Vascular transcriptome profiling identifies Sphingosine kinase 1 as a modulator of angiotensin II-induced vascular dysfunction

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
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, Mr 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 > Institute of Cardiovascular and Medical Sciences
Journal Name:Scientific Reports
Publisher:Nature Publishing Group
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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
617771BHF centre of excellenceRhian TouyzBritish Heart Foundation (BHF)RE/13/5/30177RI CARDIOVASCULAR & MEDICAL SCIENCES