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

The prevention with Mediterranean-style diet in several trials in patients with high CVRF showed that a Mediterranean diet supplemented with olive oil or nuts, reduced diastolic blood pressure by −1.5 mm Hg and − 0.7 mm Hg respectively, in comparison with low-fat diet over 4 years [35].

The recommendation to incorporate Mediterranean diet for older adults aiming its effect on BP and arterial stiffness is established in a 12-month randomized controlled trial called NU-AGE study. A total of 1294 healthy participants were included, aged 65 to 79 years, recruited from 5 European centers, and arterial stiffness was assessed in 225 participants using the Vicorder device measuring both carotid-femoral pulse wave velocity (PWV) and augmentation index (AIx) [36, 37]. The intervention group received individually tailored standardized dietary advice and commercially available foods to increase adherence to a Mediterranean diet, and the control group continued their habitual diet, and were provided with current national dietary guidance. Of the original sample, 1142 participants completed the trial, and after 1 year, the intervention group resulted in a significant reduction in systolic blood pressure (−5.5 mm Hg; 95% CI, −10.7 to −0.4; P = 0.03), and in a subset (n = 225), augmentation index was improved following intervention (−12.4; 95% CI, −24.4 to −0.5; P = 0.04), with no change in pulse wave velocity [37].

The favorable effects of the Mediterranean diet on health may result from high intake of omega-6 and omega-3 fatty acids, fibers, antioxidants, and polyphenols [38].

#### *5.1.2 Polyphenols*

There are scientific studies that showed polyphenol-enriched diet impedes hyperlipidemia and coronary endothelial dysfunction, both by counteracting vascular inflammation and oxidative damage by activating Akt/eNOS pathway [39]. Some of the polyphenol's effects are linked to the promotion of SIRT1-induced repression of the p38 MAPK/NF-kappaB pathway and ROS production [40].

When they come from virgin olive they reduce inflammatory angiogenesis in ECs through inhibition of matrix metalloproteinase-9 and cyclooxygenase-2, supporting the protective role of dietary polyphenols both in atherosclerosis and cancer [41].

#### **5.2 Pharmacological therapy**

Several drugs have actions mechanism involved in the physiological pathways of endothelial regulation and vascular tonicity, therefore this section will be discussed briefly a few of them.

### *5.2.1 PDE5i*

Phosphodiesterase of cyclic nucleotide is a family of enzymes that hydrolyzed the cyclic nucleotides 3′-5′ to their 5′ monophophates analogs [42].

Vardenafil is one of many PDE5i in which a reduction of arterial stiffness has been reported. In one study twelve patients with erectile dysfunction, mean age of 58 ± 9 years, received verdanafil20 mg per day, in a randomized, placebo-controlled, double-blind2-way crossover design. Aortic stiffness was evaluated through carotidfemoral PWV and AIx. PWV decreased significantly (0.7 m/s, P = .001), denoting a decrease in aortic stiffness, and AIx decreased significantly (by 7%, P = .008), denoting a decreased effect of wave reflections from the periphery [43].

#### *5.2.2 New therapies*

Recent studies showed that microRNAs have a key role during atherosclerotic plaque formation, representing a potential new target for developing drugs.

In atherosclerotic plaque, miR-143 was found to be upregulated, and its overexpression in human umbilical vein endothelial cells (HUVECs) suppressed glycolysis by targeting hexokinase 2, leading to endothelial dysfunction [44]. And, in vivo, the inhibition of miR-92a, a regulator of endothelial proliferation and angiogenesis after ischemia, results in beneficial effects on the endothelium such as reducing inflammation and decreasing plaque size [45, 46].

Recent evidence shows several epigenetic pathways involved in endothelial dysfunction and related to cardiovascular diseases which will be discussed in the following.

Histone deacetylase 1 (HDAC1) overexpression in bovine aortic endothelial cells triggers a reduction of eNOS lysine acetylation and NO production. Its inhibition can stand as a therapy for preventing endothelial dysfunction. Additionally, HDAC1 decline leads to no change in eNOS acetylation, otherwise increasing basal nitrate NO formation [46, 47].

Another study evidence that resveratrol, a phenol produced naturally by different plants, prevents TNF-α-induced injury from damaging HUVECs by stimulating sirtuin-1 (SIRT1) and repressing p38 MAPK/NF-kappaB pathway and ROS production [40, 46].

Additionally, another NAD-dependent deacetylase, SIRT6 is expressed in atherosclerotic disease in human patients. In several mice studies, absence and haploinsufficient SIRT6 have been associated with monocyte adhesion to endothelium, augmentation of atherosclerosis gene expression, impaired vasorelaxation, and overexpression of VCAM-1 [48, 49]. Being so this knowledge is a potential subject for investigation of novel therapies counteracting atherosclerosis and decreasing endothelial dysfunction.
