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bioRxiv · 10.1101/2024.07.29.605631

Genetic Manipulation of Caveolin-1 in the Mouse Model of Marfan Syndrome Associated Aortic Root Aneurysm: Effects on Endothelial and Smooth Muscle Function

Curry-Koski, T.·Gusek, B.·Potter, R. M.·Jones, T. B.·Dickman, R.·Johnson, N.·Vallejo-Elias, J.·Esfandiarei, M.
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Abstract

Marfan Syndrome (MFS) is a systemic connective tissue disorder caused by mutations in the gene encoding for the large glycoprotein Fibrillin-1 (Fbn1), leading to wide-spectrum clinical manifestations, with the most life-threatening being aortic root aneurysm. MFS aortic aneurysm is known to be associated with reduced endothelial nitric oxide synthase (eNOS)-mediated nitric oxide (NO) production. Previous studies have shown that caveolin-1 (Cav1), a coat protein of caveolae structure on the plasma membrane, acts as a negative regulator of eNOS activity. This suggests that Cav1 may play a role in the development of aortic root aneurysm in MFS by modulating eNOS activity. In this study, we investigated the role of Cav1 in regulating aortic smooth muscle and endothelial function, aortic wall elasticity, and wall strength by generating MFS mice (FBN1+/Cys1041Gly) lacking Cav1 gene expression (MFS/Cav1KO). Our data show that ablation of the Cav1 gene results in a significant decrease in aortic smooth muscle contraction in response to the vasoconstricting agent phenylephrine seemingly due to a marked increase in NO production within the aortic wall. We also showed that acetylcholine-induced vasorelaxation was increased in MFS/Cav1KO mice potentially through the endothelial nitric oxide-dependent mechanism, further confirming inhibitory role of Cav1 on endothelial NO production. In addition, aortic wall elastin fiber structure and strength were markedly improved in male MFS/Cav1KO mice. This study demonstrates the regulatory role of Cav1 during the development of aortic root aneurysm in MFS mice through its effects on smooth muscle and endothelial functions in an NO-dependent manner.

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Curry-Koski, T., Gusek, B., Potter, R. M., Jones, T. B., Dickman, R., Johnson, N., Vallejo-Elias, J., Esfandiarei, M.. 2024-07-30. Genetic Manipulation of Caveolin-1 in the Mouse Model of Marfan Syndrome Associated Aortic Root Aneurysm: Effects on Endothelial and Smooth Muscle Function. https://doi.org/10.1101/2024.07.29.605631

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