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Review
. 2022 Nov 10;10(11):2884.
doi: 10.3390/biomedicines10112884.

Endothelium-Derived Relaxing Factors and Endothelial Function: A Systematic Review

Francesco Nappi  1 , Antonio Fiore  2 , Joyce Masiglat  2 , Teresa Cavuoti  1 , Michela Romandini  1 , Pierluigi Nappi  3 , Sanjeet Singh Avtaar Singh  4 , Jean-Paul Couetil  1
Affiliations
Review

Endothelium-Derived Relaxing Factors and Endothelial Function: A Systematic Review

Francesco Nappi et al. Biomedicines. .

Abstract

Background: The endothelium plays a pivotal role in homeostatic mechanisms. It specifically modulates vascular tone by releasing vasodilatory mediators, which act on the vascular smooth muscle. Large amounts of work have been dedicated towards identifying mediators of vasodilation and vasoconstriction alongside the deleterious effects of reactive oxygen species on the endothelium. We conducted a systematic review to study the role of the factors released by the endothelium and the effects on the vessels alongside its role in atherosclerosis.

Methods: A search was conducted with appropriate search terms. Specific attention was offered to the effects of emerging modulators of endothelial functions focusing the analysis on studies that investigated the role of reactive oxygen species (ROS), perivascular adipose tissue, shear stress, AMP-activated protein kinase, potassium channels, bone morphogenic protein 4, and P2Y2 receptor.

Results: 530 citations were reviewed, with 35 studies included in the final systematic review. The endpoints were evaluated in these studies which offered an extensive discussion on emerging modulators of endothelial functions. Specific factors such as reactive oxygen species had deleterious effects, especially in the obese and elderly. Another important finding included the shear stress-induced endothelial nitric oxide (NO), which may delay development of atherosclerosis. Perivascular Adipose Tissue (PVAT) also contributes to reparative measures against atherosclerosis, although this may turn pathological in obese subjects. Some of these factors may be targets for pharmaceutical agents in the near future.

Conclusion: The complex role and function of the endothelium is vital for regular homeostasis. Dysregulation may drive atherogenesis; thus, efforts should be placed at considering therapeutic options by targeting some of the factors noted.

Keywords: AMP-activated protein kinase; endothelial functions; endothelium-derived relaxing factor; nitric oxide; perivascular adipose tissue; reactive oxygen species; shear stress.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
PRISMA 2020 flow diagram for new systematic reviews which included searchers of databases and registers only. From [MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372: n71. doi: 10.1136/bmj. n71].
Figure 2
Figure 2
Endothelial dysfunction is orchestrated by various mechanisms: metabolites, molecular and inflammatory. Hyperinsulinemia, CVD and vitamin D have a strong impact on homeostatic equilibrium. Both hyperinsulinemia and hyperglycaemia generate states of increased coagulation and decreased fibrinolysis. By driving the development of CVD, diabetes mellitus and obesity, they contribute to the inflammatory substrate of cytokines. They increase the ROS production due to the damage in decreasing both NAD+ and reduced glutathione (GSH). A reduction in vitamin D due to sequestration into the adipocytes induces lipogenesis with de-creased level of cathelicidin and cholecalciferol, leading to decreased levels of ChS and HSPG, regulators of RBCs deformation and increased cells agglutination. These mechanisms are all responsible for thrombosis initiation. The vascular inflammation and decreasing levels of Ch-S and HSPG are represented with coloured backgrounds being the main actors of thrombogenesis trigger. In addition, thrombogenesis, the main effect, is outlined with a different colour too. Abbreviations: Ch-S: cholesterol sulfate, CVD, cardiovascular disease; EDRFs, endothelium-derived relaxing factors, HSPG: heparan sulfate proteoglycans, NAD+: nicotinamide adenine dinucleotide, PAI-1 plasminogen activator inhibitor type 1, RBC, red blood cell; ROS: reactive oxygen species, T2DM: type 2 diabetes mellitus, SIRT3: sirtuin 3, TNF-α: tumour necrosis factor-α, IL-6: interleukin 6.
Figure 3
Figure 3
Fluid dynamics regulate the function of endothelial cell through (A) an atheroprotective effect favoured by the pulsatile flow inducing a higher expression of Kruppel-like factor 4 (KLF4) or alternatively (B) an atheroprone effect related to the oscillatory flow that causes an increased level of sterol regulatory element-binding proteins (SREBP). Different biochemical and molecular mechanisms regulate the two different conditions. Atheroprotective flow is characterised by substantial greater production of KLF4 that leads to the expression of Ch25h and LXR with increased intracellular levels. This mechanism promotes higher production of 25-HC, SREBP2 and NLRP3. Atheroprone phenotype as consequence of an atheroprone flow (oscillatory stress) led to increased level of SREBP2 due to greater expression of SRE and its encoding molecules. This nuclear activation favours a detrimental effect by increased intracellular level of KLF2, KLF4, SIRT1 (gene miR-92a), NOX2 (gene NOX2) and NLRP3 inflammasome (gene NLRP3). The results are higher level of IL-1β leading to a major production of MCP-1, VCAM-1 and ICAM-1. Abbreviations: 25-HC = 25-hydroxycholesterol, CH25H = Cholesterol 25-Hydroxylase, KLF = Kruppel-like factor, ICAM-1 = Inter Cellular Adhesion Molecule-1, IL = interleukine, (MCP-1/CCL2) = Monocyte chemoattractant protein-1, NLRP3, NOD-like receptor family, pyrin domain containing 3, SREBP2 = sterol regulatory element-binding protein-2, SIRT1 = Sirtuin 1, VCAM-1 = vascular cell adhesion molecule 1.
Figure 4
Figure 4
PVAT control vascular function by mean of precise mechanism related to adiponectin-dependent AMPK activation. Two conditions are relevant. (A) non-stimulated with no link between adiponectin (APN) and Adiponectin receptor 1 (AdipoR1). Adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1) do not work alongside protein phosphatase 2A (PP2A). Protein kinase Cζ (PKCζ) induces phosphorylation of liver kinase B 1 (LKB1) affecting its translocation to the nucleus. (B) The stimulated state induces the bind of APN to AdipoR1 with activation of APPL1 resulting in PKCζ dephosphorylation by P. Dephosphorylated PKCζ is no longer effective to phosphorylate LKB1. PP2A also dephosphorylates LKB1, which results in LKB1 translocation to the cytoplasm. LKB1 phosphorylates AMP-activated protein kinase (AMPK) in the form of the AdipoR1/APPL1/PP2A/ PKCζ/LKB1 complex. Abbreviations are in the text.
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