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.

Sphingosine Kinase 1: A Potential Therapeutic Target in Pulmonary Arterial Hypertension?

“…In this regard, chronic treatment with Ang-II increased SphK1 mRNA expression in thoracic and abdominal aorta and mesenteric arteries of mice and increased SphK1 protein expression was detected in aorta and mesenteric artery homogenates [6]. In addition, S1P levels were increased in the plasma of Ang-II-treated WT but not Sphk1…”

“…mice [6]. Of relevance, Sphk1 −/− mice developed significantly less severe Ang II-induced hypertension and cardiac hypertrophy compared to WT mice, suggesting a role for SphK1…”

“…In addition, SphK1 and S1P are linked with signaling networks that involve gene products that are significantly up-regulated in human PAH, such as the therapeutic intervention in PAH. However, targeting SphK1 might also enhance endothelial dysfunction [6], thereby potentially limiting effectiveness of SphK1 inhibitors in reducing vascular smooth muscle contractility/remodeling and blood pressure in humans. A plausible reason for this might be that SphK1 inhibitors reduce the levels of vasorelaxants released from the endothelium that function to oppose vasoconstriction/vascular remodeling.…”

Oxidative Stress, Inflammation, and Vascular Aging in Hypertension

“…This is important because it seems to modulate NO release, Nox activity, vascular contraction, and inflammation. 95 All of these are essential in accelerated vascular aging in hypertension.…”

“…Although osteoprotegerin can affect vascular function, its cardiac effects seem to be direct and independent of effects on the vasculature. 94 Recent vascular transcriptomic analysis has shown that the SPHK1 gene (sphingosine phosphate kinase 1) involved in sphingosine-1-phosphate generation is highly affected in hypertensive vasculature in response to angiotensin II 95 . This is important because it seems to modulate NO release, Nox activity, vascular contraction, and inflammation.…”