Perivascular adipose tissue from human systemic and coronary vessels: the emergence of a new pharmacotherapeutic target

Abstract

Fat cells or adipocytes are distributed ubiquitously throughout the body and are often regarded purely as energy stores. However, recently it has become clear that these adipocytes are engine rooms producing large numbers of metabolically active substances with both endocrine and paracrine actions. White adipocytes surround almost every blood vessel in the human body and are collectively termed perivascular adipose tissue (PVAT). It is now well recognized that PVAT not only provides mechanical support for any blood vessels it invests, but also secretes vasoactive and metabolically essential cytokines known as adipokines, which regulate vascular function. The emergence of obesity as a major challenge to our healthcare systems has contributed to the growing interest in adipocyte dysfunction with a view to discovering new pharmacotherapeutic agents to help rescue compromised PVAT function. Very few PVAT studies have been carried out on human tissue. This review will discuss these and the hypotheses generated from such research, as well as highlight the most significant and clinically relevant animal studies showing the most pharmacological promise.

Linked articles: This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3.

Figure 1

PVAT is the source of a number of vasoactive and metabolically significant adipokines.

Figure 2

Potential mechanisms via which perivascular adipocytes, vascular smooth muscle cells and endothelial cells interact. Dotted lines represent unproven pathways. ADRF, adventitium-derived relaxing factor; AMPK, AMP-activated protein kinase; Ang II, angiotensin II; BK_ca, large conductance calcium-activated potassium channel; H₂O₂, hydrogen peroxide; ERK, extracellular signal-regulated kinases; 5-HT, 5-hydroxytryptamine (serotonin); GTP, guanosine triphosphate; cGMP, cyclic guanosine monophosphate; IP₃, inositol triphosphate; IRAG, IP₃ receptor-associated cGMP kinase substrate; IK_ca, intermediate conductance calcium-activated potassium channel; K_v, voltage-gated potassium channel; K_ATP, ATP-sensitive potassium channel; L-Arg, L-Argine; NA, noradrenaline; NO, nitric oxide; NOS, nitric oxide synthase; O₂^.-, superoxide anion; ONOO, peroxynitrite; PCS, prostacyclin pathway; PHE, phenylephrine; PGH₂,prostaglandin H₂; PGI₂, prostaglandin I₂ (prostacyclin); PKG, protein kinase G; R, receptor; sGC, soluble guanylate cyclise; SK_ca, small conductance calcium-activated potassium channel; SOD, superoxide dismutase; SR, sarcoplasmic reticulum; TNF, tumour necrosis factor; VSMC, vascular smooth muscle cell.

Figure 3

Effect of obesity and the metabolic syndrome on anticontractile capacity of PVAT on small arteries from subcutaneous gluteal fat, *P < 0.01 (Greenstein et al., 2009). (A) In healthy control participants PVAT exerts a significant anticontractile effect (P = 0.009, multiple anova) when compared with contractility of arteries without PVAT (n = 10). (B) In patients with obesity and metabolic syndrome, presence of PVAT has no effect on contractility (n = 10). KPSS, high potassium physiological saline solution; NA, noradrenaline.

Figure 4

The presence of macrophages is the key modulator of increased vascular contractility in vessels with hypoxic PVAT (Withers et al., 2011). (A) When PVAT from mouse vessels is rendered hypoxic, there is increased sensitivity of the vessel to cumulative doses of noradrenaline. (B) In CD11b–diphtheria toxin (DT) receptor (DTR) transgenic mice (DT administration selectively kills monocytes/macrophages), hypoxia has no effect on vascular contractility. KPSS, high potassium physiological saline solution; NE, norepinephrine.