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PKC? activation promotes FGF-2 exocytosis and induces endothelial cell proliferation and sprouting.

ABSTRACT: Protein kinase C epsilon (PKC?) activation controls fibroblast growth factor-2 (FGF-2) angiogenic signaling. Here, we examined the effect of activating PKC? on FGF-2 dependent vascular growth and endothelial activation. ??RACK, a selective PKC? 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 PKC? in endothelial cells, and promotes FGF-2 export and FGF-2/FGFR1 signaling activation. ??RACK 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 ??RACK activity. In vivo ??RACK does not induce angiogenesis in the rabbit cornea. However, ??RACK 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 PKC? stimulation promotes angiogenesis and modulates VEGF activity, by inducing FGF-2 release and autocrine signaling.

SUBMITTER: Monti M

PROVIDER: S-EPMC3812807 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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PKCε activation promotes FGF-2 exocytosis and induces endothelial cell proliferation and sprouting.

Monti Martina M Donnini Sandra S Morbidelli Lucia L Giachetti Antonio A Mochly-Rosen Daria D Mignatti Paolo P Ziche Marina M

Journal of molecular and cellular cardiology 20130720

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 FG ...[more]

PMID: 23880610

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Project description:Angiogenesis, the growth of capillaries from preexisting blood vessels, has been extensively studied experimentally over the past thirty years. Molecular insights from these studies have lead to therapies for cancer, macular degeneration and ischemia. In parallel, mathematical models of angiogenesis have helped characterize a broader view of capillary network formation and have suggested new directions for experimental pursuit. We developed a computational model that bridges the gap between these two perspectives, and addresses a remaining question in angiogenic sprouting: how do the processes of endothelial cell elongation, migration and proliferation contribute to vessel formation?We present a multiscale systems model that closely simulates the mechanisms underlying sprouting at the onset of angiogenesis. Designed by agent-based programming, the model uses logical rules to guide the behavior of individual endothelial cells and segments of cells. The activation, proliferation, and movement of these cells lead to capillary growth in three dimensions. By this means, a novel capillary network emerges out of combinatorially complex interactions of single cells. Rules and parameter ranges are based on literature data on endothelial cell behavior in vitro. The model is designed generally, and will subsequently be applied to represent species-specific, tissue-specific in vitro and in vivo conditions. Initial results predict tip cell activation, stalk cell development and sprout formation as a function of local vascular endothelial growth factor concentrations and the Delta-like 4 Notch ligand, as it might occur in a three-dimensional in vitro setting. Results demonstrate the differential effects of ligand concentrations, cell movement and proliferation on sprouting and directional persistence.This systems biology model offers a paradigm closely related to biological phenomena and highlights previously unexplored interactions of cell elongation, migration and proliferation as a function of ligand concentration, giving insight into key cellular mechanisms driving angiogenesis.

Dataset Information

PKC? activation promotes FGF-2 exocytosis and induces endothelial cell proliferation and sprouting.

Publications

PKCε activation promotes FGF-2 exocytosis and induces endothelial cell proliferation and sprouting.

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