Endothelial Dysfunction and Hypertension
2014; Lippincott Williams & Wilkins; Volume: 64; Issue: 5 Linguagem: Inglês
10.1161/hypertensionaha.114.03575
ISSN1524-4563
Autores Tópico(s)Sodium Intake and Health
ResumoHomeHypertensionVol. 64, No. 5Endothelial Dysfunction and Hypertension Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBEndothelial Dysfunction and Hypertension Ralf P. Brandes Ralf P. BrandesRalf P. Brandes From the Fachbereich Medizin der Goethe-Universität, Institut für Kardiovaskuläre Physiologie, Frankfurt am Main, Germany. Originally published25 Aug 2014https://doi.org/10.1161/HYPERTENSIONAHA.114.03575Hypertension. 2014;64:924–928Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2014: Previous Version 1 The role of the vascular endothelium for hypertension development is not trivial to define. A quiescent healthy endothelium continuously releases potent vasodilators in response to the flowing blood, which have the potential to lower vascular resistance directly. Endothelial dysfunction is a condition comprising not only attenuated endothelium-dependent vasodilatation but also endothelial inflammatory activation.1 Although it is well accepted that endothelial dysfunction is a predictor of atherosclerosis development and future cardiovascular events, its role for hypertension is less well understood. To assume that attenuated endothelial vasodilator release through an increase in peripheral resistance directly translates into hypertension would be naïve. Not only that metabolic and local nervous factors have a much stronger effect on local vascular tone but also the renal and central control of blood pressure over-rule local vascular factors in their effect on blood pressure. This is easy to understand because the main objective of circulation control is the maintenance of blood pressure so that each organ separately and individually controls its perfusion through local factors. Systemic blood pressure control, however, is usually preserved in conditions associated with endothelial dysfunction, such as hypercholesterolemia and smoking, even if these may eventually result in hypertension development (Figure 1). In patients with heart failure, blood pressure is usually normal, despite the massive increase in peripheral resistance. Under this condition, low cardiac output and systemic hypoxia contribute to peripheral vasoconstriction. The latter is a consequence of increased sympathetic nerve activation and blunted endothelial NO function.2 Conversely, normalization of endothelial function does not necessarily affect blood pressure. Endothelial-specific deletion of the mineralocorticoid receptor improved endothelial function and attenuated vascular inflammation in aldosterone and deoxycorticosterone acetate (DOCA)/salt-induced vascular dysfunction in mice but did not lower blood pressure.3Download figureDownload PowerPointFigure 1. Pathways from endothelial dysfunction to hypertension. ROS indicates reactive oxygen species.Interestingly, despite the low basal vascular tone of the lung under physiological conditions, sympathetic control of vessel tone becomes important during the development of pulmonary artery hypertension (PAH): In the monocrotaline rat model of PAH, sympathetic activity was increased and ganglion blockade reduced pulmonary pressure, as well as endothelial dysfunction, and increased NO availability.4In addition to peripheral resistance, the endothelium affects other aspects contributing to hypertension development. Vascular stiffness, for example, on one hand, is an expression of systemic aging and correlates with lung stiffness,5 but on the other, this parameter is also modulated by the endothelium and thus relates to pulse wave velocity and pulse pressure. The endothelium also orchestrates vascular remodeling processes and inflammation; conversely, inflammation induces endothelial dysfunction. For example, tumor necrosis factor α–induced endothelial dysfunction in humans is partly mediated by endothelial nitric oxidase synthase (eNOS) mRNA destabilization through miR-155: eNOS is a target of miR-155 and this miR is induced by tumor necrosis factor-α. Thus tumor necrosis factor-α mediates an impairment of endothelium-dependent relaxation of the human mammary artery, an effect prevented by anti–Mir-155.6Endothelial Inflammation and HypertensionSome evidence indicates that endothelial inflammatory activation promotes hypertension development. With the variable outcome of renal artery denervation, it is important to identify biomarkers predicting the success of the procedure. In a study with 55 patients with hypertension, 9 did not respond to the procedure with an adequate antihypertensive response. These patients had significantly lower plasma levels of soluble fms-like tyrosine kinase-1 (sFLT-1), ICAM-1 and VCAM-1 than responders.7 This suggests that inflammatory activation predicts responses to the renal artery denervation. Interestingly, in keeping with the concept of hypertension being the consequence of inflammation, studies suggest that inflammatory cells are required for hypertension development. In the DOCA-salt-uninephrectomy model of hypertensive mice, the chemokine receptor CCR2 and its ligands CCL2, 7, 8, and 12 are increased. The CCR2 antagonist INCB3344 prevented vascular macrophage influx and attenuated hypertension development by ≈50%.8 Similarly, the vascular effects of aldosterone involve inflammatory cells: aldosterone requires the presence of macrophages9 and slightly decreased the number of anti-inflammatory T regulatory lymphocytes. Adoptive transfer of the latter cells attenuated the negative responses elicited by aldosterone.10 Similarly, the responses to endothelin11 and angiotensin II (Ang II)12 involve myeloid cells, and depletion of macrophages or congenital lack of macrophages in osteopetrotic mice attenuated hypertension, endothelial dysfunction, and vascular oxidative stress in response to these stimuli.13 The inflammation occurring in response to vasoconstrictor agonists, such as Ang II, is mediated by several transcription factors, including nuclear factor κB, activator protein-1, and also signal transducers and activator of transcription. Inhibition of STAT3 with a small-molecule inhibitor prevented the Ang II–induced vascular dysfunction of the murine carotid artery in and ex vivo and reduced the hypertension development in response to Ang II.14Endothelial Reactive Oxygen Species Production and HypertensionAn important consequence of the inflammation induced by Ang II is increased vascular reactive oxygen species (ROS) formation. It is well established that Ang II induces and activates Nox NADPH oxidases,15 but recently additional ROS sources have been established. In small arteries isolated from subcutaneous biopsies of patients with hypertension, a significant portion of ROS is produced by cyclooxygenase 2, which exhibits an increased expression in these patients.16 In the mouse aorta, the mitochondrial monoamine oxidase is another mediator of endothelial dysfunction after treatment with Ang II or during inflammation. Mitochondrial monoamine oxidase-A and mitochondrial monoamine oxidase-B are induced in the vessels under these conditions and generate a significant amount of hydrogen peroxide (H2O2) sufficient to attenuate endothelial NO release.17 Other mitochondrial ROS sources, such as p66Shc, probably also contribute to hypertension-induced ROS production.18 Interestingly, several mechanisms support the signaling pathway from Ang II to Nox induction and oxidative stress. In the kidney, an important role of cytochrome P450 1B1 (Cyp1B1) has been documented. Genetic deletion of the enzymes in mice prevented the Ang II–stimulated increase in 12- and 20-hydroxyeicosatetraenoic acids, ROS formation, Nox activity, and stimulation of ROS-sensitive kinases,19 and similar effects were observed in the DOCA and salt hypertension model.20 Part of the action of Cyp1B1 seems to be mediated by the metabolism of estrogens, which limit Nox activation and induction.21 This aspect is important because renal dysfunction has a much stronger effect on hypertension development than pure endothelial dysfunction in arteries or, for example, the skeletal muscle. Intrarenal vascular resistance in response to Ang II is increased in ApoE–/– mice through a ROS-dependent activation of p38 mitogen-activated protein kinase and subsequent phosphorylation of MLC20. Ang II is produced from Ang I by angiotensin-converting enzyme 1 (ACE1), whereas ACE2 generates Ang-(1-7), which in part antagonizes the responses to Ang II. Indeed, Ang-(1-7) treatment attenuates the effects of Ang II on the kidney of ApoE–/– mice and reduced the basal renal NADPH oxidase and p38 mitogen-activated protein kinase activity. Knockout of Mas, the receptor for Ang-(1-7), or inhibition of p38 mitogen-activated protein kinase blocked the beneficial effects of Ang-(1-7) on the kidney.22 Given that Ang-(1-7) is produced by ACE2, it is attractive to speculate that increasing ACE2 results in vascular protection. With the compound 1-[(2-dimethylamino)ethylamino]-4-(hydroxymethyl)-7-[(4-methylphenyl) sulfonyl oxy]-9H-xanthene-9-one (XNT), a small-molecule ACE2 activator has become available. XNT improved endothelial function in spontaneously hypertensive rats and in streptozotocin-diabetic rats through a Mas receptor–dependent effect. Similarly, xanthates attenuated the Ang II–induced ROS production of human aortic endothelial cells.23Endothelial Function: A Therapeutic Target for the Treatment of Hypertension?Changing the vascular redox environment is an alternative to directly interfering with Ang II signaling in endothelial dysfunction. Ang II–induced vascular dysfunction is endogenously partly blunted by the induction of the copper-containing extracellular superoxide dismutase 3. It turns out that this involves a mechanism in which Ang II induces the copper-low–sensitive transcription factor and copper chaperone Atox1. Deletion of Atox1 prevented the Ang II–mediated SOD3 induction. Ang II simultaneously increased the binding of Atox1 to the copper exporter ATP7A and thereby induced cytosolic copper export, which promoted copper loading of extracellular superoxide dismutase.24Another approach to restore normal endothelial function is to alter the activity of G-protein–coupled receptor (GPCR) kinases. These enzymes limit GPCR signaling by phosphorylating the activated receptor, which is then internalized. Because GPCRs mediate the harmful signaling of Ang II, thromboxane, endothelin, and other vascular growth factors or vasoactive compounds, they contribute to endothelial dysfunction and vasoconstrictor signaling. Because GPCRs, however, also facilitate endothelial vasodilator release, it was unclear whether GPCR kinases are good antihypertensive drug targets. This was studied by heterozygous deletion of the ubiquitously expressed GPCR kinase 2 in Ang II–induced vascular dysfunction in mice. Heterozygous deletion of GPCR kinase 2 resulted in attenuated Ang II–induced hypertension, remodeling, and endothelial dysfunction. This suggests that at least mild pharmacological inhibition of GPCR kinase 2 could be beneficial.25Improving endothelial function is not a main indication of cardiovascular drugs but a welcome pleiotropic effect. It was, therefore, interesting to note that fenofibrate improves flow-mediated brachial artery dilatation at 2 and 7 days in a placebo-controlled study of 12 and 10 patients in a lipid-independent manner. Probably, fenofibrate-enhanced endothelial NO production as an increased eNOS expression was noted in endothelial cells obtained from patients receiving the drug.26 Another approach to improve endothelial function is the supplementation of the polyphenol resveratrol, which induces NAD+-dependent histone deacetylases of the sirtuin family and has antioxidant and anti-inflammatory effects. Ex vivo resveratrol induced vascular relaxation and attenuated endothelial dysfunction through a pathway involving AMP-activated kinase–dependent eNOS stimulation and induction of a Nrf2 (nuclear factor erythroid 2-related factor-2)–mediated antioxidant response in the thyroid artery of patients with hypertension.27Although there is little doubt that oxidative stress will ultimately attenuate endothelium-dependent relaxation, there is a phase of compensated stress in which agonist-stimulated endothelium-dependent relaxation is unaltered or even enhanced, despite elevated ROS formation. This was documented long ago in stroke-prone spontaneously hypertensive rats28 but seems also to be true for obesity: low Ang II salt-sensitive Dahl rats exhibit vascular dysfunction under basal conditions. High-fat diet, however, did not aggravate this state but rather improved vascular function, whereas it induced vascular dysfunction in the control animals. Both effects were sensitive to losartan, illustrating that lack of Ang II and Ang II overactivation in obesity induces vascular dysfunction.29 Eventually, increased ROS formation will attenuate endothelium-dependent relaxation. This is not only the result of NO scavenging but also the consequence of attenuated NO formation because of direct oxidative modification of eNOS. This effect occurs naturally during aging of mice. Aging per se causes s-glutathionylation of eNOS and protein kinase C, as well as protein tyrosine kinases are activated and place inhibitory phosphorylations on eNOS. Ablation of antioxidant enzymes, such as glutathione peroxidase-1, increased this effect.30 This obviously brings up the question on the value of antioxidant therapy. Although antioxidant therapy does not improve cardiovascular outcome, there is evidence that in aging antioxidants have an acute positive effect on vascular responses in humans. In a double-blind crossover study, oral supplementation of an antioxidant cocktail of vitamin C, vitamin E, and α-lipoic acid was able to improve endothelium-dependent flow-induced relaxation acutely, without any beneficial effects on vascular function in young health controls31 (Figure 2).Download figureDownload PowerPointFigure 2. Multiple positive feedback loops promote oxidative stress in inflammation. Cox2 indicates cyclooxygenase 2; CYP, cytochrome P450 monoxygenases; MAO, monoamine oxidase; Mito, mitochondria; NOS, NO synthase; Nox, Nox family NADPH oxidase; and ROS, reactive oxygen species.Pregnancy, Endothelial Dysfunction, and HypertensionFemale sexual hormones delay cardiovascular aging by increasing NO availability and reducing ROS formation. Ovariectomy in rodents is known to induce endothelial dysfunction, which is mediated, in part, by increased ROS formation.32 Interestingly, under normal conditions, perivascular adventitial fat tissue promotes endothelium-dependent relaxation; this effect is lost after ovariectomy in rats.33 The protective effects of female sexual hormones and their necessity for the maintenance of pregnancy are well documented, whereas the effect of testosterone on the endothelium is less clear. Testosterone is increased in preeclampsia, in polycystic ovary disease, and in blacks with gestational hypertension. Interestingly, treatment of pregnant rats with testosterone induced gestational hypertension and endothelial dysfunction as a consequence of reduced NO availability.34 The vascular alterations in preeclampsia are manifold and are partly a consequence of oxidative stress. In the reduced utero-placental perfusion rat model of preeclampsia, vasoconstrictor responses to big endothelin-1 but not endothelin were increased in the mesenteric artery. This was a consequence of an induction of matrix metalloproteinases, which was, in part, a result of increased mesenteric eNOS expression.35 Also in other vessels, such as the aorta, eNOS expression increases in this model, which was paralleled by an induction of lectin-like oxLDL receptor 1 and an increased sensitivity to oxidized low-density lipoprotein leading to eNOS uncoupling.36 Collectively, these findings identify the utero-placental reduced perfusion model as a stage of eNOS uncoupling. Preeclampsia has numerous profound effects on the vascular system. Interestingly, it increases the plasma concentrations of the soluble vascular endothelial growth factor receptor sFLT-1, which acts as a scavenger for free vascular endothelial growth factor and thereby limits this important endothelial survival factor. sFLT-1 is produced in the placenta and remarkably parts of the placental tissue in humans are embolized physiologically into the lung during pregnancy. The embolization rate of this sFLT-1–producing material is increased during eclampsia as revealed from human autopsies.37 This raises the important question whether latent vascular dysfunction is unmasked by pregnancy. For example, giving preterm birth is associated with an increase rate of hypertension 20 years later.38 Conversely, problems during pregnancy define the later vascular function of the child: Endothelial dysfunction is increased in children of low birth weight. Growth rate from 0 to 1 month inversely associates with endothelium-dependent vasodilatation of the skin in response to acetylcholine as measured by laser Doppler in a cohort of 104 newborns.39Collectively, research in the past 2 years resulted in a refinement of the concepts of interaction of endothelial dysfunction and hypertension. Novel sources of ROS are being identified and elements beyond vascular tone are becoming appreciated, which is particularly true for pregnancy, the immune system and the sympathetic tone.Sources of FundingThis work was supported by the Goethe-University, Frankfurt and the German Research Foundation, DGF.DisclosuresNone.FootnotesCorrespondence to Ralf P. Brandes, Fachbereich Medizin der Goethe-Universität, Institut für Kardiovaskuläre Physiologie, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany. E-mail [email protected]References1. Watson T, Goon PK, Lip GY. 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