Macrophage Activation Is Responsible for Loss of Anticontractile Function in Inflamed Perivascular Fat

Abstract

Objective-The aim of this study was to determine whether macrophages dispersed throughout perivascular fat are crucial to the loss of anticontractile function when healthy adipose tissue becomes inflamed and to gain an understanding of the mechanisms involved. Methods and Results-Pharmacological studies on in vitro small arterial segments from a mouse model of inducible macrophage ablation and on wild-type animals were carried out with and without perivascular fat using 2 physiological stimuli of inflammation: aldosterone and hypoxia. Both inflammatory insults caused a similar loss of anticontractile capacity of perivascular fat and increased macrophage activation. Aldosterone receptor antagonism and free radical scavengers were able to restore this capacity and reduce macrophage activation. However, in a mouse deficient of macrophages CD11b-diptheria toxin receptor (CD11b-DTR), there was no increase in contractility of arteries following aldosterone incubation or hypoxia. Conclusion-The presence and activation of macrophages in adipose tissue is the key modulator of the increase in contractility in arteries with perivascular fat following induction of inflammation. Despite multiple factors that may be involved in bringing about the vascular consequences of obesity, the ability of eplerenone to ameliorate the inflammatory effects of both aldosterone and hypoxia may be of potential therapeutic interest. Key Words: hypoxia Ⅲ microcirculation Ⅲ obesity Ⅲ inflammation O besity is set to reach epidemic levels in many countries, 1 predisposing individuals to an increased risk of type II diabetes, hypertension, and the inevitable consequences of circulatory disease. 2 The hallmark of this phenotype is an increase in the size of individual adipocytes as excess energy is stored, together with the recruitment and activation of macrophages and the release of cytokines as local inflammation ensues. 3,4 The effect on the vasculature can be profound, with loss of vasodilator adipokine bioavailability, increased tone, 5,6 and the development of the metabolic syndrome. 7

Role of adipokines in cardiovascular disease

“…Plasma ADRF employs these channels (found in endothelium, adipocytes and VMSCs) to induce anti-contractility -including NO release from WAT and ECs (Hughes et al 2010). In hypoxia, macrophages and ROS also appear to attenuate anti-contractility in PVAT (Withers et al 2011). Obesity increases PVAT and reduces anti-contractility (Gao et al 2005), although the interplay between the chronic inflammatory state of obesity and feedback to adipokines to influence contractility (amongst other things) has yet to be researched further.…”

Inflammation and metabolic dysfunction: links to cardiovascular diseases

“…Data on the presence of immune cells in PVAT are controversial. A very recent publication analyzed macrophage content in thoracic PVAT compared with white and brown adipose tissue and found PVAT to be resistant to high-fat diet-induced immune cell infiltration similar to brown adipose tissue (303). In contrast, adipose tissue inflammation in PVAT and macrophage infiltration could be described to be responsible for a loss of anticontractile function of this fat depot in the mesenteric bed (69).…”

Mechanisms of Adiponectin-Associated Perivascular Function in Vascular Disease

“…26 Likewise, antagonism of tumor necrosis factor-α using preincubation with infliximab in the organ bath can restore normal PVAT anticontractile function as can the aldosterone antagonist spironolactone and eplerenone. 18,27 Interestingly, experimental induction of the hypoxia environment also results in the loss of anticontractile capacity of PVAT in healthy vessels; this too is restored by aldosterone antagonists thereby supporting the contributing role of the hypoxic environment and subsequent oxidative stress in the loss of PVAT function. 27 Within the inflamed PVAT environment are increased numbers of classically activated or M1 macrophages (CAMs).…”

“…18,27 Interestingly, experimental induction of the hypoxia environment also results in the loss of anticontractile capacity of PVAT in healthy vessels; this too is restored by aldosterone antagonists thereby supporting the contributing role of the hypoxic environment and subsequent oxidative stress in the loss of PVAT function. 27 Within the inflamed PVAT environment are increased numbers of classically activated or M1 macrophages (CAMs). 27 These produce the proinflammatory cytokines, such as tumor necrosis factor-α, detailed above.…”