Evaluation of the effects of mild aerobic exercise and Losartan treatment on aortic endothelial function in a mouse model of Marfan syndrome

Abstract

Marfan Syndrome (MFS) is an autosomal dominant disorder in a family of connective tissue disorders. It is well established that vascular complications in MFS is associated with endothelial dysfunction, leading to a whole host of phenotypic abnormalities. A predominant clinical concern is the development of aortic aneurysm with possible subsequent dissection and rupture.In the present study, we have utilized the ex‐vivo isometric myograph technique to examine the reactivity of isolated aortic segments from control and MFS mice in the presence or absence of different in‐vivo treatments and pharmacological agents. More specifically, we assessed the impact of mild aerobic exercise on endothelial function, aortic root growth, and aortic wall elasticity in a well‐established mouse model of MFS‐associated aortic aneurysm with special focus on nitric oxide production. Nitric oxide, as frequently demonstrated in the literature, plays a crucial role in maintaining normal vascular structure and function. In the current study, we examine the potential effects of mild aerobic exercise in the absence or presence of a potent general inhibitor of nitric oxide synthase (NOS), N5‐[imino(nitroamino)methyl]‐L‐ornithine, methyl ester, monohydrochloride (L‐NAME) on aortic contraction and endothelium‐mediated vasorelaxation in 6‐month‐old MFS mice carrying Fbn1 mutation and age‐ and sex‐matched C57BL/6J wildtype (WT) controls (male and females).At 4‐6 weeks of age, MFS mice were subjected to daily treadmill exercise (at 55% of VO2max, 8m/min, 30min/day, 5days/week) and/or drug treatment for a duration of 5 months. At 6 months of age, 2mm descending aortic rings were collected and mounted onto a small chamber myograph in order to measure the vascular reactivity in response to different vasoconstricting and vasodilating agents.Our study shows marked reduction in the phenylephrine (PE)‐induced contraction [50 µmol] and aortic wall rupture point in MFS mice aorta as compared to healthy controls. Treatment with either aerobic exercise or Losartan, an angiotensin II type 1 receptor blocker (ARB), rescued rupture point closer to WT control, but led to further decrease in PE contraction compared to MFS sedentary mice, mainly due to further increase in NO production within the aortic wall. In addition, direct inhibition of NO production via L‐Name, a nitric oxide synthase (NOS) inhibitor, effectively reduced PE‐induced contraction in MFS mice aorta that were subjected to exercise or Losartan treatment, further confirming that both exercise and Losartan treatment cause an increase in NO production.This study highlights the importance of endothelial function in improving the function and structure of aortic wall during the progression of aortic aneurysm in MFS mice and establish the notion that the protective effects of aerobic exercise and Losartan treatments are potentially through improving endothelium‐mediated nitric oxide production.