Boran Katunaric1, Gopika SenthilKumar1,2,3, Mary E Schulz1,2, Nilto De Oliveira4, Julie K Freed1,2,3. 1. Department of Anesthesiology (B.K., G.S., M.E.S., J.K.F.), Medical College of Wisconsin, Milwaukee. 2. Cardiovascular Center (B.K., G.S., M.E.S., J.K.F.), Medical College of Wisconsin, Milwaukee. 3. Department of Physiology (G.S., J.K.F.), Medical College of Wisconsin, Milwaukee. 4. Department of Surgery, Division of Adult Cardiothoracic Surgery (N.D.O.), Medical College of Wisconsin, Milwaukee.
Abstract
BACKGROUND: Preclinical studies suggest that S1P (sphingosine-1-phosphate) influences blood pressure regulation primarily through NO-induced vasodilation. Because microvascular tone significantly contributes to mean arterial pressure, the mechanism of S1P on human resistance arterioles was investigated. We hypothesized that S1P induces NO-mediated vasodilation in human arterioles from adults without coronary artery disease (non-coronary artery disease) through activation of 2 receptors, S1PR1 (S1P receptor 1) and S1PR3 (S1P receptor 3). Furthermore, we tested whether this mechanism is altered in vessels from patients diagnosed with coronary artery disease. METHODS: Human arterioles (50-200 µm in luminal diameter) were dissected from otherwise discarded surgical adipose tissue, cannulated, and pressurized. Following equilibration, resistance vessels were preconstricted with ET-1 (endothelin-1) and changes in internal diameter to increasing concentrations of S1P (10-12 to 10-7 M) in the presence or absence of various inhibitors were measured. RESULTS: S1P resulted in significant dilation that was abolished in vessels treated with S1PR1 and S1PR3 inhibitors and in vessels with reduced expression of each receptor. Dilation to S1P was significantly reduced in the presence of the NOS (NO synthase) inhibitor Nω-nitro-L-arginine methyl ester and the NO scavenger 2-4-(carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide. Interestingly, dilation was also significantly impaired in the presence of PEG-catalase (polyethylene glycol-catalase), apocynin, and specific inhibitors of NOX (NADPH oxidases) 2 and 4. Dilation in vessels from patients diagnosed with coronary artery disease was dependent on H2O2 alone which was only dependent on S1PR3 activation. CONCLUSIONS: These translational studies highlight the inter-species variation observed in vascular signaling and provide insight into the mechanism by which S1P regulates microvascular resistance and ultimately blood pressure in humans.
BACKGROUND: Preclinical studies suggest that S1P (sphingosine-1-phosphate) influences blood pressure regulation primarily through NO-induced vasodilation. Because microvascular tone significantly contributes to mean arterial pressure, the mechanism of S1P on human resistance arterioles was investigated. We hypothesized that S1P induces NO-mediated vasodilation in human arterioles from adults without coronary artery disease (non-coronary artery disease) through activation of 2 receptors, S1PR1 (S1P receptor 1) and S1PR3 (S1P receptor 3). Furthermore, we tested whether this mechanism is altered in vessels from patients diagnosed with coronary artery disease. METHODS: Human arterioles (50-200 µm in luminal diameter) were dissected from otherwise discarded surgical adipose tissue, cannulated, and pressurized. Following equilibration, resistance vessels were preconstricted with ET-1 (endothelin-1) and changes in internal diameter to increasing concentrations of S1P (10-12 to 10-7 M) in the presence or absence of various inhibitors were measured. RESULTS: S1P resulted in significant dilation that was abolished in vessels treated with S1PR1 and S1PR3 inhibitors and in vessels with reduced expression of each receptor. Dilation to S1P was significantly reduced in the presence of the NOS (NO synthase) inhibitor Nω-nitro-L-arginine methyl ester and the NO scavenger 2-4-(carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide. Interestingly, dilation was also significantly impaired in the presence of PEG-catalase (polyethylene glycol-catalase), apocynin, and specific inhibitors of NOX (NADPH oxidases) 2 and 4. Dilation in vessels from patients diagnosed with coronary artery disease was dependent on H2O2 alone which was only dependent on S1PR3 activation. CONCLUSIONS: These translational studies highlight the inter-species variation observed in vascular signaling and provide insight into the mechanism by which S1P regulates microvascular resistance and ultimately blood pressure in humans.
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