The Role of Obesity-Induced Perivascular Adipose Tissue (PVAT) Dysfunction in Vascular Homeostasis

Abstract

Perivascular adipose tissue (PVAT) is an additional special type of adipose tissue surrounding blood vessels. Under physiological conditions, PVAT plays a significant role in regulation of vascular tone, intravascular thermoregulation, and vascular smooth muscle cell (VSMC) proliferation. PVAT is responsible for releasing adipocytes-derived relaxing factors (ADRF) and perivascular-derived relaxing factors (PDRF), which have anticontractile properties. Obesity induces increased oxidative stress, an inflammatory state, and hypoxia, which contribute to PVAT dysfunction. The exact mechanism of vascular dysfunction in obesity is still not well clarified; however, there are some pathways such as renin-angiotensin-aldosterone system (RAAS) disorders and PVAT-derived factor dysregulation, which are involved in hypertension and endothelial dysfunction development. Physical activity has a beneficial effect on PVAT function among obese patients by reducing the oxidative stress and inflammatory state. Diet, which is the second most beneficial non-invasive strategy in obesity treatment, may have a positive impact on PVAT-derived factors and may restore the balance in their concentration.

Keywords: endothelial dysfunction; exercise; obesity; perivascular adipose tissue.

Figure 1

Vasodilatory and hyperpolarizing effect of perivascular adipose tissue–derived factors (PVAT-derived factors) on vascular smooth muscle cells (VSMCs) and hyperpolarizing effect of PVAT-derived factors on endothelial cells. Adiponectin causes vasodilation by affecting adiponectin receptors (AR) in endothelial cells, which contributes to the activation of locations 5′ adenosine monophosphate-activated protein kinase (AMPK), which is responsible for the activation of endothelial NO synthase (eNOS). Enhanced NO concentration induces activation of cyclic guanosine monophosphate (cGMP), which is responsible for opening large-conductance calcium-activated potassium channels (BKCa). eNOS is present in both endothelial cells and adipocytes. Leptin activates leptin receptors (LR), which are responsible for activation of not only AMPK, but also endothelium-derived hyperpolarizing factor (EDHF), which activates BKCa. Moreover, AMPK independently activates BKCa and induces a hyperpolarization effect. Hydrogen sulfide (H2S) induces activation of BKCa in VSMCs and endothelial cells. Moreover, it induces a decrease in intracellular pH by the activation of Cl⁻/HCO3⁻ ionic exchanger. Angiotensin 1–7 (Ang 1–7) by affecting endothelial Ang 1–7 receptor (MAS) activates eNOS and increases the NO concentration. Hydrogen peroxide (H₂O₂) stimulates the soluble guanylyl cyclase (sGC-1), which induces vasodilation through the NO/GC-1/cGMP pathway.

Figure 2

The influence of obesity on PVAT-derived factors’ synthesis resulting in vascular dysfunction. (PVAT: perivascular adipose tissue, RAAS: renin–angiotensin–aldosterone system, NO: nitric oxide, H₂S: hydrogen sulfide, H₂O₂: hydrogen peroxide, TNF–α: tumor necrosis factor α, and NA: noradrenaline).