Curry-Koski Tala, Gusek Brikena, Potter Ross M, Jones T Bucky, Dickman Raechel, Johnson Nathan, Stallone John N, Rahimian Roshanak, Vallejo-Elias Johana, Esfandiarei Mitra
Biomedical Sciences Program, College of Graduate Studies, Midwestern University, Glendale, AZ 85308, USA.
Department of Physiology, College of Graduate Studies, Midwestern University, Glendale, AZ 85308, USA.
Int J Mol Sci. 2024 Nov 26;25(23):12702. doi: 10.3390/ijms252312702.
Marfan syndrome (MFS) is a systemic connective tissue disorder stemming from mutations in the gene encoding Fibrillin-1 (Fbn1), a key extracellular matrix glycoprotein. This condition manifests with various clinical features, the most critical of which is the formation of aortic root aneurysms. Reduced nitric oxide (NO) production due to diminished endothelial nitric oxide synthase (eNOS) activity has been linked to MFS aortic aneurysm pathology. Caveolin-1 (Cav1), a structural protein of plasma membrane caveolae, is known to inhibit eNOS activity, suggesting its involvement in MFS aneurysm progression by modulating NO levels. In this study, we examined the role of Cav1 in aortic smooth muscle and endothelial function, aortic wall elasticity, and wall strength in male and female MFS mice () by generating developing Cav1-deficient MFS mice (MFS/KO). Our findings reveal that ablation leads to a pronounced reduction in aortic smooth muscle contraction in response to phenylephrine, attributable to an increase in NO production in the aortic wall. Furthermore, we observed enhanced aortic relaxation responses to acetylcholine in MFS/KO mice, further underscoring Cav1's inhibitory impact on NO synthesis within the aorta. Notably, van Gieson staining and chamber myography analyses showed improved elastin fiber structure and wall strength in male MFS/ mice, whereas these effects were absent in female counterparts. Cav1's regulatory influence on aortic root aneurysm development in MFS through NO-mediated modulation of smooth muscle and endothelial function, with notable sex-dependent variations.
马凡综合征（MFS）是一种全身性结缔组织疾病，由编码原纤维蛋白-1（Fbn1）的基因突变引起，Fbn1是一种关键的细胞外基质糖蛋白。这种疾病表现出多种临床特征，其中最关键的是主动脉根部动脉瘤的形成。由于内皮型一氧化氮合酶（eNOS）活性降低导致一氧化氮（NO）生成减少，这与MFS主动脉瘤的病理过程有关。小窝蛋白-1（Cav1）是质膜小窝的一种结构蛋白，已知其可抑制eNOS活性，提示其通过调节NO水平参与MFS动脉瘤的进展。在本研究中，我们通过构建Cav1缺陷的MFS小鼠（MFS/KO），研究了Cav1在雄性和雌性MFS小鼠主动脉平滑肌和内皮功能、主动脉壁弹性及壁强度中的作用。我们的研究结果表明，Cav1缺失导致主动脉平滑肌对去氧肾上腺素的收缩反应明显降低，这归因于主动脉壁中NO生成增加。此外，我们观察到MFS/KO小鼠对乙酰胆碱的主动脉舒张反应增强，进一步强调了Cav1对主动脉内NO合成的抑制作用。值得注意的是，弹力纤维染色和心室肌描记术分析显示，雄性MFS/KO小鼠的弹性纤维结构和壁强度有所改善，而雌性小鼠则没有这些效应。Cav1通过NO介导调节平滑肌和内皮功能，对MFS主动脉根部动脉瘤的发展具有调节作用，且存在明显的性别差异。
