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Aging differentially modulates the Wnt pro-survival signalling pathways in vascular smooth muscle cells.

ABSTRACT: We previously reported pro-survival effects of Wnt3a and Wnt5a proteins in vascular smooth muscle cells (VSMCs). Wnt5a achieved this through induction of Wnt1-inducible signalling pathway protein-1 (WISP-1) consequent to ?-catenin/CREB-dependent, TCF-independent, signalling. However, we found that as atherosclerosis advances, although Wnt5a protein was increased, WISP-1 was reduced. We hypothesized this disconnect could be due to aging. In this study, we elucidate the mechanism underlying Wnt3a pro-survival signalling and demonstrate the differential effect of age on Wnt3a- and Wnt5a-mediated survival. We show Wnt3a protein was expressed in human atherosclerotic coronary arteries and co-located with macrophages and VSMCs. Meanwhile, Wnt3a stimulation of primary mouse VSMCs increased ?-catenin nuclear translocation and TCF, but not CREB, activation. Wnt3a increased mRNA expression of the pro-survival factor WISP-2 in a TCF-dependent manner. Functionally, ?-catenin/TCF inhibition or WISP-2 neutralization significantly impaired Wnt3a-mediated VSMC survival. WISP-2 was upregulated in human atherosclerosis and partly co-localized with Wnt3a. The pro-survival action of Wnt3a was effective in VSMCs from young (2 month) and old (18-20 month) mice, whereas Wnt5a-mediated rescue was impaired with age. Further investigation revealed that although Wnt5a induced ?-catenin nuclear translocation in VSMCs from both ages, CREB phosphorylation and WISP-1 upregulation did not occur in old VSMCs. Unlike Wnt5a, pro-survival Wnt3a signalling involves ?-catenin/TCF and WISP-2. While Wnt3a-mediated survival was unchanged with age, Wnt5a-mediated survival was lost due to impaired CREB activation and WISP-1 regulation. Greater understanding of the effect of age on Wnt signalling may identify targets to promote VSMC survival in elderly patients with atherosclerosis.

SUBMITTER: Brown BA

PROVIDER: S-EPMC6351844 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Aging differentially modulates the Wnt pro-survival signalling pathways in vascular smooth muscle cells.

Brown Bethan A BA Connolly Georgia M GM Mill Carina E J CEJ Williams Helen H Angelini Gianni D GD Johnson Jason L JL George Sarah J SJ

Aging cell 20181212 1

We previously reported pro-survival effects of Wnt3a and Wnt5a proteins in vascular smooth muscle cells (VSMCs). Wnt5a achieved this through induction of Wnt1-inducible signalling pathway protein-1 (WISP-1) consequent to β-catenin/CREB-dependent, TCF-independent, signalling. However, we found that as atherosclerosis advances, although Wnt5a protein was increased, WISP-1 was reduced. We hypothesized this disconnect could be due to aging. In this study, we elucidate the mechanism underlying Wnt3a ...[more]

PMID: 30548452

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Project description:ObjectiveInflammation and its resolution are central to vascular injury and repair. Maresins comprise a new family of bioactive lipid mediators synthesized from docosahexaenoic acid, an ω-3 polyunsaturated fatty acid. They have been found to exert anti-inflammatory and pro-resolving responses in macrophages, neutrophils and bronchial epithelial cells and impart beneficial actions in murine models of peritonitis and colitis. We investigated the impact of maresin-1 (MaR1) on tumor necrosis factor alpha (TNF-α) induced inflammatory responses in human vascular endothelial (EC) and smooth muscle cells (VSMC).MethodsPrimary cultures of human saphenous vein EC and VSMC were employed. We tested the naturally occurring MaR1 as modulator of TNF-α effects, with examination of monocyte adhesion, oxidant stress, and intracellular inflammatory signaling pathways.ResultsMaR1 attenuated TNF-α induced monocyte adhesion and reactive oxygen species (ROS) generation in both EC and VSMC, associated with down-regulated expression (cell surface) of the adhesion molecule E-selectin (in EC) and NADPH-oxidases (NOX4, NOX1, NOX2). MaR1 attenuated TNF-α induced release of pro-inflammatory mediators by EC and VSMC. MaR1 caused an attenuation of TNF-α induced NF-κB activation in both cell types associated with inhibition of I-κ Kinase (IKK) phosphorylation, IκB-α degradation and nuclear translocation of the NF- κB p65 subunit. MaR1 also caused a time-dependent increase in intracellular cyclic AMP (cAMP) in both naive and TNF-α stimulated VSMC and EC.ConclusionsMaR1 has broad anti-inflammatory actions on EC and VSMC, which may be partly mediated through up-regulation of cAMP and down-regulation of the transcription factor NF-κB. The results suggest that the pro-resolving lipid mediator MaR1 exerts homeostatic actions on vascular cells that counteract pro-inflammatory signals. These findings may have direct relevance for acute and chronic states of vascular inflammation.

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Aging differentially modulates the Wnt pro-survival signalling pathways in vascular smooth muscle cells.

Publications

Aging differentially modulates the Wnt pro-survival signalling pathways in vascular smooth muscle cells.

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