madman
Super Moderator
Abstract
Maintenance of endothelial cell integrity is an important component of human health and disease since the endothelium can perform various functions including regulation of vascular tone, control of hemostasis and thrombosis, cellular adhesion, smooth muscle cell proliferation, and vascular inflammation. Endothelial dysfunction is encompassed by complex pathophysiology that is based on endothelial nitric oxide synthase uncoupling and endothelial activation following stimulation from various inflammatory mediators (molecular patterns, oxidized lipoproteins, cytokines). The downstream signaling via nuclear factor-κB leads to overexpression of adhesion molecules, selectins, and chemokines that facilitate leukocyte adhesion, rolling, and transmigration to the subendothelial space. Moreover, oscillatory shear stress leads to pro-inflammatory endothelial activation with increased monocyte adhesion and endothelial cell apoptosis, an effect that is dependent on multiple pathways and flow-sensitive microRNA regulation. Moreover, the role of neutrophil extracellular traps and NLRP3 inflammasome as inflammatory mechanisms contributing to endothelial dysfunction has recently been unveiled and is under further investigation. Consequently, and following their activation, injured endothelial cells release inflammatory mediators and enter a pro-thrombotic state through activation of coagulation pathways, downregulation of thrombomodulin, and an increase in platelet adhesion and aggregation owing to the action of von-Willebrand factor, ultimately promoting atherosclerosis progression.
1. Introduction
Cardiovascular diseases represent the primary cause of morbidity and mortality in western societies despite the breakthroughs in their diagnosis, treatment, and prevention. Several risk factors are implicated in their pathogenesis, such as arterial hypertension, diabetes mellitus (DM), smoking, and obesity. Interestingly, most of these processes are linked with endothelial dysfunction, the initial step of atherogenesis, which has been proven to be a precursor of adverse cardiovascular outcomes [1–4]. Recently, a lot of interest has been shown on the pro-inflammatory state stemming from the cluster of comorbidities frequently encompassing patients with cardiovascular diseases and its deleterious effect on atherosclerosis. Therefore, in the context of this narrative review, we present the inflammatory mechanisms involved in the development of endothelial dysfunction and the potential therapeutic implications according to the latest preclinical and clinical studies.
2. Physiology of the Vascular Endothelium
2.1. Endothelial Cell Anatomy and Function
The endothelium is an abundant organ consisting of a squamous cell monolayer that lines blood vessels, being in contact with the flowing blood. It consists of polarized endothelial cells (EC) adjacent to a basal lamina, together forming the tunica intima of blood vessels. ECs are frequently described as thin and slightly elongated with average dimensions of 30–50 µm length, 10–30 µm width, and 0.1–1 µm height. They are positioned along the vessel axis to mitigate the shear stress (SS) deriving from the blood flow. Even though once believed to be just a bystander, the endothelium has now been established as an endocrine organ, regulating the exchange of fluids, nutrients, and metabolites, and is characterized as a crucial mediator of various functions. Among their well-described properties are vascular tone regulation via vasoconstriction or relaxation, vascular remodeling, control of hemostasis and thrombosis, cellular adhesion, smooth muscle cell proliferation, and vascular inflammation as long as ECs REMAIN IN A HEALTHY STATE [5,6].
2.1.1. Regulation of Vascular Tone
The discovery of prostacyclin and its endothelial-related synthesis along with the work from Furchgott and Zawadzki concerning endothelial nitric oxide (eNO) demonstrated the importance of endothelium in vascular relaxation [7–9]. Consequently, tissue oxygen supply is dependent upon synthesis and release of NO, endothelial-derived hyperpolarizing factor (EDHF), arachidonic acid metabolites signaling via cyclooxygenase, lipoxygenase, and cytochrome P450 while the role of various molecules (angiotensin II (ATII), endothelin, urotensin, C-type natriuretic peptide, bradykinin, adrenomedullin, adenosine, purines, reactive oxygen species (ROS)) is vital in achieving the balance in vascular tone [10].
2.1.2. The Role of Nitric Oxide
Nitric oxide is a molecule with pleiotropic functions in endothelial function. It is synthesized from L-arginine in endothelial cells, with calcium-calmodulin-dependent NO synthase (NOS) acting as a catalyst for this reaction. Three different subtypes of NOS (neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS)) have been reported, each having different structural and functional characteristics. Calcium-dependent enzymes nNOS and eNOS are the constitutive NOS while iNOS is induced by immunological stimuli. Among the known required NOS co-factors are oxygen, nicotinamide adenine dinucleotide phosphate (NADPH), and tetrahydrobiopterin (BH4) [11]. Following its synthesis, it is distributed from the endothelial cell membrane to vascular smooth muscle cells leading to the activation of guanylate cyclase, which then converts GTP to cGMP, ultimately resulting in the removal of calcium and consequent relaxation of cells [12].
Other than its role in mediating the vascular tone via relaxation of smooth muscle cells, NO has an antithrombotic role due to the attenuation of platelet activation and aggregation, regulates the migration and adhesion of leukocytes on EC, and inhibits vascular smooth muscle cell proliferation [11]. Moreover, it has been implicated in the maintenance of endothelial integrity and permeability [13]. It should also be noted that NO is a potent oxygen-free radical scavenger by enhanced decomposition of peroxynitrite to nitrate and nitrite and inhibition of neutrophil-related O− 2 productions via limiting NADPH oxidase activity [14,15].
3. Assessment of Endothelial Function
4. Pathophysiology of Endothelial Dysfunction
4.1. eNOS Uncoupling
4.2. Cardiovascular Risk Factors and Endothelial Dysfunction
4.2.1. Smoking
4.2.2. Diabetes Mellitus
4.2.3. Arterial Hypertension
4.2.4. Hypercholesterolemia
5. The Role of Inflammation in Endothelial Dysfunction
5.1. TLRs and Endothelial Dysfunction
5.2. NLRP3 Inflammasome and Endothelial Dysfunction
5.3. The Role of NF-κB and Adhesion Molecules
5.4. The Pro-Inflammatory Effect of NOX
5.5. Neutrophil Extracellular Traps
5.6. Shear Stress
5.7. Endothelial Dysfunction in Chronic Inflammatory Diseases
6. A Link between Inflammation and Thrombosis in Endothelial Dysfunction
7. Clinical Implications and Future Directions
8. Conclusions
Endothelial dysfunction is frequently mentioned in the initial steps of atherogenesis, promoted by the highly prevalent cardiovascular risk factors. Inflammation plays an important role in its development, with recent studies providing additional knowledge on the complex pathophysiology of endothelial dysfunction. Amelioration of endothelial function could represent an additional step in cardiovascular risk reduction at the early stages of atherogenesis, with the role of genetic and epigenetic manipulation being under rigorous investigation.
Maintenance of endothelial cell integrity is an important component of human health and disease since the endothelium can perform various functions including regulation of vascular tone, control of hemostasis and thrombosis, cellular adhesion, smooth muscle cell proliferation, and vascular inflammation. Endothelial dysfunction is encompassed by complex pathophysiology that is based on endothelial nitric oxide synthase uncoupling and endothelial activation following stimulation from various inflammatory mediators (molecular patterns, oxidized lipoproteins, cytokines). The downstream signaling via nuclear factor-κB leads to overexpression of adhesion molecules, selectins, and chemokines that facilitate leukocyte adhesion, rolling, and transmigration to the subendothelial space. Moreover, oscillatory shear stress leads to pro-inflammatory endothelial activation with increased monocyte adhesion and endothelial cell apoptosis, an effect that is dependent on multiple pathways and flow-sensitive microRNA regulation. Moreover, the role of neutrophil extracellular traps and NLRP3 inflammasome as inflammatory mechanisms contributing to endothelial dysfunction has recently been unveiled and is under further investigation. Consequently, and following their activation, injured endothelial cells release inflammatory mediators and enter a pro-thrombotic state through activation of coagulation pathways, downregulation of thrombomodulin, and an increase in platelet adhesion and aggregation owing to the action of von-Willebrand factor, ultimately promoting atherosclerosis progression.
1. Introduction
Cardiovascular diseases represent the primary cause of morbidity and mortality in western societies despite the breakthroughs in their diagnosis, treatment, and prevention. Several risk factors are implicated in their pathogenesis, such as arterial hypertension, diabetes mellitus (DM), smoking, and obesity. Interestingly, most of these processes are linked with endothelial dysfunction, the initial step of atherogenesis, which has been proven to be a precursor of adverse cardiovascular outcomes [1–4]. Recently, a lot of interest has been shown on the pro-inflammatory state stemming from the cluster of comorbidities frequently encompassing patients with cardiovascular diseases and its deleterious effect on atherosclerosis. Therefore, in the context of this narrative review, we present the inflammatory mechanisms involved in the development of endothelial dysfunction and the potential therapeutic implications according to the latest preclinical and clinical studies.
2. Physiology of the Vascular Endothelium
2.1. Endothelial Cell Anatomy and Function
The endothelium is an abundant organ consisting of a squamous cell monolayer that lines blood vessels, being in contact with the flowing blood. It consists of polarized endothelial cells (EC) adjacent to a basal lamina, together forming the tunica intima of blood vessels. ECs are frequently described as thin and slightly elongated with average dimensions of 30–50 µm length, 10–30 µm width, and 0.1–1 µm height. They are positioned along the vessel axis to mitigate the shear stress (SS) deriving from the blood flow. Even though once believed to be just a bystander, the endothelium has now been established as an endocrine organ, regulating the exchange of fluids, nutrients, and metabolites, and is characterized as a crucial mediator of various functions. Among their well-described properties are vascular tone regulation via vasoconstriction or relaxation, vascular remodeling, control of hemostasis and thrombosis, cellular adhesion, smooth muscle cell proliferation, and vascular inflammation as long as ECs REMAIN IN A HEALTHY STATE [5,6].
2.1.1. Regulation of Vascular Tone
The discovery of prostacyclin and its endothelial-related synthesis along with the work from Furchgott and Zawadzki concerning endothelial nitric oxide (eNO) demonstrated the importance of endothelium in vascular relaxation [7–9]. Consequently, tissue oxygen supply is dependent upon synthesis and release of NO, endothelial-derived hyperpolarizing factor (EDHF), arachidonic acid metabolites signaling via cyclooxygenase, lipoxygenase, and cytochrome P450 while the role of various molecules (angiotensin II (ATII), endothelin, urotensin, C-type natriuretic peptide, bradykinin, adrenomedullin, adenosine, purines, reactive oxygen species (ROS)) is vital in achieving the balance in vascular tone [10].
2.1.2. The Role of Nitric Oxide
Nitric oxide is a molecule with pleiotropic functions in endothelial function. It is synthesized from L-arginine in endothelial cells, with calcium-calmodulin-dependent NO synthase (NOS) acting as a catalyst for this reaction. Three different subtypes of NOS (neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS)) have been reported, each having different structural and functional characteristics. Calcium-dependent enzymes nNOS and eNOS are the constitutive NOS while iNOS is induced by immunological stimuli. Among the known required NOS co-factors are oxygen, nicotinamide adenine dinucleotide phosphate (NADPH), and tetrahydrobiopterin (BH4) [11]. Following its synthesis, it is distributed from the endothelial cell membrane to vascular smooth muscle cells leading to the activation of guanylate cyclase, which then converts GTP to cGMP, ultimately resulting in the removal of calcium and consequent relaxation of cells [12].
Other than its role in mediating the vascular tone via relaxation of smooth muscle cells, NO has an antithrombotic role due to the attenuation of platelet activation and aggregation, regulates the migration and adhesion of leukocytes on EC, and inhibits vascular smooth muscle cell proliferation [11]. Moreover, it has been implicated in the maintenance of endothelial integrity and permeability [13]. It should also be noted that NO is a potent oxygen-free radical scavenger by enhanced decomposition of peroxynitrite to nitrate and nitrite and inhibition of neutrophil-related O− 2 productions via limiting NADPH oxidase activity [14,15].
3. Assessment of Endothelial Function
4. Pathophysiology of Endothelial Dysfunction
4.1. eNOS Uncoupling
4.2. Cardiovascular Risk Factors and Endothelial Dysfunction
4.2.1. Smoking
4.2.2. Diabetes Mellitus
4.2.3. Arterial Hypertension
4.2.4. Hypercholesterolemia
5. The Role of Inflammation in Endothelial Dysfunction
5.1. TLRs and Endothelial Dysfunction
5.2. NLRP3 Inflammasome and Endothelial Dysfunction
5.3. The Role of NF-κB and Adhesion Molecules
5.4. The Pro-Inflammatory Effect of NOX
5.5. Neutrophil Extracellular Traps
5.6. Shear Stress
5.7. Endothelial Dysfunction in Chronic Inflammatory Diseases
6. A Link between Inflammation and Thrombosis in Endothelial Dysfunction
7. Clinical Implications and Future Directions
8. Conclusions
Endothelial dysfunction is frequently mentioned in the initial steps of atherogenesis, promoted by the highly prevalent cardiovascular risk factors. Inflammation plays an important role in its development, with recent studies providing additional knowledge on the complex pathophysiology of endothelial dysfunction. Amelioration of endothelial function could represent an additional step in cardiovascular risk reduction at the early stages of atherogenesis, with the role of genetic and epigenetic manipulation being under rigorous investigation.
