Cantalupo Anna, Asano Keiichi, Dikalov Sergey, Gordon Dylan, Ramirez Francesco
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
J Vasc Res. 2025;62(2):96-108. doi: 10.1159/000542481. Epub 2025 Jan 17.
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.
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.
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.
Impaired eNOS signaling disrupts aortic cholinergic relaxation and adrenergic contraction in MFS mice with dissecting TAA.
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.
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.
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.
Impaired eNOS signaling disrupts aortic cholinergic relaxation and adrenergic contraction in MFS mice with dissecting TAA.
目前尚不清楚一氧化氮（NO）信号通路在马凡综合征（MFS）患者胸主动脉瘤（TAA）发生过程中的致病作用。我们对早发性进行性严重MFS小鼠的血管舒缩功能及其与NO生成酶活性的关系进行了表征。
采用线肌张力测定法、免疫印迹法、主动脉NO测量法和超氧化物水平测定法，比较Fbn1mgR/mgR小鼠与野生型同窝小鼠升主动脉的血管舒缩功能、收缩蛋白水平以及内皮型和诱导型一氧化氮合酶（分别为eNOS和iNOS）的活性。
对16日龄雄性Fbn1mgR/mgR小鼠主动脉环进行等长力测量发现，乙酰胆碱诱导的舒张显著降低，去氧肾上腺素（PE）促进的收缩力增加，同时伴有eNOSSer1177磷酸化异常降低、NO生成减少和超氧化物水平升高。主动脉收缩力增强与α1 -肾上腺素能受体上调和收缩蛋白水平正常有关。虽然抑制iNOS对血管舒缩功能无影响，但用非特异性NOS抑制剂预孵育的突变主动脉环对PE的反应更大，这意味着内皮功能障碍对主动脉过度收缩有显著影响。
在患有夹层TAA的MFS小鼠中，eNOS信号通路受损会破坏主动脉胆碱能舒张和肾上腺素能收缩。
目前尚不清楚一氧化氮（NO）信号通路在马凡综合征（MFS）患者胸主动脉瘤（TAA）发生过程中的致病作用。我们对早发性进行性严重MFS小鼠的血管舒缩功能及其与NO生成酶活性的关系进行了表征。
采用线肌张力测定法、免疫印迹法、主动脉NO测量法和超氧化物水平测定法，比较Fbn1mgR/mgR小鼠与野生型同窝小鼠升主动脉的血管舒缩功能、收缩蛋白水平以及内皮型和诱导型一氧化氮合酶（分别为eNOS和iNOS）的活性。
对16日龄雄性Fbn1mgR/mgR小鼠主动脉环进行等长力测量发现，乙酰胆碱诱导的舒张显著降低，去氧肾上腺素（PE）促进的收缩力增加，同时伴有eNOSSer1177磷酸化异常降低、NO生成减少和超氧化物水平升高。主动脉收缩力增强与α1 -肾上腺素能受体上调和收缩蛋白水平正常有关。虽然抑制iNOS对血管舒缩功能无影响，但用非特异性NOS抑制剂预孵育的突变主动脉环对PE的反应更大，这意味着内皮功能障碍对主动脉过度收缩有显著影响。
在患有夹层TAA的MFS小鼠中，eNOS信号通路受损会破坏主动脉胆碱能舒张和肾上腺素能收缩。
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