**3.1 Consumption of bioavailable NO**

Altered NO metabolism due to elevated degradation of NO, inactivation of NO, or presence of NO inhibitors may be due to the elevation in oxidative stress [10]. NO is a highly diffusible and reactive species with an unpaired electron, because of this, there are a variety of chemical components that impede appropriate signaling [11]. Some of the principal agents of this deficiency are ROS and superoxide (O2−).

ROS increases the activity of stimulants such as inflammation, radiation, advanced age, obesity, and sundry chemical substances. Superoxide is an important

#### **Figure 2.**

*Amino acid sequence of ET1, characterized by the presence of 21 amino acids and two disulfide junctions. Original graphic created with BioRender.com.*

#### **Figure 3.**

*The ET-1, synthesized from pre-pro ET1 by the activity of ECE in ECs, binds to ETA receptor in vascular smooth muscle and activates the pathway Gq-PLC-IP3, which rises cytosolic Ca2+ and induces muscular contraction. ET-1 can also activate ETB receptor in ECs leading to an increase in NOS activity and augmentation of bioavailable NO. Original graphic created with BioRender.com.*

radical for cardiovascular biology, formed by one-electron reduction of oxygen. At a cellular level, increase oxidative stress causes damage by altering several molecules' structures like deoxyribonucleic acid, proteins, lipids, and carbohydrates [12].

### **3.2 Deficit production of NO**

Approaching ECD through the deficit of NO production, modifications of eNOS is one of the processes that stand out in this category, being eNOS uncoupling is a major mechanism. This enzyme requires dimerization in the presence of heme and BH4 for an effective electron movement to L-arginine and the subsequent formation of NO and L-citrulline [3, 4, 13]. When this relation is disrupted, the outcome is that eNOS function as a weak NADPH oxidase, generating O2− instead of NO, a process denominated eNOS uncoupling. Several mechanisms induce eNOS uncoupling, which increases local oxidative stress and removes the vasodilatation effect of NO [13].

Many pathways contribute to eNOS uncoupling, being ONOO one of the main. Also known as peroxynitrite, ONOO is an oxidant and nitrating agent with an unstable structural isomer of nitrate. The formation of this molecule is due to the reaction of free radical superoxide, with free radical nitric oxide. ONOO disrupts a zinc-thiolate cluster in eNOS and oxidizes BH4 to BH3, both creating an eNOS uncoupling and creating a cycle of ROS production [14].

Other, but also well-known, mechanism is L-arginine decrease associated with its inhibitor asymmetric dimethyl-L-arginine (ADMA). ADMA is an endogenous protein produced by N-methyltransferase type 1, elevated in redox status, and degraded by dimethylarginine dimethylaminohydrolase, altered by oxidative stress [15, 16].

*DOI: http://dx.doi.org/10.5772/intechopen.107481 Endothelial Dysfunction, Molecular Biology, Physiopathology, Diagnosis, and Treatment*
