Effects of the sympathetic nervous system on perivascular adipose tissue function in health and disease

Abstract

Background: Healthy perivascular adipose tissue (PVAT) exerts an anti-contractile effect which is vital in regulating blood pressure, and evidence suggests that sympathetic nervous stimulation of PVAT triggers the release of anti-contractile factors, some of which are released via activation of Beta3-adrenoceptors. In obesity over-activity of the autonomic nervous system occurs, which may result in a loss of PVAT function and subsequent hypertension. Accordingly, we have investigated sympathetic function in PVAT depots from healthy and obese small mammals. Methods: C57BL/6J mice were fed a high fat diet (HFD, 60%) for 10-12 weeks to induce obesity. Age-matched C57BL/6J mice fed a standard chow were used as a control group. An additional group was used whereby after six weeks of HFD, mice were subjected to forced swimming for 4-6 weeks. PVAT-denuded and PVAT-intact mesenteric resistance arteries from obese, exercised, and age-matched control mice fed a standard chow were mounted on a wire myograph, and vascular contractility to electrical field stimulation (EFS) was assessed in the presence of pharmacological tools. Immunohistochemistry was used to detect changes in the PVAT environment. Results: High fat feeding induced autonomic dysfunction, hypertension and type-II diabetes, which was reversed using exercise; independent of weight loss. In healthy control mice, activation of sympathetic nerves in PVAT exerts an anti-contractile effect mediated through OCT3, and release of adiponectin via Beta3-adrenoceptor activation. This mechanism was also dependent on nitric oxide synthase (NOS). In obesity, the anti-contractile effect was lost, and could not be restored via Beta3-adrenoceptor activation. Using immunohistochemistry, Beta3-adrenoceptors and OCT3 were shown to be downregulated in obesity. Moreover, adiponectin no longer exerts vasodilation. However, activation of NOS was able to restore anti-contractile function. Additionally, healthy sympathetic hyperstimulation i.e. exercise, reversed PVAT dysfunction in obesity by reducing inflammation of PVAT, and increasing Beta3-adrenoceptor and OCT3 expression; restoring the healthy PVAT anti-contractile mechanism. Furthermore, the vasodilator effects of adiponectin were restored. Conclusions: Loss of the neurally mediated PVAT anti-contractile effect in obesity will contribute to the development of hypertension and type-II diabetes. Exercise training, or pharmacological intervention at the level of NO signalling, will restore function and treat the vascular complications of obesity.

Date of Award	1 Aug 2017
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Anthony Heagerty (Supervisor), Jacqueline Ohanian (Supervisor) & Sarah Withers (Supervisor)