STAT3 signaling induced by IL-6 family cytokines modulates angiogenesis

Abstract

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.

HSPs/STAT3 Interplay Sustains DDR and Promotes Cytokine Release by Primary Effusion Lymphoma Cells

“…As shown in Figure 3 A, STAT3 phosphorylation was reduced by treatment with inHSP27 (J2), inHSP70 (PES) and inHSP90 (17AAG), in both BC3 and BCBL1 cells. As this transcription factor is strongly interconnected with the release of cytokines, such as IL-6, IL-10 and VEGF [ 19 , 20 ], that contribute to PEL cells growth [ 5 ], we performed a Luminex assay to evaluate their production by PEL cells undergoing treatment with HSP27, HSP70 and HSP90 inhibitors. Although the HSP90 inhibitor was more effective, all three HSP inhibitors impaired the release of these cytokines ( Figure 3 B), an effect that could contribute to their cytotoxic effects against PEL.…”

Oncostatin M Reduces Pathological Neovascularization in the Retina Through Müller Cell Activation

“…The spheroid sprouting assay was performed as previously published. 17 In brief, HUVECs in EGM-2 supplemented with 0.25% carboxymethylcellulose (#M0512; Sigma-Aldrich) formed hanging drops overnight. Spheroids were seeded in a three-dimensional collagen matrix consisting of 50% rat tail collagen (#354236; Corning, Corning, NY, USA), 48% EBM containing 0.25% carboxymethylcellulose, and 2% FBS.…”

“…In contrast to CNTF, it is known for its strong pro-angiogenic effects on vascular endothelial cells despite sharing crucial receptor and signaling components including gp130 and STAT3. 15 – 17 Our own in vitro studies revealed that OSM and CNTF induced similar transcriptomic changes in vascular endothelial cells, but only OSM strongly enhanced their metabolic activity to fuel endothelial cell proliferation, migration, and sprouting. 17 In humans, OSM binds to a heterodimeric signaling complex of gp130 and OSM receptor-beta (OSMRβ) or leukemia inhibiting factor receptor (LIFR), 18 whereas for mice murine OSM only signals through its specific receptor and not LIFR.…”

“… 15 – 17 Our own in vitro studies revealed that OSM and CNTF induced similar transcriptomic changes in vascular endothelial cells, but only OSM strongly enhanced their metabolic activity to fuel endothelial cell proliferation, migration, and sprouting. 17 In humans, OSM binds to a heterodimeric signaling complex of gp130 and OSM receptor-beta (OSMRβ) or leukemia inhibiting factor receptor (LIFR), 18 whereas for mice murine OSM only signals through its specific receptor and not LIFR. 19 Next to the STAT family, particularly STAT3 but also STAT1 and STAT5, OSM activates the ERK and AKT cascades.…”

Angiogenic activity of mitochondria; beyond the sole bioenergetic organelle

“…These features show that STAT3/OPA1/P65 pathway is one of the molecular mechanisms by which mitochondria can regulate EC angiogenesis, indicating mitochondrion-targeted therapy under pathological conditions. Upon the inhibition of STAT3 using selective siRNAs, the phosphorylation of ERK and STAT1 and activation of IL-6 cytokine-related oncostatin M were activated to increase VEGF and angiogenesis potential (Rapp et al, 2023). It has been shown that the selective inhibition of SIRT1 can diminish the mitochondrial activity of ECs and thus vascular branching (Caja & Enríquez, 2017).…”