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Page 2 of 10 Reiss et al. Vessel Plus 2020;4:19 I http://dx.doi.org/10.20517/2574-1209.2020.04

the harmful cardiovascular consequences of obesity as an alternative or adjunct to weight-loss programs,
which are known to have limited long-term success.

Adipose tissue acts as an active metabolic endocrine organ that releases not only hormone-like adipokines
and inflammatory cytokines, but also cargo-carrying vesicles such as exosomes that may be considered a
form of adipokine that contributes to the development of atherosclerosis [7-10] .

Adipose tissue in obese subjects is inflamed as compared to lean subjects and displays greater macrophage
[11]
infiltration . In the obese state, adipose tissue can no longer accommodate excess energy stores and
among the maladaptive changes that occur are infiltration by a variety of inflammatory immune cells
[12]
that interact with adipocytes to promote chronic inflammation . Atherosclerosis progression is driven
by inflammation and the pro-inflammatory environment fostered by excess adiposity is thought to be a
critical link between obesity and ASCVD [13,14] . Sequential steps in atherosclerosis are: circulating monocyte
adhesion to endothelium, penetration through the compromised barrier, differentiation into macrophages
[15]
and excessive uptake of lipids . Each of these steps may be vulnerable to interference by exosomes. This
review will discuss the connection between adipose tissue and atherosclerosis and the potential role of
exosomes in communicating atherogenic signals from fat depots to the arterial wall. Understanding these
relationships may be invaluable in the understanding, prevention and treatment of ASCVD.

ATHEROSCLEROSIS, INFLAMMATION AND LIPIDS
Atherosclerosis is a process that takes place in the arterial wall and its earliest stage involves a breach of the
[16]
vascular endothelium by monocytes, which settle in the subendothelial space and become macrophages .
In an inflammatory environment, these macrophages in the subendothelial intima may exhibit impairment
of cholesterol efflux, which leads to intracellular accumulation of modified low-density lipoprotein
(LDL) and subsequent formation of plaque-forming lipid-rich foam cells [17,18] . Macrophages may become
classically or alternatively activated to the M1 or M2 phenotype, respectively. During atherogenesis,
monocytes enter the atheroma and differentiate into the M1 macrophage subtype and it is these M1
[19]
macrophages that play a crucial role in the initiation and progression of atherosclerosis . M1 macrophages
are considered pro-atherogenic because they easily transform into cholesterol-overloaded foam cells while
the M2 subtype is less atherogenic and has a lesser propensity to form foam cells. M2 macrophages are
[20]
associated with tissue repair and are enriched in regressing plaques .
Macrophage cholesterol homeostasis is a delicate balance among influx, endogenous synthesis,
[21]
esterification/hydrolysis and efflux . The low grade chronic inflammation associated with obesity is a
likely driver of dysregulated macrophage cholesterol homeostasis. It has also been shown to adversely affect
expression of the proteins responsible for cholesterol influx and efflux by our group and others [22-29] .

A variety of cytokines may stimulate the atherosclerotic process, including interferon (IFN)-γ, tumor
necrosis factor (TNF)-α, and interleukin (IL)-1β [30,31] . TNF-α and IL-1β induce cytokine and adhesion
molecule expression and also encourage the migration of vascular smooth muscle and endothelial cells [32,33] .
IFN-γ promotes foam cell formation [25,34] .

One of the most compelling clinical challenges of our time is the increasing prevalence of obesity
and its detrimental effects on the cardiovascular system. Obesity influences inflammation and the
[35]
pathophysiological processes involved in atherosclerotic disease development . Obesity and overweight
are accompanied by unfavorable blood lipid profile patterns [36,37] . Dyslipidemia is a major risk factor for
coronary artery disease. Among obese patients, the estimated prevalence of hypertriglyceridemia is twice
[38]
as high as in non-obese individuals . In addition, the atherogenic combination of hypertriglyceridemia
with high LDL and low HDL is more prevalent in obese and overweight patients [39,40] . Unfortunately, high