Abstract
Williams-Beuren syndrome (WBS) is a rare disorder caused by a heterozygous deletion of 26–28 contiguous genes that affects the brain and cardiovascular system. Here, we investigated whether WBS affects aortic structure and function in the complete deletion (CD) mouse model harbouring the most common deletion found in WBS patients. Thoracic aortas from 3–4 months-old male CD mice and wild-type littermates were mounted in wire myographs or were processed for histomorphometrical analysis. Nitric oxide synthase (NOS) isoforms and oxidative stress levels were assessed. Ascending aortas from young adult CD mice showed moderate (50%) luminal stenosis, whereas endothelial function and oxidative stress were comparable to wild-type. CD mice showed greater contractions to KCl. However, α1-adrenergic contractions to phenylephrine, but not with a thromboxane analogue, were compromised. Decreased phenylephrine responses were not affected by selective inducible NOS blockade with 1400 W, but were prevented by the non-selective NOS inhibitor L-NAME and the selective neuronal NOS inhibitor SMTC. Consistently, CD mice showed increased neuronal NOS expression in aortas. Overall, aortic stenosis in CD mice coexists with excessive nNOS-derived NO signaling that compromises ascending aorta α1-adrenergic contractions. We suggest that increased neuronal NOS signaling may act as a physiological ‘brake’ against the detrimental effects of stenosis.
Highlights
Williams-Beuren syndrome (WBS) [OMIM 194050] is a rare congenital multisystem disorder caused by a recurrent heterozygous deletion of 26–28 contiguous genes on chromosome band 7q11.231
We provide the first comprehensive assessment of thoracic aorta structure and reactivity in young complete deletion (CD) mice, a mouse model carrying the most common deletion found in WBS patients, which often manifest cardiovascular disease early in life
These results suggest the presence of ascending aorta stenosis in CD mice
Summary
Williams-Beuren syndrome (WBS) [OMIM 194050] is a rare congenital multisystem disorder caused by a recurrent heterozygous deletion of 26–28 contiguous genes on chromosome band 7q11.231. This syndrome affects males and females with a prevalence that is estimated to range between 1/7,500 and 1/10,0002. Aortic function has never been explored in the ascending aorta of either CD mice or other mouse models carrying WBS chromosome microdeletions. We provide the first comprehensive assessment of thoracic aorta structure and reactivity in young CD mice, a mouse model carrying the most common deletion found in WBS patients, which often manifest cardiovascular disease early in life. We conclude that ascending aortas from young CD mice show stenosis and impaired phenylephrine-induced α1-adrenergic contractions because of a NO-mediated desensitization
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