sdc4 S183E mutant (a cytoplasmic domain mutation that blocks Sdc4-dependent PKCα activation) into Sdc4(-/-) endothelial cells was not able to rescue the loss of PGE2-induced ERK activation, whereas a transduction with full-length Sdc4 resulted in full rescue. Furthermore, PGE2-induced angiogenesis was also reduced in PKCα(-/-) mice. Taken together, these results demonstrate that PGE2-induced activation of angiogenesis is mediated via syndecan-4-dependent activation of PKCα.
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Federico
authors.initials: F
authors.lastname: Corti
authors.forename: Federica
authors.initials: F
authors.lastname: Finetti
authors.forename: Marina
authors.initials: M
authors.lastname: Ziche
authors.forename: Michael
authors.initials: M
authors.lastname: Simons
mesh_terms: D000818:Animals; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism*; D053671:Syndecan-4 / Q000235:genetics / Q000378:metabolism*
chemical_list: C508304:SDC4 protein, human; C508306:Sdc4 protein, mouse; D053671:Syndecan-4; C496628:PRKCA protein, human; C496630:Prkca protein, mouse; D051571:Protein Kinase C-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D015232:Dinoprostone
keywords: Angiogenesis; Cell Signaling; Prostaglandins; Protein Kinase C (PKC); Proteoglycan; Syndecan 4