Synergy between Sphingosine 1-Phosphate and Lipopolysaccharide Signaling Promotes an Inflammatory, Angiogenic and Osteogenic Response in Human Aortic Valve Interstitial Cells

Fernández‐Pisonero, Isabel; López, Javier; Onecha, Esther; Dueñas, Antonio; Maeso, Patricia; Crespo, Mariano Sánchez; Román, José Alberto San; García-Rodríguez, Carmen

doi:10.1371/journal.pone.0109081

Cited by 24 publications

(17 citation statements)

References 42 publications

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“…Examples include sphingosine-1-phosphate (immunomodulation) 35 , docosahexaenoic acid (cognitive function) 36 , carnitine (fertility) 37 , anandamide (neurological disorders) 38 , and melatonin (sleep) 39 , to name a few. However, the use of metabolomics data to characterize dysregulated metabolites of interest is gaining more attention because this approach is able to detect a wide range of small molecules at low concentrations, increasing throughput.…”

Section: Discussionmentioning

confidence: 99%

Metabolomics activity screening for identifying metabolites that modulate phenotype

et al. 2018

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Metabolomics, in which small-molecule metabolites (the metabolome) are identified and quantified, is broadly acknowledged to be the omics discipline that is closest to the phenotype1–3. Although appreciated for its role in biomarker discovery programs, metabolomics can also be used to identify metabolites that could alter a cell’s or an organism’s phenotype. Metabolomics activity screening (MAS) as described here integrates metabolomics data with metabolic pathways and systems biology information, including proteomics and transcriptomics data, to produce a set of endogenous metabolites that can be tested for functionality in altering phenotypes. A growing literature reports the use of metabolites to modulate diverse processes, such as stem cell differentiation, oligodendrocyte maturation, insulin signaling, T-cell survival and macrophage immune responses. This opens up the possibility of identifying and applying metabolites to affect phenotypes. Unlike genes or proteins, metabolites are often readily available, which means that MAS is broadly amenable to high-throughput screening of virtually any biological system.

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Section: Discussionmentioning

confidence: 99%

Metabolomics activity screening for identifying metabolites that modulate phenotype

et al. 2018

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“…Combinatory supplementation exhibited a cumulative effect, which was attenuated by FTY720 the (Figure 6c,d), suggesting that S1P contributes to Aβ42-induced NFκB signaling. S1P receptors have been found to interact with TLR4 functionally to enhance proinflammatory cytokine production in human gingival epithelial cells and lung cells (Eskan et al, 2008;Fernandez-Pisonero et al, 2014;Roviezzo et al, 2017). Aβ42 is also found binds to TLR4/TLR2/CD14 to activate microglia (Doens & Fernandez, 2014;Frank et al, 2008;Saijo, Crotti, & Glass, 2013).…”

Section: Discussionmentioning

confidence: 99%

Lipid transporter Spns2 promotes microglia pro‐inflammatory activation in response to amyloid‐beta peptide

Zhong

Jiang

Zhu

et al. 2018

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Accumulating evidence indicates that neuroinflammation contributes to the pathogenesis and exacerbation of neurodegenerative disorders, such as Alzheimer's disease (AD). Sphingosine‐1‐phosphate (S1P) is a pleiotropic bioactive lipid that regulates many pathophysiological processes including inflammation. We present evidence here that the spinster homolog 2 (Spns2), a S1P transporter, promotes microglia pro‐inflammatory activation in vitro and in vivo. Spns2 knockout (Spns2KO) in primary cultured microglia resulted in significantly reduced levels of pro‐inflammatory cytokines induced by lipopolysaccharide (LPS) and amyloid‐beta peptide 1–42 oligomers (Aβ42) when compared with littermate controls. Fingolimod (FTY720), a S1P receptor 1 (S1PR1) functional antagonist and FDA approved drug for relapsing–remitting multiple sclerosis, partially blunted Aβ42‐induced pro‐inflammatory cytokine generation, suggesting that Spns2 promotes microglia pro‐inflammatory activation through S1P‐signaling. Spns2KO significantly reduced Aβ42‐induced nuclear factor kappa B (NFκB) activity. S1P increased, while FTY720 dampened, Aβ42‐induced NFκB activity, suggesting that Spns2 activates microglia inflammation through, at least partially, NFκB pathway. Spns2KO mouse brains showed significantly reduced Aβ42‐induced microglia activation/accumulation and reduced levels of pro‐inflammatory cytokines when compared with age‐matched controls. More interestingly, Spns2KO ameliorated Aβ42‐induced working memory deficit detected by Y‐Maze. In summary, these results suggest that Spns2 promotes pro‐inflammatory polarization of microglia and may play a crucial role in AD pathogenesis.

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“…Pericytes guide vessel formation through paracrine and direct contact signaling mechanisms, several of which have been investigated in regards to valve cells. 8,9,25,30,37 Despite the evidence for a subpopulation of cells in calcified valves that have pericyte-like characteristics, 35 VIC-endothelial cell studies to date have yet to induce quantifiable pericyte-mimicking behavior.…”

Section: Discussionmentioning

confidence: 99%

Valve Interstitial Cells Act in a Pericyte Manner Promoting Angiogensis and Invasion by Valve Endothelial Cells

et al. 2016

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Neovascularization is an understudied aspect of calcific aortic valve disease (CAVD). Within diseased valves, cells along the neovessels' periphery stain for pericyte markers, but it is unclear whether valvular interstitial cells (VICs) can demonstrate a pericyte-like phenotype. This investigation examined the perivascular potential of VICs to regulate valve endothelial cell (VEC) organization and explored the role of Angiopoeitin1-Tie2 signaling in this process. Porcine VECs and VICs were fluorescently tracked and co-cultured in Matrigel over 7 days. VICs regulated early VEC network organization in a ROCK-dependent manner, then guided later VEC network contraction through chemoattraction. Unlike vascular control cells, the valve cell cultures ultimately formed invasive spheroids with 3D angiogenic-like sprouts. VECs co-cultured with VICs displayed significantly more invasion than VECs alone; with VICs generally leading and wrapping around VEC invasive sprouts. Lastly, Angiopoietin1-Tie2 signaling was found to regulate valve cell organization during VEC/VIC spheroid formation and invasion. VICs demonstrated pericyte-like behaviors toward VECs throughout sustained co-culture. The change from a vasculogenic network to an invasive sprouting spheroid suggests that both cell types undergo phenotypic changes during long-term culture in the model angiogenic environment. Valve cells organizing into spheroids and undergoing 3D invasion of Matrigel demonstrated several typical angiogenic-like phenotypes dependent on basal levels of Angiopoeitin1-Tie2 signaling and ROCK activation. These results suggest that the ectopic sustained angiogenic environment during the early stages of valve disease promotes organized activity by both VECs and VICs, contributing to neovessel formation and the progression of CAVD.

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Synergy between Sphingosine 1-Phosphate and Lipopolysaccharide Signaling Promotes an Inflammatory, Angiogenic and Osteogenic Response in Human Aortic Valve Interstitial Cells

Cited by 24 publications

References 42 publications

Metabolomics activity screening for identifying metabolites that modulate phenotype

Metabolomics activity screening for identifying metabolites that modulate phenotype

Lipid transporter Spns2 promotes microglia pro‐inflammatory activation in response to amyloid‐beta peptide

Valve Interstitial Cells Act in a Pericyte Manner Promoting Angiogensis and Invasion by Valve Endothelial Cells

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