Perivascular adipose tissue as a regulator of vascular disease pathogenesis: identifying novel therapeutic targets

Abstract

Adipose tissue (AT) is an active endocrine organ with the ability to dynamically secrete a wide range of adipocytokines. Importantly, its secretory profile is altered in various cardiovascular disease states. AT surrounding vessels, or perivascular AT (PVAT), is recognized in particular as an important local regulator of vascular function and dysfunction. Specifically, PVAT has the ability to sense vascular paracrine signals and respond by secreting a variety of vasoactive adipocytokines. Due to the crucial role of PVAT in regulating many aspects of vascular biology, it may constitute a novel therapeutic target for the prevention and treatment of vascular disease pathogenesis. Signalling pathways in PVAT, such as those using adiponectin, H₂ S, glucagon-like peptide 1 or pro-inflammatory cytokines, are among the potential novel pharmacological therapeutic targets of PVAT.

Linked articles: This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue - Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc.

Figure 1

Overview of the potential cardiovascular pharmacology of PVAT. PVAT secretes adipocytokines originating from adipocytes (e.g. adiponectin, leptin, omentin, H₂S, DPP4 and aldosterone) or from immune cells such as lymphocytes and macrophages (TNF, IL‐6 and other IL). These adipocytokines influence vascular redox state (i.e. the production of reactive oxygen species (ROS), such as O₂ ^.‐, H₂O₂ and peroxynitrite (ONOO^‐)), as well as the migration and proliferation of VSMCs, regulating vascular injury and atherogenesis. Various pharmacological agents influence the secretome of PVAT. PPARγ agonists, statins, ACEi and ARBs as well as mineralocorticoid receptor antagonists and aldosterone antagonists all up‐regulate PPARγ, in contrast with thiazides. PPARγ in turn stimulates adiponectin secretion from adipocytes, which inhibits oxidative stress and restores the bioavailability of tetrahydrobiopterin (BH₄), a critical co‐factor of eNOS, resulting in improved eNOS coupling and increased NO bioavailability. Adiponectin expression is also up‐regulated in response to vascular oxidative injury via novel mediators such as 4‐hydroxynonenal (4HNE), a lipid peroxidation product. ACEi, ARB and aldosterone inhibitors as well as MR inhibitors also inhibit the detrimental pro‐oxidant effects of AngII and aldosterone signalling. ROS as well as cytokines produced by immune cells of PVAT are also involved in vascular oxidative injury and pro‐inflammatory signalling, and these effects are inhibited by statins and possibly DPP4 inhibitors. Statins also up‐regulate adipocyte production of H₂S, a gas with vasorelaxant and PPARγ‐stimulating roles, possibly via enzymes such as cystathionine γ‐lyase (CSE). Further investigation of local PVAT‐vessel interactions may provide novel therapeutic options for vascular disease.