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.