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Fibrillin-1 Deficiency Perturbs Aortic Cholinergic Relaxation and Adrenergic Contraction in a Mouse Model of Early
Anna Cantalupo1,2, Keiichi Asano1, Sergey Dikalov3
1Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Introduction:
The pathogenic role of nitric oxide (NO) signaling during development of thoracic aortic aneurysm (TAA) in Marfan syndrome (MFS) is currently unclear. We characterized vasomotor function and its relationship to the activity of the NO-generating enzymes in mice with early onset progressively severe MFS.
Methods:
Wire myography, immunoblotting, measurements of aortic NO, and superoxide levels were used to compare vasomotor function, contractile protein levels, and the activity of endothelial and inducible NO synthase (eNOS and iNOS, respectively) in ascending thoracic aortas of Fbn1mgR/mgR mice relative to wild-type littermates.
Results:
Isometric force measurements of aortic rings from 16-day-old male Fbn1mgR/mgR mice revealed a significant reduction in acetylcholine-induced relaxation and increased phenylephrine (PE)-promoted contractility, associated with abnormally low eNOSSer1177 phosphorylation, decreased NO production, and augmented superoxide levels. Greater aortic contractility was associated with α1-adrenoceptor upregulation and normal levels of contractile proteins. While iNOS inhibition had no effect on vasomotor functions, mutant aortic rings preincubated with a nonspecific NOS inhibitor yielded a greater PE response, implying a significant contribution of endothelial dysfunction to aortic hypercontractility.
Conclusion:
Impaired eNOS signaling disrupts aortic cholinergic relaxation and adrenergic contraction in MFS mice with dissecting TAA.
Introduction:
The pathogenic role of nitric oxide (NO) signaling during development of thoracic aortic aneurysm (TAA) in Marfan syndrome (MFS) is currently unclear. We characterized vasomotor function and its relationship to the activity of the NO-generating enzymes in mice with early onset progressively severe MFS.
Methods:
Wire myography, immunoblotting, measurements of aortic NO, and superoxide levels were used to compare vasomotor function, contractile protein levels, and the activity of endothelial and inducible NO synthase (eNOS and iNOS, respectively) in ascending thoracic aortas of Fbn1mgR/mgR mice relative to wild-type littermates.
Results:
Isometric force measurements of aortic rings from 16-day-old male Fbn1mgR/mgR mice revealed a significant reduction in acetylcholine-induced relaxation and increased phenylephrine (PE)-promoted contractility, associated with abnormally low eNOSSer1177 phosphorylation, decreased NO production, and augmented superoxide levels. Greater aortic contractility was associated with α1-adrenoceptor upregulation and normal levels of contractile proteins. While iNOS inhibition had no effect on vasomotor functions, mutant aortic rings preincubated with a nonspecific NOS inhibitor yielded a greater PE response, implying a significant contribution of endothelial dysfunction to aortic hypercontractility.
Conclusion:
Impaired eNOS signaling disrupts aortic cholinergic relaxation and adrenergic contraction in MFS mice with dissecting TAA.
Insights
Nitric oxide (NO) signaling is impaired in Marfan syndrome (MFS) mice, leading to reduced aortic relaxation and increased contractility. This endothelial dysfunction contributes to thoracic aortic aneurysm (TAA) development.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Genetics
Background:
- The role of nitric oxide (NO) in thoracic aortic aneurysm (TAA) development within Marfan syndrome (MFS) remains incompletely understood.
- This study investigates NO signaling pathways in MFS, focusing on early-onset, progressive disease in a mouse model.
Purpose of the Study:
- To characterize the vasomotor function in MFS mice.
- To determine the relationship between NO-generating enzyme activity and TAA pathogenesis in MFS.
Main Methods:
- Wire myography was employed to assess aortic ring function.
- Immunoblotting, NO, and superoxide level measurements were conducted.
- Activity of endothelial (eNOS) and inducible (iNOS) NO synthase was compared between MFS and wild-type mice.
Main Results:
- MFS mice exhibited reduced acetylcholine-induced relaxation and increased phenylephrine-induced contractility.
- Abnormalities included decreased eNOS phosphorylation at Ser1177, reduced NO production, and elevated superoxide levels.
- Aortic hypercontractility was linked to alpha1-adrenoceptor upregulation, with endothelial dysfunction playing a significant role.
Conclusions:
- Impaired endothelial nitric oxide synthase (eNOS) signaling disrupts normal aortic relaxation and contraction.
- This disruption contributes to the development of dissecting thoracic aortic aneurysms in Marfan syndrome.
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