Perivascular Adipose Tissue Regulates Vascular Function by Targeting Vascular Smooth Muscle Cells

Abstract

Adipose tissues are present at multiple locations in the body. Most blood vessels are surrounded with adipose tissue which is referred to as perivascular adipose tissue (PVAT). Similarly to adipose tissues at other locations, PVAT harbors many types of cells which produce and secrete adipokines and other undetermined factors which locally modulate PVAT metabolism and vascular function. Uncoupling protein-1, which is considered as a brown fat marker, is also expressed in PVAT of rodents and humans. Thus, compared with other adipose tissues in the visceral area, PVAT displays brown-like characteristics. PVAT shows a distinct function in the cardiovascular system compared with adipose tissues in other depots which are not adjacent to the vascular tree. Growing and extensive studies have demonstrated that presence of normal PVAT is required to maintain the vasculature in a functional status. However, excessive accumulation of dysfunctional PVAT leads to vascular disorders, partially through alteration of its secretome which, in turn, affects vascular smooth muscle cells and endothelial cells. In this review, we highlight the cross talk between PVAT and vascular smooth muscle cells and its roles in vascular remodeling and blood pressure regulation.

Keywords: brown adipose tissue; cardiovascular diseases; endothelial cells; hypertension; vascular smooth muscle cells.

Figure 1.. Crosstalk between PVAT and VSMC in vascular remodeling.

Smooth muscle-like cells in the neointimal area of the vascular wall originate from four sources: 1) Wnt1 positive progenitors in PVAT; 2) PVAT-resident or bone marrow-derived mesenchymal stem cells; 3) local VSMC stimulated by signaling from PVAT adipocytes and mediated by adipokines, growth factors and extracellular vesicles; and 4) adventitia-derived cells. Additionally, Wnt1-positive progenitors in PVAT and VSMC in the vascular wall can be differentiated into brown-like adipocytes in PVAT.

Figure 2.. PVAT regulates VSMC dilation and contraction.

PVAT (perivascular adipose tissue) regulates vascular tone through relaxing factors and contractile factors. PVAT adipocytes express CBS (cystathionine β-synthase), CSE (cystathionine γ-lyase) and eNOS (endothelial nitric oxide synthase). CBS and CSE catalyze generation of H₂S (hydrogen sulfide) from cysteine, which induces VSMC (vascular smooth muscle cells) dilation by opening BKCa (calcium activated K⁺-channels) on VSMC, and eNOS-dependent NO production from L-arginine which induces vasodilation mediated by the cGMP signaling pathway. Additionally, EFS (electrical field stimulation) induces PVAT adipocytes to release adiponectin, PGI2 and CGRP which induce vasodilation as well. On the other side, EFS induces PVAT release of 5-HT, dopamine and norepinephrine which cause VSMC contraction thorough adrenergic receptors (AdR) on VSMC. EFS also induces VSMC contraction by stimulating secretion of PGF_2a, chemerin and O₂^.- from PVAT adipocytes. Additionally, PVAT adipocyte-derived calpastatin might induce VSMC contraction mediated by Ca_v1.2 channels on VSMC.

Figure 3.. Strategy for hypertension prevention through PVAT browning.

Brown-like adipocytes in PVAT produce more PVAT-derived relaxing factors (PVRF), while white-like adipocytes produce more PVAT-derived contraction factors (PVCF). PVRF mediate anti-contractile effects of PVAT and reduce BP (blood pressure), while PVCF account for contractile effects of PVAT and increase blood pressure. Induction or maintenance of PVAT browning by drugs, but not cold stimuli, can be an efficient strategy to prevent hypertension development.