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Lithium upregulates vascular endothelial growth factor in brain endothelial cells and astrocytes.
Stroke. 2009 Feb; 40(2):652-5.S

Abstract

BACKGROUND AND PURPOSE

We recently reported that delayed lithium therapy can improve stroke recovery in rats by augmenting neurovascular remodeling. We tested the hypothesis that lithium can promote the expression of growth factors in brain endothelial cells and astrocytes.

METHODS

Human brain microvascular endothelial cells and primary rat cortical astrocytes were exposed to lithium chloride in serum-free medium. We examined 2 representative growth factors: brain-derived neurotrophic factor and vascular endothelial growth factor (VEGF). Cell lysates were collected for Western blot analysis. Conditioned media was analyzed with enzyme-linked immunosorbent assay. SB-216763 and LY294002 were used to assess the roles of the glycogen synthase kinase-3beta (GSK-3beta) and PI3-K signaling in the lithium-induced responses.

RESULTS

No consistent responses were observed for brain-derived neurotrophic factor. However, lithium (0.2 to 20 mmol/L) increased the phosphorylation of GSK-3beta and promoted VEGF secretion in a concentration-dependent manner in both endothelial and astrocyte cells. For endothelial cells, the potent GSK-3beta inhibitor SB-216763 upregulated VEGF, whereas inhibition of PI3-K with LY294002 suppressed lithium-induced responses in both phospho-GSK-3beta and VEGF. In contrast, neither inhibition of GSK-3beta nor inhibition of PI3-K had any detectable effects on VEGF levels in astrocytes.

CONCLUSIONS

Lithium promotes VEGF expression through PI3-K/GSK-3beta-dependent and -independent pathways in brain endothelium and astrocytes, respectively. This growth factor signaling mechanism may contribute to lithium's reported ability to promote neurovascular remodeling after stroke.

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Authors+Show Affiliations

Guo S
Department of Radiology and Neurology, Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. Lo@helix.mgh.harvard.edu
Arai K
No affiliation info available
Stins MF
No affiliation info available
Chuang DM
No affiliation info available
Lo EH
No affiliation info available

MeSH

AstrocytesBlotting, WesternBrainBrain ChemistryBrain-Derived Neurotrophic FactorChromonesDose-Response Relationship, DrugEndothelial CellsEnzyme InhibitorsGlycogen Synthase Kinase 3HumansIndolesLithium ChlorideMaleimidesMorpholinesUp-RegulationVascular Endothelial Growth Factor A

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

18974377

Citation

Guo, Shuzhen, et al. "Lithium Upregulates Vascular Endothelial Growth Factor in Brain Endothelial Cells and Astrocytes." Stroke, vol. 40, no. 2, 2009, pp. 652-5.
Guo S, Arai K, Stins MF, et al. Lithium upregulates vascular endothelial growth factor in brain endothelial cells and astrocytes. Stroke. 2009;40(2):652-5.
Guo, S., Arai, K., Stins, M. F., Chuang, D. M., & Lo, E. H. (2009). Lithium upregulates vascular endothelial growth factor in brain endothelial cells and astrocytes. Stroke, 40(2), 652-5. https://doi.org/10.1161/STROKEAHA.108.524504
Guo S, et al. Lithium Upregulates Vascular Endothelial Growth Factor in Brain Endothelial Cells and Astrocytes. Stroke. 2009;40(2):652-5. PubMed PMID: 18974377.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lithium upregulates vascular endothelial growth factor in brain endothelial cells and astrocytes. AU - Guo,Shuzhen, AU - Arai,Ken, AU - Stins,Monique F, AU - Chuang,De-Maw, AU - Lo,Eng H, Y1 - 2008/10/30/ PY - 2008/11/1/pubmed PY - 2009/2/21/medline PY - 2008/11/1/entrez SP - 652 EP - 5 JF - Stroke JO - Stroke VL - 40 IS - 2 N2 - BACKGROUND AND PURPOSE: We recently reported that delayed lithium therapy can improve stroke recovery in rats by augmenting neurovascular remodeling. We tested the hypothesis that lithium can promote the expression of growth factors in brain endothelial cells and astrocytes. METHODS: Human brain microvascular endothelial cells and primary rat cortical astrocytes were exposed to lithium chloride in serum-free medium. We examined 2 representative growth factors: brain-derived neurotrophic factor and vascular endothelial growth factor (VEGF). Cell lysates were collected for Western blot analysis. Conditioned media was analyzed with enzyme-linked immunosorbent assay. SB-216763 and LY294002 were used to assess the roles of the glycogen synthase kinase-3beta (GSK-3beta) and PI3-K signaling in the lithium-induced responses. RESULTS: No consistent responses were observed for brain-derived neurotrophic factor. However, lithium (0.2 to 20 mmol/L) increased the phosphorylation of GSK-3beta and promoted VEGF secretion in a concentration-dependent manner in both endothelial and astrocyte cells. For endothelial cells, the potent GSK-3beta inhibitor SB-216763 upregulated VEGF, whereas inhibition of PI3-K with LY294002 suppressed lithium-induced responses in both phospho-GSK-3beta and VEGF. In contrast, neither inhibition of GSK-3beta nor inhibition of PI3-K had any detectable effects on VEGF levels in astrocytes. CONCLUSIONS: Lithium promotes VEGF expression through PI3-K/GSK-3beta-dependent and -independent pathways in brain endothelium and astrocytes, respectively. This growth factor signaling mechanism may contribute to lithium's reported ability to promote neurovascular remodeling after stroke. SN - 1524-4628 UR - https://www.unboundmedicine.com/medline/citation/18974377/Lithium_upregulates_vascular_endothelial_growth_factor_in_brain_endothelial_cells_and_astrocytes_ L2 - https://www.ahajournals.org/doi/10.1161/STROKEAHA.108.524504?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -