**3. Reactive oxygen-derived species (ROS) in endothelium**

Endothelial cells generate ROS, including the superoxide radical (O2 .−), hydrogen peroxide (H2O2), peroxynitrite (ONOO− ), hydroxyl radical (. OH), among others [15, 16]. In endothelial cells, the main sources of ROS are the enzymatic complex xanthine oxidoreductase (XOR) [17], the complex of membrane nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) [18], eNOS itself when it is "uncoupled" due to lack of tetrahydrobiopterin (BH4) or L-arginine [19], mitochondrial cytochromes [20], and hemoglobin [21].

Among all endothelial ROS sources, NADPH oxidases are enzymes whose primary function is the generation of ROS and they play an important role in redox signaling [22]. On the other hand, the activity of NADPH oxidase can cause the uncoupling of eNOS by the oxidative degradation of BH4, leading to the eNOSdependent synthesis of O2 ·− and detriment of the synthesis of NO [18, 23]. Once O2 ·− is synthesized, it can act as a precursor to other ROS due to its use by superoxide dismutase (SOD) to generate H2O2 that has greater stability and capacity to cross biological membranes, and it therefore can act as a modulator of signal transduction pathways [24]. Furthermore, O2 ·− reacts quickly with NO to generate ONOO− , a powerful oxidizing agent that causes DNA fragmentation and lipid oxidation [25].

It is currently postulated that the mechanism by which O2 ·− "kidnaps" NO would play a central role in the development of endothelial dysfunction that is seen in pathologies such as diabetes mellitus [26–28], preeclampsia [29, 30], and hypertension [31].
