Sex-Dependent Vascular Responses to Atorvastatin Across Multiple Arterial Beds in a Mouse Model of Marfan Syndrome

Marfan syndrome (MFS) is characterized by progressive aortic aneurysm formation resulting from mutations in the fibrillin-1 (Fbn1) gene. Although the thoracic aorta is the primary site of pathology, accumulating evidence indicates that vascular dysfunction in MFS extends beyond the aorta to involve multiple arterial beds. Statins have been shown to attenuate aneurysm progression in experimental models of MFS; however, their effects on systemic vascular remodeling and arterial stiffness outside the aorta remain poorly characterized. In this study, we investigated the impact of chronic atorvastatin therapy on vascular structure and hemodynamic function across multiple vascular beds in the Fbn1^C1041G/+^ mouse model of MFS. Male and female control and MFS mice received drinking water with or without atorvastatin (1 g/kg/day) from 4 weeks to 6 months of age, enabling the effects of atorvastatin to be assessed in both healthy and MFS arteries. High-frequency ultrasound imaging was used to assess vascular parameters in the aorta, left common carotid artery (LCCA), and posterior cerebral artery (PCA). Atorvastatin treatment significantly attenuated aortic root dilation in both male and female MFS mice and reduced aortic pulse wave velocity (PWV), indicating improved arterial compliance. In the carotid circulation, atorvastatin significantly reduced LCCA wall thickness and carotid PWV, although carotid wall strain did not improve. Atorvastatin raised both systolic and diastolic blood pressure in male and female MFS mice relative to untreated MFS animals, reaching levels not significantly different from untreated controls in both sexes, while having little effect in healthy controls apart from a rise in female diastolic pressure. In the posterior cerebral artery, peak systolic velocity, a hemodynamic index rather than a direct measure of perfusion, showed similarly sex-dependent changes, increasing in female MFS mice but decreasing further in males after atorvastatin. Collectively, these findings demonstrate that atorvastatin exerts systemic but heterogeneous vascular effects in MFS, improving arterial stiffness and structural remodeling across multiple arterial beds while producing sex-specific hemodynamic responses that warrant further investigation.