Effect of the General Inhibitor of Nitric Oxide Synthase (L‐NAME) On Cardiac and Aortic Function and Structure in A Mouse Model of Marfan Syndrome‐Associated Aortic Aneurysm

Abstract

Marfan Syndrome (MFS) is an autosomal‐dominant connective tissue disorder caused by missense mutations in the gene that encodes for Fibrillin‐1 (FBN1). FBN1 is an extracellular matrix glycoprotein that functions as a scaffolding protein during the formation and maturation of elastic fibers. The mechanism underlying MFS pathogenesis stems from a crosstalk between the Angiotensin‐II pathway and over activation of transforming growth factor‐beta signaling. There are several clinical manifestations seen in MFS, but the most serious and life‐threatening is the aortic aneurysm due to degradation and fragmentation of aortic wall elastin fibers. If left untreated, aortic aneurysm progression may lead to dissection and rupture.Previous studies in the MFS mouse model have shown that the progression of aortic aneurysm is associated with a significant decline in endothelial function and nitric oxide (NO) production in the aortic wall, and that overexpression of endothelial nitric oxide synthase (eNOS) could delay the progression of aortic root aneurysm in MFS mice. A recent study in our lab has also shown that mild aerobic exercise can block aortic aneurysm in MFS mice. It is well established that exercise can improve endothelial function mainly through an increase in eNOS‐mediated NO production. Therefore, we tested the hypothesis that mild aerobic exercise prevents aortic aneurysm progression in the mouse model of MFS mainly through increasing the production of NO within the aortic wall.To test this hypothesis, C57BL/6 WT and MFS mice were subjected to daily treadmill exercise (at 55% of VO2max, starting at 4 weeks of age) in the absence or presence of the general inhibitor of NO production, N(G)‐Nitro‐L‐arginine methyl ester (L‐NAME) at 0.05 g per 100 mL of drinking water. At 6‐months of age, in vivo imaging of the aortic root diameter and pulse wave velocity (PWV) as an index of wall stiffness, was performed using a high‐resolution Vevo2100 ultrasound system. The aortic root diameter at the sinus of Valsalva, and pulse wave velocity were both increased in MFS mice compared to WT, however MFS mice subjected to treadmill exercise had significantly decreased aortic root diameter and pulse wave velocity compared to sedentary MFS mice. In situ analysis of aortic wall integrity was analyzed at 6 months by Van Geison staining. Our results revealed that MFS mice had an increase in elastin fragment count and a decrease in elastin fiber length compared to WT. Interestingly, MFS mice subjected to exercise had fewer elastin fragment count and an increase in elastin fiber length compared to sedentary MFS mice. Interestingly, L‐NAME treatment reversed the protective effects of exercise on aortic root diameter and pulse wave velocity in MFS mice to a level that was not different than MFS sedentary groups. This study provides preliminary evidence that mild aerobic exercise blocks the progression of aortic root dilation in MFS mice through increasing the production of NO within the aortic wall, and further emphasizes the value of increased physical activity in aneurysm population.