title: Vascular transcriptome profiling identifies Sphingosine kinase 1 as a modulator of angiotensin II-induced vascular dysfunction.
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.
authors.affiliation: Department of Internal and Agricultural Medicine, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Siedlinski
authors.affiliation: Department of Internal and Agricultural Medicine, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland.|British Heart Foundation Centre for Excellence, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, UK.
authors.forename: Ryszard
authors.initials: R
authors.lastname: Nosalski
authors.affiliation: Department of Internal and Agricultural Medicine, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Szczepaniak
authors.affiliation: Centre for Medical Genomics-OMICRON, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Agnieszka H
authors.initials: AH
authors.lastname: Ludwig-Gałęzowska
authors.affiliation: Department of Internal and Agricultural Medicine, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland.|British Heart Foundation Centre for Excellence, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, UK.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Mikołajczyk
authors.affiliation: Department of Internal and Agricultural Medicine, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Filip
authors.affiliation: Department of Internal and Agricultural Medicine, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Osmenda
authors.affiliation: Department of Internal and Agricultural Medicine, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Wilk
authors.affiliation: Department of Internal and Agricultural Medicine, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Nowak
authors.affiliation: Centre for Medical Genomics-OMICRON, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Wołkow
authors.affiliation: Department of Internal and Agricultural Medicine, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland.|British Heart Foundation Centre for Excellence, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, UK.
authors.forename: Tomasz J
authors.initials: TJ
authors.lastname: Guzik
mesh_terms: D000784:Aortic Dissection / Q000139:chemically induced* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000804:Angiotensin II / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D020869:Gene Expression Profiling; D006973:Hypertension / Q000139:chemically induced* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D000099157:Sphingosine Kinase
chemical_list: D000804:Angiotensin II; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase