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AKAP12 deficiency impairs VEGF-induced endothelial cell migration and sprouting.

ABSTRACT: AIM:Protein kinase (PK) A anchoring protein (AKAP) 12 is a scaffolding protein that anchors PKA to compartmentalize cyclic AMP signalling. This study assessed the consequences of the downregulation or deletion of AKAP12 on endothelial cell migration and angiogenesis. METHODS:The consequences of siRNA-mediated downregulation AKAP12 were studied in primary cultures of human endothelial cells as well as in endothelial cells and retinas from wild-type versus AKAP12-/- mice. Molecular interactions were investigated using a combination of immunoprecipitation and mass spectrometry. RESULTS:AKAP12 was expressed at low levels in confluent endothelial cells but its expression was increased in actively migrating cells, where it localized to lamellipodia. In the postnatal retina, AKAP12 was expressed by actively migrating tip cells at the angiogenic front, and its deletion resulted in defective extension of the vascular plexus. In migrating endothelial cells, AKAP12 was co-localized with the PKA type II-? regulatory subunit as well as multiple key regulators of actin dynamics and actin filament-based movement; including components of the Arp2/3 complex and the vasodilator-stimulated phosphoprotein (VASP). Fitting with the evidence of a physical VASP/AKAP12/PKA complex, it was possible to demonstrate that the VEGF-stimulated and PKA-dependent phosphorylation of VASP was dependent on AKAP12. Indeed, AKAP12 colocalized with phospho-Ser157 VASP at the leading edge of migrating endothelial cells. CONCLUSION:The results suggest that compartmentalized AKAP12/PKA signalling mediates VASP phosphorylation at the leading edge of migrating endothelial cells to translate angiogenic stimuli into altered actin dynamics and cell movement.

SUBMITTER: Benz PM

PROVIDER: S-EPMC6916389 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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AKAP12 deficiency impairs VEGF-induced endothelial cell migration and sprouting.

Benz Peter M PM Ding Yindi Y Stingl Heike H Loot Annemarieke E AE Zink Joana J Wittig Ilka I Popp Rüdiger R Fleming Ingrid I

Acta physiologica (Oxford, England) 20190621 1

<h4>Aim</h4>Protein kinase (PK) A anchoring protein (AKAP) 12 is a scaffolding protein that anchors PKA to compartmentalize cyclic AMP signalling. This study assessed the consequences of the downregulation or deletion of AKAP12 on endothelial cell migration and angiogenesis.<h4>Methods</h4>The consequences of siRNA-mediated downregulation AKAP12 were studied in primary cultures of human endothelial cells as well as in endothelial cells and retinas from wild-type versus AKAP12<sup>-/-</sup> mice. ...[more]

PMID: 31162891

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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

AKAP12 deficiency impairs VEGF-induced endothelial cell migration and sprouting.

Publications

AKAP12 deficiency impairs VEGF-induced endothelial cell migration and sprouting.

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