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Quantitative and qualitative assessment of aortic structure and function, and elastic fiber ultrastructure in the mouse model of Marfan syndrome Cui, Zhe (Jason)

Abstract

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene, with aortic aneurysm considered as the most life-threatening complication. Previous studies have shown that doxycycline, a general inhibitor of matrix metalloproteinases (MMPs), can improve aortic contractility and elastin structure in the mouse model of MFS. However, the longitudinal effects of MMPs inhibition on the gradual progression of aneurysm and aortic wall biophysical properties in a live animal have not yet been investigated. Therefore, we assessed the hypothesis that a long-term treatment with doxycycline would delay the progression of aortic aneurysm, improve aortic wall elasticity, and protect the ultrastructure of elastin in MFS mice. In this study, non-invasive and label-free multiphoton microscopy imaging was used to quantify fiber morphology and volumetric density of aortic and cutaneous elastin and collagen in MFS mice. We also utilized non-invasive high-resolution echocardiography to conduct a longitudinal in vivo study of the structural, functional, and biophysical properties of the aortic wall in control and MFS mice in the absence and presence of doxycycline treatment. The ultrastructure of aortic elastic fibers was also assessed by electron microscopy. Multiphoton imaging revealed significant elastin fragmentation and disorganization within the aortic wall of MFS mice, which was also associated with reduction in cutaneous volumetric density of elastin and collagen. Ultrasound imaging showed that aortic pulse wave velocity (PWV) was significantly elevated in MFS mice starting at the age of 6-month-old, which was associated with a distinct increase in aortic root dimeter in the regions of aortic annulus and sinus of Valsalva. Long-term treatment with doxycycline resulted in a significant improvement in elastin organization, reduction of aortic root growth and aortic PWV in MFS mice. These findings underscore the key role of MMPs in the pathogenesis, and provide new insights into the potential therapeutic value of doxycycline in blocking MFS-associated aneurysm. Furthermore, the use of multiphoton imaging to detect the signs of elastin degradation in the skin dermis may be considered as the first step towards the potential development of a non-invasive approach for monitoring the aneurysm progression in MFS patients.

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