Introduction
The endothelium is a thin monolayer of cells that covers the blood
vessel lumen, creating a barrier, between blood and surrounding tissues,
and playing an active role in vascular functioning and homeostasis.
Endothelial cells (EC) are involved in the maintenance of vascular tone,
blood fluidity, and leukocyte trafficking; they also mediate
blood-tissue exchange, and participate in hemostasis and
neovascularization, acting as a real organ.
Endothelial dysfunction is a complex event triggered by different
agents, such as cytokines and oxidized low-density lipoproteins (oxLDL),
that alter the normal state and induce a pro-inflammatory and
pro-coagulant phenotype in EC. The occurrence of this condition is
considered as a crucial event in the pathogenesis of cardiovascular
disease. The expression of cell surface adhesion molecules, such as
vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion
molecule-1 (ICAM-1), and endothelial leukocyte adhesion molecule
(E-selectin), has been proposed as biomarker of endothelial cell
activation. On the other hand, the decreased synthesis of
endothelium-derived nitric oxide (NO), which acts as a vasodilator and
antithrombotic agent, represents the earliest and one of the most
important event involved in endothelial dysfunction (Liao, 2013).
A reduction in NO availability may occur as a consequence of an
accelerated degradation of NO under oxidative stress conditions, i.e. in
the presence of superoxide anions NO is transformed into peroxynitrite,
or due to a decreased endothelial nitric oxide synthase (eNOS) protein
expression and/or activity (Förstermann and Münzel, 2006). Direct
binding of eNOS to the scaffolding domain of caveolin-1 (Cav-1) is a
more recent described mechanism for inactivating eNOS (Chen et
al ., 2012). Cav-1 is the most abundant protein associated with caveolae
which are important mediators of endocytosis, transcytosis, lipid
homeostasis, and signal transduction in EC (Shvets et al ., 2014).
The endothelium is indeed permeable to small molecules with a diameter
below 6 nm and nearly impermeable to macromolecules. Thus, the transport
of lipoproteins, including oxLDL, across the cell membrane occurs via
transcytosis (Zhang et al ., 2018). The transcytosis of
low-density lipoproteins (LDL) into the intima can be associated with
their modification (e.g., oxidation) that leads to EC dysfunction (Sunet al ., 2010). On the other hand, it has been suggested that
circulating oxLDL and oxysterols may induce perturbations of membrane
cholesterol, thus affecting integrity and dynamics of cholesterol-rich
domains such as caveolae (Levitan and Shentu, 2011).
In this paper, the current knowledge on the possible interplay between
uptake and transcytosis of LDL/oxLDL, disruption of cholesterol
homeostasis, and alteration of caveolae architecture and signaling
function is reviewed and discussed considering their implications in
oxLDL-induced endothelial cell activation and dysfunction.