title: PKCε activation promotes FGF-2 exocytosis and induces endothelial cell proliferation and sprouting.
abstract: Protein kinase C epsilon (PKCε) activation controls fibroblast growth factor-2 (FGF-2) angiogenic signaling. Here, we examined the effect of activating PKCε on FGF-2 dependent vascular growth and endothelial activation. ψεRACK, a selective PKCε agonist induces pro-angiogenic responses in endothelial cells, including formation of capillary like structures and cell growth. These effects are mediated by FGF-2 export to the cell membrane, as documented by biotinylation and immunofluorescence, and FGF-2/FGFR1 signaling activation, as attested by ERK1/2-STAT-3 phosphorylation and de novo FGF-2 synthesis. Similarly, vascular endothelial growth factor (VEGF) activates PKCε in endothelial cells, and promotes FGF-2 export and FGF-2/FGFR1 signaling activation. ψεRACK fails to elicit responses in FGF-2(-/-) endothelial cells, and in cells pretreated with methylamine (MeNH2), an exocytosis inhibitor, indicating that both intracellular FGF-2 and its export toward the membrane are required for the ψεRACK activity. In vivo ψεRACK does not induce angiogenesis in the rabbit cornea. However, ψεRACK promotes VEGF angiogenic responses, an effect sustained by endothelial FGF-2 release and synthesis, since anti-FGF-2 antibody strongly attenuates VEGF responses. The results demonstrate that PKCε stimulation promotes angiogenesis and modulates VEGF activity, by inducing FGF-2 release and autocrine signaling.
authors.affiliation: Department of Life Sciences, University of Siena, 53100 Siena, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Monti
authors.forename: Sandra
authors.initials: S
authors.lastname: Donnini
authors.forename: Lucia
authors.initials: L
authors.lastname: Morbidelli
authors.forename: Antonio
authors.initials: A
authors.lastname: Giachetti
authors.forename: Daria
authors.initials: D
authors.lastname: Mochly-Rosen
authors.forename: Paolo
authors.initials: P
authors.lastname: Mignatti
authors.forename: Marina
authors.initials: M
authors.lastname: Ziche
mesh_terms: D000818:Animals; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation; D005089:Exocytosis / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D021381:Protein Transport; D011817:Rabbits; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology
chemical_list: C477271:His-Asp-Ala-Pro-Ile-Gly-Tyr-Asp; D009842:Oligopeptides; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D051744:Protein Kinase C-epsilon
keywords: Angiogenesis; Endothelial cells; Exocytosis; Fibroblast growth factor-2; Protein kinase C ε; Vascular endothelial growth factor