Highlight on Endothelial Activation and Beyond
2018; Lippincott Williams & Wilkins; Volume: 38; Issue: 12 Linguagem: Inglês
10.1161/atvbaha.118.312054
ISSN1524-4636
Autores Tópico(s)Cardiovascular Disease and Adiposity
ResumoHomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 38, No. 12Highlight on Endothelial Activation and Beyond Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBHighlight on Endothelial Activation and Beyond Chantal M. Boulanger Chantal M. BoulangerChantal M. Boulanger Correspondence to Chantal M. Boulanger, PhD, INSERM UMR-970, Paris Cardiovascular Research Center, 56 rue Leblanc, 75737 Paris cedex 15. Email E-mail Address: [email protected] From the INSERM UMR-970, Paris Cardiovascular Research Center, Paris Descartes University, France. Originally published20 Nov 2018https://doi.org/10.1161/ATVBAHA.118.312054Arteriosclerosis, Thrombosis, and Vascular Biology. 2018;38:e198–e201Endothelial cells are major players in vascular homeostasis because of their anatomic location in close vicinity to the circulating blood and the underlying vascular wall. Endothelial atheroprotective functions are tightly regulated to shield the arterial wall against thrombosis, vasospasm, adhesion, and transmigration of circulating inflammatory cells, as well as uptake of lipoproteins. This review extends previous ones published in Arteriosclerosis, Thrombosis, and Vascular Biology1,2 by summarizing recent findings about the mechanisms regulating endothelial activation, and their impact during the development of atherosclerosis and metabolic diseases.Modulators of Endothelial FunctionDisturbed Blood FlowAtherosclerotic lesions built preferentially in specific areas where blood flow is low or disturbed. A large body of experimental studies demonstrates that blood flow patterns are associated with changes in endothelial atheroprotective functions.3,4 Breton-Romero et al5 now extend these findings to human subjects by reporting the association of oscillatory brachial blood flow with impaired vasodilator function and increased aortic stiffness in the large community-based Framingham study. In preventive strategies, it is of upmost importance to visualize areas of the arterial tree predisposed to develop flow-induced endothelial dysfunction in a noninvasive manner. An interesting molecular imaging target is the junctional adhesion molecule-A, which rapidly redistributes from intercellular tight junctions toward the luminal endothelial surface after exposure to changes in blood flow or to proinflammatory cytokines.6 Molecular ultrasound imaging of junctional adhesion molecule-A is capable of identifying flow-activated endothelial areas in a model of carotid artery ligation in apolipoprotein-E deficient mice,7 as well as endothelial cells lining vulnerable atherosclerotic plaques.8Recent studies in Arteriosclerosis, Thrombosis, and Vascular Biology have focused on the role of mechanical dragging forces exerted by circulating blood at the lining of arterial wall and the molecular mechanisms involved in sensing and translating these mechanical signals into biological responses. In a zebrafish model of flow manipulation, functional screening of mechanosensitive genes in vascular endothelial cells identified p53-related protein and programmed cell death 2-like protein as positive regulators of apoptosis, whereas angiopoietin-like 4 and cadherin 13 were negative regulators.9 Endothelial cells detect different flow patterns through the same initial molecular platform which includes the mechanosensitive cation Piezo1 channel, the purinergic P2Y2 receptor and Gq/G11.10 However, only disturbed flow causes Piezo1- and Gq/G11-dependent activation of NF-κB (nuclear factor-κB).10 Activation of flow-induced NF-κB signaling by disturbed flow patterns also results from increased expression of cystathionine γ-lyase,11 a major source of endothelial hydrogen sulfide (H2S); this in turn drives ICAM-1 (intercellular adhesion molecule–1)/VCAM-1 (vascular cell adhesion molecule 1) expression and inflammatory cell recruitment. However, H2S appears to have both proinflammatory and anti-inflammatory effects, which depend upon the dose or the pool of sulfur species involved.12 Recent studies demonstrate that cystathionine γ-lyase-derived H2S anti-inflammatory effects result from constitutive S-sulfhydration of the RNA-binding protein HuR, preventing its homodimerization and subsequent expression of E-selectin.13In addition to promoting an endothelial proinflammatory phenotype, disturbed blood flow increases the expression of endothelial CD36 scavenger receptor, favoring incorporation of oxidized LDL (low-density lipoprotein) in the vessel wall and leading to vascular stiffness in proatherogenic vascular areas.14 Recent experimental evidence also demonstrates that endothelial CD36 is involved in circulating free fatty acid uptake and regulates important downstream effects on glucose utilization and insulin action in tissues.15 These findings illustrate the augmented uptake of lipids and macromolecule in the vascular wall which contribute to the development of atherosclerotic lesions (reviewed in16).HIF1α PathwayFeng et al17 reported that under normoxic conditions, low shear stress regions in arteries expressed the transcriptional factor HIF1α (hypoxia-inducible factor 1α), a master regulator of cellular responses to hypoxia. They further deciphered the molecular mechanisms regulating HIF1α endothelial expression in low shear stress areas and demonstrated upregulation of HIF1α results from NF-κB–dependent induction of HIF1α transcripts and increased stabilization of HIF1α protein caused by induction of the deubiquitinating enzyme Cezanne. Carotid artery partial ligation of wild-type and apolipoprotein E-deficient mice revealed that endothelial HIF1α increased the expression of regulators of glycolysis and inflammatory markers E-selectin, ICAM-1, VCAM-1, and MCP-1 (monocyte chemoattractant protein 1). Increased glycolysis augmented endothelial proliferation in low shear stress areas, whereas high shear stress decreased glycolysis by activating Kruppel like factor 2 for transcriptional repression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3.18 All together, these findings and others point out the role of cellular metabolism in the regulation of endothelial atheroprotective functions.17,19,20 Disturbed flow and HIF1α also upregulate endothelial semaphorin 7A.21,22 Deletion of semaphorin 7A decreased leucocyte adhesion and the formation of atherosclerotic lesions in ApoE−/− mice; this effect was likely mediated by vascular semaphorin 7A and integrin β1, one of its membrane receptor, through activation of focal adhesion kinase, mitogen-activated protein kinase ½ and NF-κB.21 Whether the proatherogenic effect of endothelial semaphorin 7A results from flow-dependent regulation of HIF1α requires further investigations. Other strategies interacting with HIF1α pathway may also have beneficial effects for the treatment of metabolic dysfunctions and atherosclerosis. For instance, inhibitors of PHD2 (hypoxia-inducible factor prolyl 4-hydroxylase), an enzyme that targets HIF1α for proteasome degradation, are currently explored for treatment of anemia and protection against obesity and metabolic dysfunction. Treatment of LDL receptor-deficient mice with PHD2 inhibitors reduces the formation of atherosclerotic plaques by modulating lipid profiles, the innate immune system and by decreasing inflammation.23Endothelial Dysfunction and InflammationOur lifestyle directly influences endothelial function and our cardiovascular health. Consumption of sweetened beverages by young healthy individuals acutely impairs endothelial function both at the micro- and the macrocirculation level.24 This effect is fully alleviated by antioxidants, indicating that sweetened beverage-induced endothelial dysfunction is partly because of increased oxidative stress that hampers nitric oxide bioavailability. Both smoking and second-hand smoking also have a negative impact on endothelial function by decreasing endothelial nitric oxide bioavailability.25,26 Recent findings demonstrate that flavoring compounds used in alternative tobacco products and electronic cigarettes increase the release of the proinflammatory cytokine interleukin-6, impair nitric oxide production in cultured endothelial cells and therefore might blunt in vivo endothelial function.27Inflammatory Gene RegulationThe elegant study of Poulsen et al28 explored the mechanisms underlying the cross-talk between endothelial inflammatory signaling and the Notch pathway.29 These authors demonstrated that Notch regulates chromatin structure in genome regions which contain high levels of transcription factor binding sites regulating the expression of many inflammatory genes implicated in atherosclerosis.28,30 However, they did not observe the previously reported Notch-dependent NF-κB activation in their experimental conditions.31 The RGC-32 (response gene to complement 32) protein, which is mostly expressed in endothelial cells overlying atherosclerotic plaques, also stimulates atherogenesis by direct interaction and nuclear translocation of NF-κB and increase TNF (tumor necrosis factor)-α–induced NF-κB binding to ICAM-1 and VCAM-1 promoters.32Reactive Oxygen Species and Mitochondrial DysfunctionAlterations in reactive oxygen species (ROS) homeostasis play an important role in initiation and progression of vascular endothelial dysfunction. Mitochondrial dysfunction damages mitochondria and generates high levels of oxidative stress, which impair endothelial homeostasis. Peroxisome PGC-1α (proliferator receptor-γ coactivator 1α), a transcriptional coactivator linked to mitochondrial biogenesis, plays a key role in endothelial and smooth muscle cell oxidative stress and apoptosis and upregulation of PGC-1α prevents atherosclerotic lesion development.33 Several antioxidant enzymes, such as thioredoxin reductase 2, control mitochondrial ROS levels. Using a murine model of endothelial-specific deletion of thioredoxin reductase 2, Kirsch et al34 demonstrate that lack of endothelial thioredoxin reductase 2 caused a vascular proinflammatory and prothrombotic phenotype associated with increased ROS and altered mitochondrial membrane potential and impaired endothelial function resulting from inadequate nitric oxide signaling. Mitochondrial ROS might also serve as signaling mediators of endothelial activation induced by lysophosphatidylcholine in early atherosclerosis.35 However, increased endothelial expression of ROS-generating enzymes is not always deleterious during the development of atherosclerosis. For instance, increased expression of the superoxide-generating NOX4 (type 4 NADPH oxidase) in human atherosclerosis is a negative regulator of inflammation, promoting atheroprotection.36Endothelial Activation in Atherosclerosis and Metabolic DiseasesSpecific inactivation of the nucleotide P2Y2 receptor expression in the endothelium of apolipoprotein-E deficient mice decreases the formation of atherosclerotic plaques, characterized by less macrophage infiltration, and increased smooth muscle cell and collagen content; this leads to the formation of a subendothelial fibrous cap and promotes plaque stability.37 To evaluate the potential role of high-density lipoprotein-induced cholesterol efflux during atherosclerosis, expression of ABCA1 and ABCG1 (ATP-binding cassette transporters A1 and G1, respectively) was inactivated in endothelial cells of ldlr-deficient mice. Using this model, Westerterp et al38 reported that ABCA1 and ABCG1 transporters are independently atheroprotective. Deficiency in endothelial ABCA1 or ABCG1 transporters decreased endothelial nitric oxide synthase activity and increased monocytic infiltration in particular in areas of disturbed arterial blood flow.Vascular microenvironment, in particular the perivascular adipose tissue, also influences endothelial functions in the setting of obesity and metabolic diseases. For instance, diet-induced obesity uncouples endothelial nitric oxide synthase, an effect that can be reversed by L-arginine supplementation and arginase inhibitors.39 Excessive ROS produced by NOX impair endothelial vasodilation in human obese subjects, an effect that can be prevented by physical exercise.40 Microvascular endothelial dysfunction also results from the inducible nitric oxide synthase activity expressed by macrophages in the perivascular adipose tissue, that hampers H2S bioavailability.41 Activation of adipose tissue during aging is accompanied by increased expression of ADAM17, the TNF-α converting enzyme.42 The resulting increased cytokine levels then impair endothelium-dependent dilatation of human coronary artery.In conclusion, recent publications in Arteriosclerosis, Thrombosis, and Vascular Biology highlight the importance of understanding the mechanisms regulating the atheroprotective properties of endothelial cells in the context of atherosclerosis and metabolic diseases. These studies underline the emerging modulators that could be targeted in the future to prevent endothelial dysfunction or restore endothelial properties as novel therapeutic strategies in cardiovascular diseases.Sources of FundingThis work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM) and by Agence Nationale de Recherche (ANR-16-CE14-0015-01, ANR-16-CE92-0032-02, ANR-17-ECVD-0002-01).DisclosuresNone.FootnotesCorrespondence to Chantal M. Boulanger, PhD, INSERM UMR-970, Paris Cardiovascular Research Center, 56 rue Leblanc, 75737 Paris cedex 15. Email chantal.[email protected]frReferences1. Godo S, Shimokawa H. Endothelial functions.Arterioscler Thromb Vasc Biol. 2017; 37:e108–e114. doi: 10.1161/ATVBAHA.117.309813LinkGoogle Scholar2. Wang M, Hao H, Leeper NJ, Zhu L; Early Career Committee. Thrombotic regulation from the endothelial cell perspectives.Arterioscler Thromb Vasc Biol. 2018; 38:e90–e95. doi: 10.1161/ATVBAHA.118.310367LinkGoogle Scholar3. 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December 2018Vol 38, Issue 12 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.118.312054PMID: 30571176 Originally publishedNovember 20, 2018 Keywordsmetabolic diseasesthrombosislipoproteinhomeostasisatherosclerosisPDF download Advertisement SubjectsAtherosclerosisBasic Science ResearchVascular Disease
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