Aerobic Exercise Prevents Arterial Stiffness and Attenuates Hyperexcitation of Sympathetic Nerves in Perivascular Adipose Tissue of Mice after Transverse Aortic Constriction

Abstract

We aimed to investigate the efficacy of exercise on preventing arterial stiffness and the potential role of sympathetic nerves within perivascular adipose tissue (PVAT) in pressure-overload-induced heart failure (HF) mice. Eight-week-old male mice were subjected to sham operation (SHAM), transverse aortic constriction-sedentary (TAC-SE), and transverse aortic constriction-exercise (TAC-EX) groups. Six weeks of aerobic exercise training was performed using a treadmill. Arterial stiffness was determined by measuring the elastic modulus. The elastic and collagen fibers of the aorta and sympathetic nerve distribution in PVAT were observed. Circulating noradrenaline (NE), expressions of β3-adrenergic receptor (β3-AR), and adiponectin in PVAT were quantified. During the recovery of cardiac function by aerobic exercise, thoracic aortic collagen elastic modulus (CEM) and collagen fibers were significantly decreased (p < 0.05, TAC-SE vs. TAC-EX), and elastin elastic modulus (EEM) was significantly increased (p < 0.05, TAC-SE vs. TAC-EX). Circulating NE and sympathetic nerve distribution in PVAT were significantly decreased (p < 0.05, TAC-SE vs. TAC-EX). The expression of β3-AR was significantly reduced (p < 0.05, TAC-SE vs. TAC-EX), and adiponectin was significantly increased (p < 0.05, TAC-SE vs. TAC-EX) in PVAT. Regular aerobic exercise can effectively prevent arterial stiffness and extracellular matrix (ECM) remodeling in the developmental course of HF, during which sympathetic innervation and adiponectin within PVAT might be strongly implicated.

Keywords: PVAT; arterial stiffness; exercise; heart failure; sympathetic nerves.

Figure 1

Effects of exercise on cardiac function in mice after TAC. EF (A) was calculated by using the formula (EDV - ESV)/EDV × 100%, and FS (B) was calculated by using the formula (LVDd − LVDs)/LVDd × 100%. Heart weight per body weight (HW/BW) ratio (C) and heart weight per tibia length (HW/TL) ratio (D). Original image following WGA staining (E), and CM size was measured (F). Data were analyzed using one-way ANOVA; values are mean ± SD. * indicates p < 0.05. Abbreviations: EF, ejection fraction; EDV, end-diastolic volume; ESV, end-systolic volume; FS, fractional shortening; LVDd, left ventricular end-diastolic dimension; LVDs, left ventricular end-contractile diameter; HW, heart weight; BW, body weight; TL, tibia length; WGA, wheat germ agglutinin; CM, cardiomyocyte; SHAM, sham surgery; TAC-SE, transverse aortic constriction-sedentary; and TAC-EX, transverse aortic constriction-exercise.

Figure 2

Effects of exercise on aortic elastic/collagen fiber area and aortic morphology in mice after TAC. Elastic fibers of aorta were stained with EVG (A,B) and collagen fibers with Sirius Red (C,D) in PVAT. (E) Aorta were stained with H&E to compare differences between groups on thickness/diameter (F). Data were analyzed using one-way ANOVA; values are mean ± SD. * indicates p < 0.05. Abbreviations: EVG, Elastica van Gieson; H&E, hematoxylin and eosin; SHAM, sham surgery; TAC-SE, transverse aortic constriction-sedentary; and TAC-EX, transverse aortic constriction-exercise.

Figure 3

Effects of exercise on aortic stiffness in mice after TAC. Representative images of the force–time curve for each group (A); EEM (B) and CEM (C) were calculated using the slope of stress–strain curves. Data were analyzed using one-way ANOVA; values are mean ± SD. * indicates p < 0.05. Abbreviations: EEM, elastin elastic modulus; CEM, collagen elastic modulus; SHAM, sham surgery; TAC-SE, transverse aortic constriction-sedentary; and TAC-EX, transverse aortic constriction-exercise.

Figure 4

Effects of exercise on hyperexcitation of sympathetic nerves in PVAT of mice after TAC. Circulating levels of NE were determined using ELISA (A). Density of TH-immunoreactive parenchymal nerve fibers were calculated by the number of fibers every 100 adipocytes (B). Sympathetic nerve fibers were stained with TH antibody in PVAT, as indicated by arrowheads (C). Data were analyzed using one-way ANOVA; values are mean ± SD. * indicates p < 0.05. Abbreviations: NE, noradrenaline; TH, tyrosine hydroxylase; SHAM, sham surgery; TAC, transverse aortic constriction; TAC-SE, transverse aortic constriction-sedentary; and TAC-EX, transverse aortic constriction-exercise.

Figure 5

Effects of exercise on the expressions of β3-AR and adiponectin in PVAT of mice after TAC. Representative Western blot assessment of β3-AR (A) and adiponectin (B) expressions in PVAT normalized to the expressions of GAPDH. Data were analyzed using one-way ANOVA; values are mean ± SD. * indicates p < 0.05. Abbreviations: β3-AR, β3-adrenergic receptor; SHAM, sham surgery; TAC-SE, transverse aortic constriction-sedentary; and TAC-EX, transverse aortic constriction-exercise.