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• W2169319351 abstract "HomeHypertensionVol. 57, No. 3Endothelium-Dependent Contractions in Hypertension Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBEndothelium-Dependent Contractions in HypertensionWhen Prostacyclin Becomes Ugly Paul M. Vanhoutte Paul M. VanhouttePaul M. Vanhoutte From the Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, and the Department of BIN Fusion Technology, Chonbuk National University, Jeonju, Korea. Search for more papers by this author Originally published10 Jan 2011https://doi.org/10.1161/HYPERTENSIONAHA.110.165100Hypertension. 2011;57:526–531Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2011: Previous Version 1 Most isolated arteries respond to shear stress and several vasodilator substances, as demonstrated first for acetylcholine,1 by releasing endothelium-derived relaxing factor (or nitric oxide [NO]), and various endothelium-derived hyperpolarizing signals.2–5 However, in certain blood vessels, when exposed to stretch, agonists such as thrombin, acetylcholine, and adenosine nucleotides (adenosine diphosphate [ADP] and adenosine triphosphate [ATP]) or calcium ionophores, the endothelium produces diffusible cyclooxygenase (COX)-derived vasoconstrictor prostanoids (endothelium-derived contracting factors [EDCF])6–11 Endothelial cells also produce vasoconstrictor peptides, in particular, endothelin-1.12 The attribution of a role to endothelin-1 in instantaneous changes in vascular tone has been made difficult by the almost insurmountable nature of the vasoconstriction caused by the peptide that can only be tempered by NO or calcitonin gene-related peptide.13,14 Likewise, the evidence linking acute release of endothelin-1 to constriction of arteries is still limited.15 Therefore, the present article focuses on the mechanisms leading to the production of endothelial COX-derived vasoconstrictors, in particular, in the rat aorta, which has been the standard preparation used by the author and his collaborators for the study of EDCF-mediated responses However, the occurrence of such EDCF-mediated responses can vary widely, depending on the species and the blood vessel studied. For example, they are prominent in canine veins but not arteries.6 In the mouse, endothelium-dependent contractions are more pronounced in the carotid artery than in the aorta.16,17 Further, in any given blood vessel, the production of endothelium-derived vasoconstrictor prostanoids is exacerbated by aging and disease, in particular, hypertension.10,11,18,19The Trigger: CalciumAcetylcholine (which activates endothelial M3-muscarinic receptors)20 and ADP and ATP (which activate endothelial purinoceptors)21,22 evoke endothelium-dependent contractions and release of calcium from the sarcoplasmic reticulum.23 Lowering the extracellular calcium concentration reduces endothelium-dependent contractions,24 whereas calcium ionophores, in particular, A23187, evoke endothelium-dependent contractions.25–29 During endothelium-dependent contractions induced by acetylcholine, the endothelial cytosolic calcim concentration increases28,29 and this increment is larger in aortae of spontaneously hypertensive rats (SHR) than in those of normotensive Wistar-Kyoto rats, in line with the larger EDCF-mediated responses in the preparations of the hypertensive strain.8,28,30 Taken in conjunction, those findings imply that an increase in endothelial cytosolic calcium concentration is the initiating event leading to the release of EDCF. In the case of acetylcholine, the muscarinic agonist binds to G-protein–coupled M3 receptors on the endothelial cell membrane and activates phospholipase C, which produces inositol triphosphate, causing the release of calcium from intracellular stores. The resulting calcium depletion process favors the production of calcium influx factor,31 which displaces calmodulin from the calcium-independent phospholipase A2 (iPLA2).32–35 The activation of iPLA2 is the initiating event in endothelium-dependent contractions to acetylcholine.36 The lysophospholipids produced by the activated iPLA2 open store-operated calcium channels, allowing influx of extracellular calcium into the endothelial cells.35,37 The resulting increase in cytosolic calcium ions28,29 then activates calcium-dependent PLA2, which transforms membrane phospholipids into arachidonic acid, providing substrate for COX and thus for the production of EDCF (Figure 1).Download figureDownload PowerPointFigure 1. Endothelium-dependent contraction is likely to comprise 2 components: generation of prostanoids and ROS. Each component depends on the activity of endothelial COX-1 and the stimulation of the TP receptors located on the smooth muscle to evoke contraction. In the SHR aorta, there is an increased expression of COX-1 and EP3 receptors, increased release of calcium, ROS, endoperoxides, and other prostanoids, which facilitates the greater occurrence of endothelium-dependent contraction in the hypertensive rat. The necessary increase in intracellular calcium can be triggered by receptor-dependent agonists, such as acetylcholine or ADP, or mimicked with calcium-increasing agents, such as the calcium ionophore A23187. The abnormal increase in intracellular ROS can be mimicked by the exogenous addition of H2O2 or the generation of extracellular ROS by incubation of xanthine with xanthine oxidase. AA indicates arachidonic acid; Ach, acetycholine; H2O2, hydrogen peroxide; M, muscarinic receptors; P, purinergic receptors; PGIS, prostacyclin synthase; TXA2, thromboxane A2; TXAS, thromboxane synthase; X+XO, xanthine plus xanthine oxidase.5The Mediators: ProstanoidsThe 2 isoforms of COX, COX-1, and COX-2,38–40 can contribute to the generation of EDCF depending on the species, the blood vessel studied, and the health conditions of the donor.5,11,27,41,42 Nonselective COX inhibitors (eg, indomethacin) abrogate endothelium-dependent contractions.7,8,25 Preferential inhibitors of COX-1, but not those of COX-2, prevent endothelium-dependent contractions in the SHR aorta.30,43–45 Although in that preparation, COX-1 is expressed in both endothelial and vascular smooth muscle cells, the gene encoding for this isoform is overexpressed only in the endothelial cells of the SHR,46 and only the activation of endothelial COX contributes to the generation of EDCF.30 Endothelium-dependent contractions are absent in the aorta of COX-1 but not in that of COX-2 knockout mice.47 Taken in conjunction, these findings suggest that COX-1 is the preferential isoform of COX involved in endothelium-dependent contractions in large arteries of rats and mice. COX-1 overexpression is not observed in the aorta of young SHR, and this isoform is more prominent in arteries from older than young normotensive rats.46,48,49 This then suggests the conclusion that the COX-1 overexpression in arteries from the adult SHR reflects premature aging of the vascular wall rather than a genetic predisposition. However, with aging or disease, if COX-2 is induced, it also contributes to EDCF-mediated responses,50–53 as it does in arteries in which it is constitutively expressed.42 COX-1 and COX-2 convert arachidonic acid into endoperoxides, which either diffuse to the underlying vascular smooth muscle cells (see below) or are metabolized by individual synthases,54 mainly into either prostacyclin (PGI2) or thromboxane A2, although the other prostaglandins (prostaglandin D2 [PGD2], prostaglandin E2 [PGE2], and prostaglandin F2α [PGF2α]) can contribute to EDCF-mediated responses (Figure 2).26,42,46,55,56Download figureDownload PowerPointFigure 2. Endothelium-dependent effects of acetylcholine in rat aorta. Left, Endothelium-dependent relaxations in normotensive rats. Right, COX-dependent, endothelium-dependent contractions to acetylcholine in SHR aorta. R indicates receptor; IP, PGI2 receptor; TP, TP receptor; AA, arachidonic acid; S-18886 (terutroban), antagonist of TP receptors; M, muscarinic receptor; PGIS, prostacyclin synthase; PGH2, endoperoxides; sGC, soluble guanylyl cyclase; AC, adenylyl cyclase; SR, sarcoplasmic reticulum; +, activation; −, inhibition; ?, unknown site of formation. (Modified from Vanhoutte et al, 2009.5)Endoperoxides are unstable, but they can activate thromboxane-prostanoid (TP) receptors of vascular smooth muscle and thus contribute to endothelium-dependent contractions.43,57,58 In particular, acetylcholine causes a greater release of endoperoxides in the aorta of the SHR than in that of normotensive rats.43,48 The contribution of endoperoxides to EDCF-mediated responses may become even more important when the activity of PGI2 synthase is reduced by tyrosine nitration resulting from the local production of peroxynitrite.55,59,60PGI2 is the major product of COX in endothelial cells.61 The expression of the gene encoding for PGI2 synthase in endothelial cells is augmented with age and by hypertension.46,62 During endothelium-dependent contractions of the SHR aorta to acetylcholine, the production of PGI2 is by far larger than that of other prostaglandins and reaches levels compatible with the activation of TP receptors of the vascular smooth muscle cells, making the prostanoid a major EDCF.11,18,51,55During endothelium-dependent increases in tension to ADP and A23187, the release of thromboxane A2 is augmented as well, and those contractions, unlike the one in response to acetylcholine, are reduced partially by inhibitors of thromboxane A2 synthase.26,56,63 Thus, thromboxane A2 contributes to EDCF-mediated responses elicited by these agonists. Likewise, PGE2 and PGF2α contribute to EDCF-mediated responses in the hamster aorta or in arteries of aging and diabetic rats.42,64 This contribution results from enhanced oxidative stress and the augmented generation of peroxynitrite, which inhibits PGI2 synthase and diverts arachidonic acid toward PGE2 and PGF2α synthases.55,59,60,65,66The Amplifiers: Reactive Oxygen SpeciesThe exaggerated production of reactive oxygen species (ROS) causes oxidative stress and is a hallmark of atherosclerosis, diabetes, and hypertension.67–69 In the canine basilar artery, superoxide anions mediate endothelium-dependent contractions.70,71 Although hydrogen peroxide can act as a vasodilator,72,73 it contributes to the stimulation by ROS of COX in vascular smooth muscle cells and thus can act either directly as EDCF or potentiate their response to endothelium-derived prostanoids.52,69,74–77 Superoxide anions also indirectly can amplify EDCF-mediated responses by reducing the bioavailability of NO.78–83 The production of ROS in endothelial cells is augmented during endothelium-dependent contractions to acetylcholine or A23187.28 Further, antioxidants reduce endothelium-dependent contractions, suggesting that ROS augment or even mediate part of the response.55,68,77 To judge from results obtained in the rat pulmonary artery, the ROS-induced contraction involves the activity of protein kinase C in the vascular smooth muscle.84 In the rat aorta, ROS cause calcium sensitization, which is mediated by the activation of Rho and an increase in Rho kinase activity, which plays a key role in the response of the vascular smooth muscle to EDCF.85,86 In addition, ROS directly depolarize vascular smooth muscle cells by inhibiting various potassium channels.87–89The Intercellular Links: Gap JunctionsEndothelium-dependent contractions to acetylcholine are smaller in layered bioassay (“sandwich”) preparations than in intact rings,77 illustrating that the contact between endothelial and vascular smooth muscle cells is important in the genesis of EDCF-mediated responses. In bioassay preparations, the endothelium-derived prostanoids diffuse freely across the intercellular gap between the donor (containing endothelial cells) and the effector (without endothelium, responsible for the contraction), and cell-impermeable antioxidants reduce the response to acetylcholine, whereas they do not in intact rings in which intracellular antioxidants inhibit EDCF-mediated responses.30,74 Thus, ROS exert their facilitatory effect by either acting in the endothelial cells or being transported from the latter to the vascular smooth muscle cells via preferential channels not accessible to cell-impermeable antioxidants. One possible channel for linking the endothelial and vascular smooth muscle cells are the myoendothelial gap junctions. This interpretation is prompted by the observation that gap junction inhibitors reduce endothelium-dependent contractions to acetylcholine and the calcium ionophore A23187.49The Effectors: The TP ReceptorsTP receptor antagonists abrogate endothelium-dependent contractions in mouse, rabbit, and rat arteries.17,30,47,63,90–92 In SHR aorta, the expression of the gene encoding for and the protein presence of TP receptors are comparable in the aortae of Wistar-Kyoto rats and SHR, but the contractions evoked by endoperoxides are larger in the latter,43,46 suggesting that this hyper-responsiveness contributes to the prominence of endothelium-dependent contractions in the hypertensive strain. Because the hyper-responsiveness is present already in young SHR, it thus is not a consequence of the chronic exposure of the endothelium to the high arterial blood pressure and constitutes a genetic platform leading to endothelial dysfunction.48 In addition, vascular smooth muscle cells of older Wistar-Kyoto rats (in which endothelium-dependent contractions appear progressively with aging) and of SHR no longer relax when exposed to PGI2, despite an unchanged expression of IP receptors.46,55,93,94 It is unknown whether or not this lack of responsiveness of IP receptors initiates a positive feedback on the endothelial cells, leading to the abundant overexpression of PGI2 synthase and the predominant release of PGI2 by endothelial cells stimulated by acetylcholine or A23187. However, the large amounts of PGI2 become important enough to bind with TP receptors55,95 (Figure 2). The contraction of the latter on TP receptor activation is attributable to the combination of an increased entry of Ca2+ resulting from the opening of both receptor-operated and voltage-gated Ca2+ channels and Rho kinase–mediated sensitization of the myofilaments.24,96,97 In turn, the binding of endoperoxides and PGI2 to these receptors activates the downstream Rho kinase pathway, leading to the increased contractile activity of the vascular smooth muscle.86The Gatekeeper: NONO inhibits endothelium-dependent contractions,45,79 and thus inhibitors of NO synthases cause an immediate potentiation of EDCF-mediated responses. Further, previous exposure to endothelium-derived or exogenous NO results in long-term inhibition of endothelium-dependent contractions16 (Figure 1). Thus, one can predict that EDCF-mediated responses will become prominent, in particular, when the release of endothelium-derived NO is curtailed by aging or disease.5,13Hallmark of Vascular DiseaseEndothelium-dependent contractions are exacerbated by aging and vascular disease.5,11,98,99 Thus, the blunted vasodilatation to acetylcholine observed in the forearm of essential hypertensive patients is nearly normalized by indomethacin, indicating that COX-derived vasoconstrictor prostanoids contribute importantly to the abnormal endothelial response.100 The indomethacin-sensitive impairment of the response to muscarinic agonists is accentuated by aging.99 Endothelium-dependent contractions become more prominent in arteries of older compared with younger animals.21,101,102 This increased response is accompanied by an increased expression of COX-1.46 When COX-2 is induced by the aging process or by disease, this isoform of the enzyme can contribute in part to endothelium-dependent contractions.52 This is illustrated in the human by the observations that in patients with endothelial dysfunction, an improvement was observed with COX-2 inhibitors.103,104 The prominence of endothelium-dependent contractions observed in arteries of aging animals and humans, in particular, in subjects with essential/spontaneous hypertension, results from the progressive inability of the endothelial cells to generate NO with, as consequence, a facilitated release of EDCF.5,13SummaryEndothelial cells release not only NO and other relaxing factors but can generate COX-derived vasoconstrictor prostanoids and ROS, termed EDCF. The sequence of events (Figure 1) leading to endothelium-dependent contractions first requires an increase in endothelial Ca2+ concentration. This activates calcium-dependent PLA2, which provides the substrate for COX to yield the vasoconstrictor prostanoids involved in EDCF-mediated contractions. These include primarily endoperoxides and PGI2 and, to a lesser extent, thromboxane A2 and other prostaglandins. EDCF activates TP receptors of the vascular smooth muscle cells, which initiate the contractile process (Figure 1). When IP receptor signaling is impaired,18,55,94 PGI2 no longer causes dilatation but becomes a prominent endothelium-derived vasoconstrictor activating TP receptors (Figure 2). EDCF-mediated responses are exacerbated in aging normotensive,21,42 hypertensive,8 and diabetic52,68,69,90 animals. In hypertensive patients, EDCF contributes importantly to the endothelial dysfunction that accompanies aging, atherosclerosis, myocardial infarction, and essential hypertension.99,105,106AcknowledgmentsI sincerely thank my collaborators who, over the years, have helped to unravel the mechanisms leading to endothelium-dependent contractions, in particular, Drs Jo DeMey, Virginia Miller, Zvonimir Katusic, Thomas Luescher, Michel Feletou, Eva Tang, Shi Yi, and Michael Wong.Sources of FundingThe author's current research on the topic is supported by the University of Hong Kong and the Research Grant Council of the Hong Kong Special Administrative Region and by the World Class University program (R31-20029) funded by the Ministry of Education, Science and Technology, South Korea.DisclosuresNone.FootnotesCorrespondence to Paul M. 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• W2169319351 date "2011-03-01" @default.
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• W2169319351 title "Endothelium-Dependent Contractions in Hypertension" @default.
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• W2169319351 doi "https://doi.org/10.1161/hypertensionaha.110.165100" @default.
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