Unraveling the Sex-Dependent 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

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene, affecting multiple systems including the musculoskeletal, cardiovascular, and pulmonary systems. Vascular complications, particularly aortic root aneurysm, dissection, and rupture, are hallmark features of MFS. In recent decades, advances in diagnostics and treatments have significantly improved life expectancy for individuals with MFS; however, other vascular complications have become more concerning. On the other hand, the cardiovascular benefits of moderate exercise are well-documented, with evidence also suggesting that aerobic exercise improves vascular structure and cognitive function. The present study investigates the effects of mild aerobic exercise on the progression of aortic aneurysm in male and female MFS mice. Using high-resolution in vivo ultrasound imaging, the study assesses the functional properties of multiple key arteries, including the aorta, posterior cerebral, carotid, coronary, pulmonary, and renal arteries, and explore the relationship between aortic root diameters, arterial wall stiffness, and phenotypic changes across these arteries, aiming to identify key predictors that could provide insights into vascular health and the influence of exercise on arterial function and structure. Based on our findings, MFS mice exhibited significant increases in carotid PWV (wall stiffness), carotid wall thickness, coupled with reduced carotid distensibility, in both sexes compared to controls. Reduced PSV was observed in the pulmonary and posterior cerebral arteries of MFS mice, while coronary and renal arteries showed no changes. Mild exercise attenuated aortic and carotid pathology, reversing aortic root diameter growth, PWV, and carotid wall thickness, while improving carotid distensibility and restoring posterior cerebral artery blood flow, particularly in female MFS mice. In males, aortic PWV strongly correlated with posterior cerebral and pulmonary artery flow, while sinus of Valsalva diameter predicted carotid artery PWV and wall thickness in both sexes. Notably, the relationship between carotid distensibility and vascular metrics varied by sex. These findings underscore the vascular impacts of MFS, the therapeutic potential of mild exercise, and notable sex-specific differences in disease progression and arterial function.