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Assessment of endothelial dysfunction in childhood obesity and clinical use.

Bruyndonckx L, Hoymans VY, Van Craenenbroeck AH, Vissers DK, Vrints CJ, Ramet J, Conraads VM - Oxid Med Cell Longev (2013)

Bottom Line: The aim of this paper is to provide a critical overview on both in vivo as well as in vitro markers for endothelial integrity.Additionally, an in-depth description of the mechanisms that disrupt the delicate balance between endothelial damage and repair will be given.Finally, the effects of lifestyle interventions and pharmacotherapy on endothelial dysfunction will be reviewed.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cellular and Molecular Cardiology, University Hospital Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium. luc.bruyndonckx@ua.ac.be

ABSTRACT
The association of obesity with noncommunicable diseases, such as cardiovascular complications and diabetes, is considered a major threat to the management of health care worldwide. Epidemiological findings show that childhood obesity is rapidly rising in Western society, as well as in developing countries. This pandemic is not without consequences and can affect the risk of future cardiovascular disease in these children. Childhood obesity is associated with endothelial dysfunction, the first yet still reversible step towards atherosclerosis. Advanced research techniques have added further insight on how childhood obesity and associated comorbidities lead to endothelial dysfunction. Techniques used to measure endothelial function were further brought to perfection, and novel biomarkers, including endothelial progenitor cells, were discovered. The aim of this paper is to provide a critical overview on both in vivo as well as in vitro markers for endothelial integrity. Additionally, an in-depth description of the mechanisms that disrupt the delicate balance between endothelial damage and repair will be given. Finally, the effects of lifestyle interventions and pharmacotherapy on endothelial dysfunction will be reviewed.

Show MeSH

Related in: MedlinePlus

Normal endothelial function versus endothelial dysfunction. Schematic overview of nitric oxide (NO) production and relaxation of Vascular Smooth Muscle Cells (VSMC). In response to increased shear stress or as a result of insulin signaling, the phosphoinositol 3 kinase (PI3K)/akt pathway is activated leading to phosphorylation of endothelial Nitric Oxide Synthase (eNOS). eNOS, together with the necessary cofactor tetrahydrobiopterin (BH4), converts L-arginine to L-citrulline and NO. NO activates guanylyl cyclase, which induces smooth muscle relaxation, through increased production of cyclic Guanosine MonoPhosphate (cGMP). Superoxide reduced NO bioavailability by reacting with NO to form peroxynitrite (ONOO−), which has strong oxidant properties. Endothelial dysfunction in obese children is characterized by insulin resistance impairing insulin-mediated NO production and subsequent vasodilation. Furthermore, oxidized LDL and ADMA are inhibitors of eNOS activation. In the situation of diminished availability of BH4, eNOS becomes “uncoupled” and paradoxically leads to increased reactive oxygen species (ROS) generation, which also contributes to reduced bioavailability of NO and vasoconstriction. ADMA, Asymmetric DiMethylArginine; PI3K, PhosphatidylInositol 3-Kinase; BH4, tetrahydrobiopterin; eNOS, endothelial Nitric Oxide Synthase; O2−, superoxide; ONOO−, peroxynitrite; GTP, Guanosine TriPhosphate; cGMP, cyclic Guanylyl MonoPhosphate; NADPH oxidase, Nicotinamide Adenine Dinucleotide Phosphate oxidase; OxLDL, Oxidized Low-Density Lipoprotein Cholesterol.
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Related In: Results  -  Collection


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fig1: Normal endothelial function versus endothelial dysfunction. Schematic overview of nitric oxide (NO) production and relaxation of Vascular Smooth Muscle Cells (VSMC). In response to increased shear stress or as a result of insulin signaling, the phosphoinositol 3 kinase (PI3K)/akt pathway is activated leading to phosphorylation of endothelial Nitric Oxide Synthase (eNOS). eNOS, together with the necessary cofactor tetrahydrobiopterin (BH4), converts L-arginine to L-citrulline and NO. NO activates guanylyl cyclase, which induces smooth muscle relaxation, through increased production of cyclic Guanosine MonoPhosphate (cGMP). Superoxide reduced NO bioavailability by reacting with NO to form peroxynitrite (ONOO−), which has strong oxidant properties. Endothelial dysfunction in obese children is characterized by insulin resistance impairing insulin-mediated NO production and subsequent vasodilation. Furthermore, oxidized LDL and ADMA are inhibitors of eNOS activation. In the situation of diminished availability of BH4, eNOS becomes “uncoupled” and paradoxically leads to increased reactive oxygen species (ROS) generation, which also contributes to reduced bioavailability of NO and vasoconstriction. ADMA, Asymmetric DiMethylArginine; PI3K, PhosphatidylInositol 3-Kinase; BH4, tetrahydrobiopterin; eNOS, endothelial Nitric Oxide Synthase; O2−, superoxide; ONOO−, peroxynitrite; GTP, Guanosine TriPhosphate; cGMP, cyclic Guanylyl MonoPhosphate; NADPH oxidase, Nicotinamide Adenine Dinucleotide Phosphate oxidase; OxLDL, Oxidized Low-Density Lipoprotein Cholesterol.

Mentions: The endothelial cell-layer is located at the border between circulating blood and vascular smooth muscle cells (VSMC) [11]. In response to stimuli that indicate increased blood flow demand (e.g., increased shear stress), activation of the PhosphoInositol 3-Kinase (PI3K)/Akt pathway will lead to phosphorylation of endothelial Nitric Oxide Synthase (eNOS), which is necessary for its activation and the generation of Nitric Oxide (NO) (Figure 1) [12]. By fine-tuning vascular smooth muscle relaxation, NO is one of the main regulators of vascular tone [13, 14]. In addition, healthy endothelium is responsible for the maintenance of an atheroprotective environment: it prevents platelet aggregation, proliferation of VSMC, and adhesion and subsequent diapedesis of leukocytes through the vascular wall [15].


Assessment of endothelial dysfunction in childhood obesity and clinical use.

Bruyndonckx L, Hoymans VY, Van Craenenbroeck AH, Vissers DK, Vrints CJ, Ramet J, Conraads VM - Oxid Med Cell Longev (2013)

Normal endothelial function versus endothelial dysfunction. Schematic overview of nitric oxide (NO) production and relaxation of Vascular Smooth Muscle Cells (VSMC). In response to increased shear stress or as a result of insulin signaling, the phosphoinositol 3 kinase (PI3K)/akt pathway is activated leading to phosphorylation of endothelial Nitric Oxide Synthase (eNOS). eNOS, together with the necessary cofactor tetrahydrobiopterin (BH4), converts L-arginine to L-citrulline and NO. NO activates guanylyl cyclase, which induces smooth muscle relaxation, through increased production of cyclic Guanosine MonoPhosphate (cGMP). Superoxide reduced NO bioavailability by reacting with NO to form peroxynitrite (ONOO−), which has strong oxidant properties. Endothelial dysfunction in obese children is characterized by insulin resistance impairing insulin-mediated NO production and subsequent vasodilation. Furthermore, oxidized LDL and ADMA are inhibitors of eNOS activation. In the situation of diminished availability of BH4, eNOS becomes “uncoupled” and paradoxically leads to increased reactive oxygen species (ROS) generation, which also contributes to reduced bioavailability of NO and vasoconstriction. ADMA, Asymmetric DiMethylArginine; PI3K, PhosphatidylInositol 3-Kinase; BH4, tetrahydrobiopterin; eNOS, endothelial Nitric Oxide Synthase; O2−, superoxide; ONOO−, peroxynitrite; GTP, Guanosine TriPhosphate; cGMP, cyclic Guanylyl MonoPhosphate; NADPH oxidase, Nicotinamide Adenine Dinucleotide Phosphate oxidase; OxLDL, Oxidized Low-Density Lipoprotein Cholesterol.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3649697&req=5

fig1: Normal endothelial function versus endothelial dysfunction. Schematic overview of nitric oxide (NO) production and relaxation of Vascular Smooth Muscle Cells (VSMC). In response to increased shear stress or as a result of insulin signaling, the phosphoinositol 3 kinase (PI3K)/akt pathway is activated leading to phosphorylation of endothelial Nitric Oxide Synthase (eNOS). eNOS, together with the necessary cofactor tetrahydrobiopterin (BH4), converts L-arginine to L-citrulline and NO. NO activates guanylyl cyclase, which induces smooth muscle relaxation, through increased production of cyclic Guanosine MonoPhosphate (cGMP). Superoxide reduced NO bioavailability by reacting with NO to form peroxynitrite (ONOO−), which has strong oxidant properties. Endothelial dysfunction in obese children is characterized by insulin resistance impairing insulin-mediated NO production and subsequent vasodilation. Furthermore, oxidized LDL and ADMA are inhibitors of eNOS activation. In the situation of diminished availability of BH4, eNOS becomes “uncoupled” and paradoxically leads to increased reactive oxygen species (ROS) generation, which also contributes to reduced bioavailability of NO and vasoconstriction. ADMA, Asymmetric DiMethylArginine; PI3K, PhosphatidylInositol 3-Kinase; BH4, tetrahydrobiopterin; eNOS, endothelial Nitric Oxide Synthase; O2−, superoxide; ONOO−, peroxynitrite; GTP, Guanosine TriPhosphate; cGMP, cyclic Guanylyl MonoPhosphate; NADPH oxidase, Nicotinamide Adenine Dinucleotide Phosphate oxidase; OxLDL, Oxidized Low-Density Lipoprotein Cholesterol.
Mentions: The endothelial cell-layer is located at the border between circulating blood and vascular smooth muscle cells (VSMC) [11]. In response to stimuli that indicate increased blood flow demand (e.g., increased shear stress), activation of the PhosphoInositol 3-Kinase (PI3K)/Akt pathway will lead to phosphorylation of endothelial Nitric Oxide Synthase (eNOS), which is necessary for its activation and the generation of Nitric Oxide (NO) (Figure 1) [12]. By fine-tuning vascular smooth muscle relaxation, NO is one of the main regulators of vascular tone [13, 14]. In addition, healthy endothelium is responsible for the maintenance of an atheroprotective environment: it prevents platelet aggregation, proliferation of VSMC, and adhesion and subsequent diapedesis of leukocytes through the vascular wall [15].

Bottom Line: The aim of this paper is to provide a critical overview on both in vivo as well as in vitro markers for endothelial integrity.Additionally, an in-depth description of the mechanisms that disrupt the delicate balance between endothelial damage and repair will be given.Finally, the effects of lifestyle interventions and pharmacotherapy on endothelial dysfunction will be reviewed.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cellular and Molecular Cardiology, University Hospital Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium. luc.bruyndonckx@ua.ac.be

ABSTRACT
The association of obesity with noncommunicable diseases, such as cardiovascular complications and diabetes, is considered a major threat to the management of health care worldwide. Epidemiological findings show that childhood obesity is rapidly rising in Western society, as well as in developing countries. This pandemic is not without consequences and can affect the risk of future cardiovascular disease in these children. Childhood obesity is associated with endothelial dysfunction, the first yet still reversible step towards atherosclerosis. Advanced research techniques have added further insight on how childhood obesity and associated comorbidities lead to endothelial dysfunction. Techniques used to measure endothelial function were further brought to perfection, and novel biomarkers, including endothelial progenitor cells, were discovered. The aim of this paper is to provide a critical overview on both in vivo as well as in vitro markers for endothelial integrity. Additionally, an in-depth description of the mechanisms that disrupt the delicate balance between endothelial damage and repair will be given. Finally, the effects of lifestyle interventions and pharmacotherapy on endothelial dysfunction will be reviewed.

Show MeSH
Related in: MedlinePlus