Unraveling the Relationship Between Central, Peripheral and Cerebral Arteries Function in a Mouse Model of Marfan Syndrome: Benefits of Exercise Training on Vascular Function and Blood Flow

Abstract

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene affecting the musculoskeletal, cardiovascular, and pulmonary systems, with a notable vascular effect leading to aortic aneurysm, dissection, and rupture. In recent decades, better diagnostics and advances in medical and surgical treatments have increased the life expectancy in individuals with MFS, hence, other vascular complications have become more concerning. Aging is the dominant risk factor for clinically significant atherosclerotic lesions affecting most often the carotid arteries and carotid artery tortuosity is highly associated with connective tissue diseases, particularly MFS. There is an increased prevalence of intracranial aneurysms and ischemic stroke in hospitalized patients with MFS when compared with healthy controls. Despite these reports our understanding of cerebrovascular and carotid artery function and structure in MFS is very limited. In addition, the cardiovascular benefits of moderate exercise training have been well documented in the literature. Numerous studies have shown that aerobic exercise can improve cognitive function, decrease neuropsychiatric and neurodegenerative symptoms. This study sought to explore the impact of mild aerobic exercise on the progression of vascular complications in both male and female MFS mice, utilizing high-resolution in vivo ultrasound imaging for precise analysis. The research focused on assessing the functional properties of multiple key arteries, including the aorta, posterior cerebral, carotid, coronary, pulmonary, and renal arteries, in both male and female MFS mice. The study also aimed to explore the relationship between MFS-associated structural and functional changes in the aortic root and phenotypic alterations in other arteries, with the objective of identifying key predictors that could provide insights into vascular health and the potential impact of exercise on arterial structure and function. At 6 weeks of age, male and female control (Fbn1+/+) and MFS (Fbn1C1041G/+) were divided into three experimental groups: Ctrl, MFS, MFS + exercise. MFS mice were subjected to an exercise regimen of 8m/min, 30min/day, 5days/week. At 7 months of age, in vivo ultrasound imaging was performed to measure aortic root diameters and pulse wave velocity, the carotid artery pulse wave velocity (PWV), wall thickness and distensibility, and the peak systolic velocity (PSV) of the posterior cerebral arteries, coronary, pulmonary, and renal arteries. Our data showed significant increases in aortic root diameter and pulse wave velocity (PWV), carotid wall thickness and arterial stiffness, along with reduced carotid distensibility, in both sexes in MFS mice compared to controls. Peak systolic velocity (PSV) was significantly reduced in the pulmonary and posterior cerebral arteries of MFS mice, with no changes observed in coronary or renal arteries. Mild exercise mitigated aortic and carotid pathology by reducing aortic root diameter, PWV, and carotid wall thickness, while restoring carotid distensibility and posterior cerebral artery blood flow, especially in female MFS mice. Sex-specific analyses showed that aortic PWV was a strong predictor of posterior cerebral artery blood flow and pulmonary artery flow in males, whereas sinus of Valsalva diameter strongly predicted carotid artery PWV and wall thickness in both sexes. However, the relationships involving arterial distensibility differed between males and females. These findings highlighted the vascular impact of MFS, the therapeutic potential of exercise, and significant sex-specific differences in disease progression and associated metrics.