Siedlinski, M. et al. (2017) Vascular transcriptome profiling identifies Sphingosine kinase 1 as a modulator of angiotensin II-induced vascular dysfunction. Scientific Reports, 7, 44131. (doi: 10.1038/srep44131) (PMID:28276483) (PMCID:PMC5343497)
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Abstract
Vascular dysfunction is an important phenomenon in hypertension. We hypothesized that angiotensin II (AngII) affects transcriptome in the vasculature in a region-specific manner, which may help to identify genes related to vascular dysfunction in AngII-induced hypertension. Mesenteric artery and aortic transcriptome was profiled using Illumina WG-6v2.0 chip in control and AngII infused (490 ng/kg/min) hypertensive mice. Gene set enrichment and leading edge analyses identified Sphingosine kinase 1 (Sphk1) in the highest number of pathways affected by AngII. Sphk1 mRNA, protein and activity were up-regulated in the hypertensive vasculature. Chronic sphingosine-1-phosphate (S1P) infusion resulted in a development of significantly increased vasoconstriction and endothelial dysfunction. AngII-induced hypertension was blunted in Sphk1(-/-) mice (systolic BP 167 ± 4.2 vs. 180 ± 3.3 mmHg, p < 0.05), which was associated with decreased aortic and mesenteric vasoconstriction in hypertensive Sphk1(-/-) mice. Pharmacological inhibition of S1P synthesis reduced vasoconstriction of mesenteric arteries. While Sphk1 is important in mediating vasoconstriction in hypertension, Sphk1(-/-) mice were characterized by enhanced endothelial dysfunction, suggesting a local protective role of Sphk1 in the endothelium. S1P serum level in humans was correlated with endothelial function (arterial tonometry). Thus, vascular transcriptome analysis shows that S1P pathway is critical in the regulation of vascular function in AngII-induced hypertension, although Sphk1 may have opposing roles in the regulation of vasoconstriction and endothelium-dependent vasorelaxation.
| Item Type: | Articles |
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| Additional Information: | Acknowledgements: This work was supported by the National Science Centre grant (decision no. DEC-2012/07/D/NZ4/00644 to MS) and International Senior Research Fellowship from the Wellcome Trust (to TJG), Foundation for Polish Science Welcome Grant (FNP/2009/Welcome02) and BHF Centre for Research Excellence (RE/13/5/30177). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Nosalski, Dr Ryszard and Mikolajczyk, Dr Tomasz and Guzik, Professor Tomasz |
| Authors: | Siedlinski, M., Nosalski, R., Szczepaniak, P., Ludwig-Gałęzowska, A. H., Mikolajczyk, T., Filip, M., Osmenda, G., Wilk, G., Nowak, M., Wołkow, P., and Guzik, T. J. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
| Journal Name: | Scientific Reports |
| Publisher: | Nature Research |
| ISSN: | 2045-2322 |
| ISSN (Online): | 2045-2322 |
| Copyright Holders: | Copyright © 2017 The Authors |
| First Published: | First published in Scientific Reports 7:44131 |
| Publisher Policy: | Reproduced under a creative commons license |
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