Aberrant angiogenesis is a hallmark of cardiovascular and retinal neovascular disease. The STAT3 pathway represents a potential pharmacological target for those diseases due to its impact on angiogenesis. Surprisingly some STAT3 activators including the IL6 cytokine member oncostatin M (OSM) enhance angiogenesis whereas others like ciliary neurotropic factor (CNTF) reduce it. This study aims to clarify those conflicting effects. In contrast to the antiangiogenic cytokine CNTF, the proangiogenic OSM was able to activate intracellular signaling pathways beyond STAT3 including ERK and AKT. These differences translated into transcriptomic and metabolic shifts. siRNA mediated STAT3 knockdown experiments showed a decrease in VEGF-induced endothelial migration and sprouting while enhancing OSMs proangiogenic drive and switching CNTF's antiangiogenic to a proangiogenic response. These effects correlated with a transcriptomic shift representing enhanced STAT1 and ERK activity following STAT3 knockdown including a compensatory prolonged pSTAT1 activity. In conclusion, the angiogenic effect of STAT3 seems to be determined by cytokine-induced STAT3 specificity and simultaneous activity of other intracellular signaling pathways while the STAT3 pathway, predominantly recognized for its proangiogenic phenotypes, reveals novel antiangiogenic potential.
STAT3 signaling induced by IL-6 family cytokines modulates angiogenesis
- Award Group:
- Funder(s): Deutsche Forschungsgemeinschaft
- Award Id(s): Bu3135/3-1
- Funder(s):
- Award Group:
- Funder(s): Retinologische Gesellschaft
- Award Id(s): Dr. Werner-Jackstadt-Nachwuchspreis
- Funder(s):
- Award Group:
- Funder(s): Medizinische Fakultat der Albert-Ludwigs-Universitat Freiburg
- Award Id(s): Berta-Ottenstein-Program for Clinician Scientists and Advanced Clinician Scientists
- Funder(s):
- Award Group:
- Funder(s): Deutsche Forschungsgemeinschaft
- Award Id(s): GRK 2606
- Funder(s):
- Award Group:
- Funder(s): European Research Council
- Award Id(s): 337689
- Funder(s):
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- Accepted Manuscript 02 December 2022
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Julian Rapp, Malte Jung, Rhena F. U. Klar, Julian Wolf, Jakob Arnold, Oliver Gorka, Olaf Groß, Clemens Lange, Hansjürgen Agostini, Günther Schlunck, Felicitas Bucher; STAT3 signaling induced by IL-6 family cytokines modulates angiogenesis. J Cell Sci 2022; jcs.260182. doi: https://doi.org/10.1242/jcs.260182
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