Evaluation of the effects of Marfan pathogenesis and losartan treatment on coronary and cerebral arteries in the well‐established Marfan Syndrome mouse model

Abstract

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 (FBN1) gene. This mutation manifests in a variety of phenotypic changes with a notable cardiovascular effect leading to aortic aneurysm, dissection, and rupture. This results in a significant increase in morbidity and mortality in these patients. The angiotensin II type I receptor (AT1R) signalling pathway has previously been shown to contribute to the cardiovascular effects in the progression of this disease. Prior studies have demonstrated the protective effects of Losartan, an AT1R blocker, on slowing the progression of aortic root aneurysm in the well-established mouse model of MFS (Fbn1 +/- p. Cys1041Gly). In this study, we are further investigating the impact of MFS pathogenesis and Losartan treatment on other vessels such as the posterior cerebral artery and coronary artery. Mice (male + female) were divided into experimental groups: Control, MFS, MFS + 0.6g/L losartan. Drug therapy consisted of 0.6g/L of losartan in drinking water. Water intakes were recorded to ensure the mice were receiving the treatment. At 7 months of age, in vivo ultrasound imaging was performed to measure aortic diameters, aortic pulse wave velocity (PWV), and peak blood flow of the coronary and posterior cerebral arteries. In order to assess elastin fragmentation in the aortic wall, 5μm aortic cross-sections were subjected to Van Geison elastin staining. Blood pressure (BP) measurements were also obtained, using the tail-cuff method. Our results demonstrate that Losartan reduces aortic root diameters at the sinus of Valsalva and reduced the PWV, an index of aortic stiffness, in MFS mice at 7 months of age. Losartan also reduces elastin fragmentation in the aortic wall of MFS mice. The systolic coronary peak flow demonstrates a statistically significant decrease in MFS when compared to CTRL. Losartan treatment has no effect on the systolic coronary peak flow. There is no statistical significance in diastolic coronary peak flow between CTRL vs. MFS and MFS vs. MFS + Losartan. There is no statistical significance in comparison of the posterior cerebral artery peak flow between CTRL to MFS and MFS to MFS + Losartan. There is also no statistical significance in the systolic and diastolic BP between the groups. Our results show that Losartan has beneficial effects in delaying the progression of aortic aneurysm, reduces vessel wall stiffness, and reduces elastin fragmentation in the aortic root. This study also provides an early insight into the disease progression of MFS in the less investigated coronary and cerebral arteries, as well as investigates the preliminary potential effects of Losartan on peak flow in coronary and cerebral vessels in the well-established MFS mouse model.