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Updated: Jul 16, 2026
Measurement of Endothelium-Dependent Vasorelaxation in the Mouse Thoracic Aorta Using Tensometric Small Volume Chamber Myography
Published on: August 12, 2022
Endothelial dysfunction and compromised eNOS/Akt signaling in the thoracic aorta during the progression of Marfan
A W Y Chung1, K Au Yeung, S F Cortes
1Child and Family Research Institute and Departments of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada. achung@mrl.ubc.ca
Background And Purpose:
Aortic complications account for the major mortality in Marfan syndrome (MFS), a connective tissue disorder caused by mutations in FBN1 encoding fibrillin-1. We hypothesized that MFS impaired endothelial function and nitric oxide (NO) production in the aorta.
Experimental Approach:
Mice (at 3, 6, 9 and 12 months of age) heterozygous for the Fbn1 allele encoding a cysteine substitution (Fbn1 (C1039G/+), Marfan mice, n=75), the most common class of mutation in MFS, were compared with age-matched control littermates (n=75). Thoracic and abdominal aortas from the two groups were studied.
Key Results:
Isometric force measurements revealed that relaxation to ACh (but not to sodium nitroprusside) was diminished in the phenylephrine-precontracted Marfan thoracic aorta at 6 months of age (pEC(50)=6.12+/-0.22; maximal response, E(max)=52.7+/-6.8%; control: pEC(50)=7.34+/-0.19; E(max)=84.8+/-2.2%). At one year, both inhibition of NO production with N(omega)-nitro-L-arginine methyl ester, or denudation of endothelium increased the phenylephrine-stimulated contraction in the control thoracic aorta by 35%, but had no effect in the Marfan aorta, indicating a loss of basal NO production in the Marfan vessel. From 6 months, a reduced phosphorylation of endothelial NOS (eNOS)(Ser1177) and Akt(Thr308) detected by Western blotting was observed in the Marfan thoracic aorta, which was accompanied by decreased levels of cGMP. Expressions of Akt and eNOS in the abdominal aorta were not different between the two groups.
Conclusions And Implications:
MFS impairs endothelial function and signaling of NO production in the thoracic aorta, suggesting the importance of NO in the age-related progression of thoracic aortic manifestations.
Insights
Marfan syndrome (MFS) impairs aortic endothelial function and nitric oxide (NO) production, particularly in the thoracic aorta. This dysfunction contributes to the progression of aortic complications in MFS patients.
Area of Science:
- Cardiovascular Biology
- Connective Tissue Disorders
- Endothelial Function
Background:
- Marfan syndrome (MFS) is a genetic disorder caused by FBN1 mutations, leading to significant aortic complications and mortality.
- Endothelial dysfunction and impaired nitric oxide (NO) production are implicated in cardiovascular disease progression.
Purpose of the Study:
- To investigate the impact of Marfan syndrome on endothelial function and NO production in the aorta.
- To determine if FBN1 mutations affect the signaling pathways involved in NO synthesis.
Main Methods:
- Comparison of Marfan mice (Fbn1 C1039G/+) with age-matched controls at various ages (3-12 months).
- Assessment of aortic function using isometric force measurements and biochemical analyses (Western blotting).
- Evaluation of nitric oxide production and signaling pathways, including eNOS phosphorylation and cGMP levels.
Main Results:
- Marfan mice exhibited diminished aortic relaxation to acetylcholine, indicating impaired endothelial-dependent vasodilation.
- Loss of basal NO production was observed in the thoracic aorta of Marfan mice by one year of age.
- Reduced phosphorylation of endothelial NO synthase (eNOS) and Akt, along with decreased cGMP levels, was evident in the Marfan thoracic aorta.
Conclusions:
- Marfan syndrome significantly impairs endothelial function and NO signaling in the thoracic aorta.
- These findings highlight the critical role of NO in the age-related development of aortic abnormalities in MFS.
- Targeting NO pathways may offer therapeutic potential for managing aortic complications in Marfan syndrome.
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