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Published on: February 25, 2016
Enhanced vasoconstrictor responses in eNOS deficient mice
Kathryn Lamping1, Frank Faraci
1Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA. kathryn-lamping@uiowa.edu
Abstract:
Previous studies suggest that vasoconstriction is modulated by nitric oxide (NO). Contractions to ET-1 and/or thromboxane may be enhanced during chronic deficiency in expression or activity of NO synthase (NOS). Multiple isoforms of NOS are expressed within the vessel wall and purely pharmacological approaches cannot define the role of each. We tested the hypothesis that vasoconstriction to endothelin-1 (ET-1) and/or the thromboxane mimetic, U46619, is enhanced under conditions of chronic, selective deficiency in endothelial NOS (eNOS-/-) by examining responses in aorta from eNOS-/- mice compared to wild type (eNOS+/+). ET-1 produced dose-dependent contraction of aorta from eNOS+/+ mice that was increased twofold following acute inhibition of all NOS isoforms with N(G)-nitro-L-arginine (L-NNA). In eNOS-/- mice, contractions to ET-1 were increased twofold compared to eNOS+/+. L-NNA had no effect. Although contraction of the aorta to thromboxane mimetic U46619 was increased at lower concentrations, maximal contractions to U46619 were not increased following acute inhibition of NOS or in eNOS-/- mice. These studies provide direct evidence that vasoconstriction to ET-1 and thromboxane is augmented in the face of eNOS deficiency, demonstrating that eNOS normally inhibits vascular contractile responses.
Insights
Endothelial nitric oxide synthase (eNOS) normally inhibits vasoconstriction. Its deficiency enhances blood vessel contractions to endothelin-1 and thromboxane, impacting vascular tone regulation.
Area of Science:
- Vascular Biology
- Cardiovascular Physiology
- Nitric Oxide Signaling
Background:
- Nitric oxide (NO) modulates vasoconstriction.
- Chronic deficiency in NO synthase (NOS) may enhance contractions to endothelin-1 (ET-1) and thromboxane.
- Multiple NOS isoforms exist in the vessel wall, necessitating isoform-specific studies.
Purpose of the Study:
- To test if vasoconstriction to ET-1 and U46619 is enhanced in mice with chronic endothelial NOS (eNOS) deficiency.
- To compare vascular responses in eNOS knockout (eNOS-/-) mice versus wild-type (eNOS+/+) mice.
Main Methods:
- Examined vasoconstrictive responses to ET-1 and U46619 in mouse aorta.
- Utilized eNOS-/- mice to model chronic eNOS deficiency.
- Administered N(G)-nitro-L-arginine (L-NNA) to acutely inhibit all NOS isoforms.
Main Results:
- ET-1 caused dose-dependent contractions in eNOS+/+ aorta, which doubled with L-NNA.
- eNOS-/- mice showed twofold increased contractions to ET-1 compared to eNOS+/+ mice, with no effect of L-NNA.
- Maximal contractions to U46619 were not increased in eNOS-/- mice or with L-NNA, though lower concentrations showed increased contraction.
Conclusions:
- Vascular contractions to ET-1 and thromboxane are augmented in the absence of eNOS.
- eNOS plays a crucial inhibitory role in regulating vascular contractile responses.
- Selective eNOS deficiency enhances vasoconstriction, highlighting its physiological importance.
