sign in sign up
<<
Home , Autacoid, Purinergic signalling

Autonomic & Autacoid Pharmacology

Autonomic & Autacoid Pharmacology REVIEW 2009, 29, 63–72

Purinergic regulation of vascular tone and remodelling

G. Burnstock

Correspondence: Autonomic Neuroscience Centre, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, G. Burnstock United Kingdom

Summary 1 Purinergic signalling is involved both in short-term control of vascular tone and in longer- term control of proliferation, migration and death involved in vascular remodelling. 2 There is dual control of vascular tone by 5¢-triphosphate (ATP) released from perivascular nerves and by ATP released from endothelial cells in response to changes in blood flow (shear stress) and hypoxia. 3 Both ATP and its breakdown product, adenosine, regulate and endothelial cell proliferation. 4 These regulatory mechanisms are important in pathological conditions, including hyper- tension, atherosclerosis, restenosis, diabetes and vascular pain.

Keywords: atherosclerosis, adenosine 5¢-triphosphate, hypertension, pain, purinergic, reste- nosis

recognized as a cotransmitter in sympathetic, Introduction parasympathetic, sensory-motor and enteric nerves Purinergic signalling, i.e. adenosine 5¢-triphos- (Burnstock, 1976). There was early resistance to phate (ATP) acting as an extracellular signalling this concept (see Burnstock, 2006a,b), but the roles molecule, was proposed by Burnstock in 1972 of and as extracellular when evidence was presented that ATP was the signalling molecules are now well established in in non-adrenergic, non-choliner- both neural and non-neural tissues (Burnstock & 2009 gic neuromuscular transmission in the gut and Knight, 2004; Burnstock, 2007a). P1 receptors for Blackwell Publishing Ltd urinary bladder (Burnstock, 1972). Later, it was adenosine, of which four subtypes (A1,A2A,A2B

doi: 10.1111/j.1474-8673.2009.00435.x 63 PURINERGIC REGULATION OF VASCULAR TONE AND REMODELLING

Autonomic & Autacoid and A3) have been cloned and characterized, ation, differentiation and death during angiogene- Pharmacology have been distinguished from P2 receptors for sis, atherosclerosis and restenosis following 2009, 29, 63–72 ATP, (ADP) and angioplasty (Erlinge & Burnstock, 2008). 5¢-triphosphate (UTP) (Burnstock, 1978), and P2 receptors have been divided into P2X -gated Regulation of vascular tone ion channel and P2Y G protein-coupled families. Seven subtypes of P2X receptors and eight In the vascular system, short-term purinergic sig- subtypes of P2Y receptors have been cloned and nalling events associated with the dual control of characterized (Ralevic & Burnstock, 1998; Burn- vascular tone by ATP released from nerves and stock, 2007b). The majority of studies involving endothelial cells have been clearly demonstrated purinergic signalling have been concerned with (Burnstock, 1990a, 1999; Boarder & Hourani, short-term events, such as or 1998) (See Fig. 1). secretion. However, there is growing interest in the Adenosine 5¢-triphosphate released as a cotrans- long-term trophic actions of extracellular nucleo- mitter with noradrenaline (NA) from perivascular tides and nucleosides on cell proliferation and sympathetic nerves acts mainly on P2X1 receptors death (Neary et al., 1996; Abbracchio & Burn- on medial vascular smooth muscle to produce stock, 1998). constriction, whereas ATP released as a cotrans- Adenosine 5¢-triphosphate and adenosine are mitter from sensory-motor nerves during Ôaxon involved in the mechanisms underlying local con- reflex’ activity dilates some vessels (Burnstock, trol of vessel tone (Burnstock, 1988; Burnstock & 2006c). There is transient constriction of cere- Ralevic, 1994) as well as cell migration, prolifer- bral arterioles via P2X receptors and sustained

Figure 1 Schematic diagram illustrating the main receptor subtypes for and pyrimidines present in blood vessels involved in control of vascular tone. Adenosine 5¢-triphosphate (ATP) is released as a cotransmitter with noradrenaline (NA) and neuropeptide Y

(NPY) from sympathetic nerves in the adventitia to act at smooth muscle P2X1 receptors and, in some vessels, P2X2, P2X4 and P2Y2 and

P2Y6 receptors, resulting in ; ATP is released with calcitonin gene-related peptide (CGRP) and substance P (SP) from sensory-motor nerves during Ôaxon reflex’ activity to act on smooth muscle P2Y receptors, resulting in either vasodilatation or

vasoconstriction. P1 (A1) receptors on nerve terminals of sympathetic and sensory nerves mediate adenosine (arising from ecto-

enzymatic breakdown of ATP) modulation of transmitter release. P2X2 ⁄ 3 receptors are present on a subpopulation of sensory nerve

terminals. P1 (A2) receptors on vascular smooth muscle mediate vasodilatation. Endothelial cells release ATP and uridine 5¢-

triphosphate (UTP) during shear stress and hypoxia to act on P2Y1, P2Y2 and sometimes P2Y4, P2Y11 and P2X4 receptors, leading to the production of (NO) and subsequent vasodilatation. ATP, after its release from aggregating , also acts, together with

its breakdown product ADP, on these endothelial receptors. Blood-borne platelets possess P2Y1 and ADP-selective receptors as

2009 well as P2X1 receptors, whereas immune cells of various kinds possess P2X7 as well as P1, P2X1, P2Y1 and P2Y2 receptors [figure is Blackwell Publishing Ltd modified from Burnstock (1989b) with permission from Oxford University Press].

64 G. BURNSTOCK

Autonomic & Autacoid constriction of large cerebral vessels, largely cell migration and proliferation (McAuslan et al., Pharmacology through P2Y2 receptors (Sprague et al., 2003). 1983). Angiogenesis (or neovascularization) begins 2009, 29, 63–72 Adenosine 5¢-triphosphate released from endo- with the migration of endothelial cells, originating thelial cells during changes in blood flow (producing from capillaries, into the being vascularized. shear stress) or hypoxia acts on P2 receptors on ADP and to a lesser extent adenosine and , endothelial cells to release nitric oxide (NO), result- showed strong chemotactic activity and were pos- ing in relaxation (Bodin & Burnstock, 1996; tulated to be angiogenesis factors in vivo (Teuscher Burnstock, 1999). P2Y1 receptors are dominant in & Weidlich, 1985). Adenine nucleotides were some vessels activated selectively by ADP (Ralevic & shown to have a mitogenic action on aortic endo- Burnstock, 1998), in other vessels P2Y2 receptors are thelial cells, probably via P2Y receptors (Van present that are activated equally by ATP and UTP Coevorden et al., 1989). ATP has also been shown (Motte et al., 1995). UTP has been shown to be to produce proliferation of cultured bovine corneal released from endothelial cells by shear stress (Saı¨ag endothelial cells (Cha et al., 2000). The source of the et al., 1995). Endothelial cells in some vessels also purines involved in these trophic actions is largely express other types of purinergic receptors (P2Y4 from the endothelial cells, suggesting an autocrine and P2Y6) (Ralevic, 2001); and yet another P2Y mechanism. ATP and ADP released from aggregat- receptor subtype (P2Y11) is present on endothelial ing platelets may also play a role. Stretch-induced cells of human mammary artery and umbilical vein changes in endothelial cell shape and changes (Wang et al., 2002). Endothelial cells of arteries and produced by hypoxic stress may be mediated by veins express different levels of P2X4 receptors and it the ATP (and adenosine after ecto-enzymatic break- has been reported that, in some blood vessels, P2X4 down) released from endothelial cells under both receptors induced vascular dilatation in an NO- these conditions (see Bodin & Burnstock, 2001). dependent manner (Yamamoto et al., 2006). In rat There is increasing evidence that cell prolifera- mesenteric arteries, P2X1 receptors mediated endo- tion and programmed cell death () are thelial-dependent , but a NO synthase linked (Di Virgilio, 2000). For example, VEGF inhibitor had no effect on dilation (Harrington & turns on cell proliferation, but inhibits apoptosis Mitchell, 2004). P2X4 and P2X6 receptors (perhaps (Mallat & Tedgui, 2000). Distinct signal transduc- as heteromultimers) were reported to be associated tion cascades, composed of at least three protein with vascular endothelial-cadherin in human endo- kinases, mediate cell proliferation and differentia- thelial cells, suggesting a role for these receptors in tion, growth arrest and apoptosis (Neary, 1997). In modulating adhesion junctions between endothelial diseases such as carcinogenesis, degenerative dis- cells (Glass et al., 2002). Adenosine produced after orders and ischaemia ⁄ reperfusion injury, there is breakdown of released ATP from nerves and an imbalance between cell division and cell death. endothelial cells causes vasodilatation via smooth Extracellular ATP and adenosine have been shown muscle P1 (usually A2 subtype) receptors. to cause apoptosis of pulmonary artery endothelial cells (Dawicki et al., 1997). It has been speculated that ATP released from cells undergoing cytolysis Purinergic signalling involved in proliferation or degranulation may cause endothelial cell death, of endothelial cells and smooth muscle perhaps by inhibition of methyltransferase activity and that this may be important in acute vascular Endothelial cells injury or in limiting angiogenesis (Rounds et al., Administration of adenosine was reported to 1998). In a study of porcine aortic endothelial cells, induce endothelial cell proliferation in the aorta, extracellular ATP and ADP, probably acting coronary vessels and human umbilical veins (see through P2X7 receptors, were shown to activate Burnstock, 2002). Adenosine has also been shown nuclear factor-jB (NF-jB), a transcription factor to stimulate canine retinal microvascular endothe- involved in induction of apoptosis (von Albertini lial cell migration and tube formation (Lutty et al., et al., 1998). 1998). The action of adenosine in producing endothelial cell proliferation is mediated by A 2A Smooth muscle and A2B receptors partly by the modulation of vascular endothelial growth factor (VEGF) (Grant An early study reported that adenosine produces et al., 1999). The selective A2B receptor antagonists changes in cyclic and and 3-isobutyl-8-pyrrolidinoxanthine DNA synthesis in cultured arterial smooth muscle inhibited 5¢-(N-ethylcarboxamido)-adenosine stim- cells leading to inhibition of cell proliferation and ulated proliferation of human retinal endothelial the authors speculated that adenosine could be one cells, extracellular signal-regulated kinase (ERK) of several regulatory factors in the development of activation, cell migration and capillary tube for- atherosclerosis and might also regulate the release mation (Grant et al., 2001). of a smooth muscle mitogen, -derived 2009 Adenosine diphosphate was shown to be one of growth factor (PDGF), from platelets (Jonzon Blackwell Publishing Ltd several agonists that induced cultured endothelial et al., 1985). A selective A2 receptor agonist,

65 PURINERGIC REGULATION OF VASCULAR TONE AND REMODELLING

Autonomic & Autacoid 2-octynyladenosine, reduced neointimal thickening neointimal formation after balloon angioplasty Pharmacology in a rat femoral artery injury model (Takiguchi (Hou et al., 1999). Fig. 2 is a schematic summa- 2009, 29, 63–72 et al., 1995). rizing these events. Adenosine 5¢-triphosphate and ADP stimulate DNA synthesis and cell proliferation of cultured Purinergic signalling in vascular diseases porcine artery vascular smooth muscle cells, an action mediated by P2Y receptors (Wang et al., The migration, proliferation and death of vascular 1992). It was speculated that this mechanism was smooth muscle and endothelial cells play an involved in the regulation of vascular smooth important role in the development of intimal muscle cell proliferation during embryonic and thickening during arterial diseases, such as arterio- early postnatal development, after injury and in sclerosis and restenosis after angioplasty, and in the arteriosclerosis. It was further suggested that the growth of new vessels that takes place during ATP released from endothelial cells causes not only wound and in tumours. ATP, ADP, UTP autocrine mitogenic stimulation of the endothelial and adenosine play pivotal signalling roles in these cells themselves but also paracrine stimulation of long-term events (Erlinge, 1998; Neary & Abbrac- the smooth muscle cells that migrate to the intima chio, 2001; Burnstock, 2002; Ralevic & Burnstock, after injury. Exogenous ATP and UTP also induce a 2003; Erlinge & Burnstock, 2008). limited cell cycle progression in arterial smooth muscle cells as well as having powerful mitogenic Athersclerosis and restenosis actions, probably via P2Y2 or P2Y4 receptors (Malam-Souley et al., 1996; Miyagi et al., 1996). There is growing evidence that ATP signalling is Sympathetic nerves exert a trophic influence on involved in atherosclerosis (Burnstock, 2002, 2008; vascular smooth muscle (Southwell et al., 1985; Di Virgilio & Solini, 2002; Seye et al., 2006). Bevan, 1989). As ATP as well as NA and neuro- Adenosine and ATP mediate endothelial and peptide Y are known to be released as cotransmit- smooth muscle cell proliferation and an increase ters from sympathetic nerves (Burnstock, 1990b), in the expression of VEGF mRNA, which plays an this was consistent with the possibility that ATP important role in the development of intimal and ⁄ or its breakdown product, adenosine, might thickening during atherosclerosis, in restenosis after be involved in these trophic actions. angioplasty, and in the growth of new vessels that Adenosine diphosphate contributes significantly takes place during wound healing and in tumours. in synergy with the peptide growth factors PDGF, It was speculated early on that adenosine could epidermal growth factor and transforming growth be one of several regulatory factors in the devel- factor-b, to the platelet-induced proliferation of opment of atherosclerosis and might also regulate vascular smooth muscle (Crowley et al., 1994). the release of a smooth muscle mitogen, PDGF The mitogenic effect of ATP on vascular smooth (Jonzon et al., 1985). There is now supporting muscle cells is synergistic with other mitogens, evidence that adenosine does indeed regulate including insulin and insulin-like growth factor-1 smooth muscle cell proliferation in angiogenesis (Wang et al., 1992). ATP-stimulated vascular (Adair, 2005). Endothelial cell proliferation is smooth muscle cell proliferation via P2Y receptors mediated by A2A and A2B receptors. involves activation of protein kinase C, Raf 1 and It has been shown that ecto-5¢-nucleotidase mitogen-activated protein kinase (MAPK) and (CD73)-derived adenosine acts as an endogenous requires independent ERK and phosphatidylinosi- modulator protecting against vascular inflammation tol 3-kinase-signalling pathways (Yu et al., 1996; and monocyte recruitment, thus limiting the pro- Wilden et al., 1998). There are two phenotypes of gression of atherosclerosis (Buchheiser et al., 2007). smooth muscle: the contractile phenotype and the Up-regulation of vascular smooth muscle P2Y2 synthetic (proliferative) phenotype. In a study of receptors by MAPK-dependent growth factor may cultures expressing these two phenotypes using be important in atherosclerosis and neointimal quantitative reverse transcription-polymerase chain formation after balloon angioplasty (Hou et al., reaction, it was shown that P2X1 receptors were 2000). It has been proposed that up-regulation of strongly expressed in the contractile phenotype. In P2Y2 receptors may be a useful diagnostic indicator the synthetic (proliferative) phenotype, the mito- for the early stages of atherosclerosis (Elmaleh genic P2Y1 and P2Y2 receptor transcripts were up- et al., 1998). A novel role for P2Y2 receptors in the regulated 342- and 8-fold, respectively, whereas development of atherosclerosis has been suggested, the contractile P2X1 receptor was totally down- whereby UTP induces vascular cell adhesion mol- regulated, while the P2Y4 and P2Y6 receptors were ecule-1 expression in coronary artery endothelial unchanged (Erlinge et al., 1998). Furthermore, cells that mediate the recruitment of monocytes MAPK kinase-dependent growth factor induced (Seye et al., 2003). the up-regulation of P2Y2 receptors in vascular Vascular injury represents a critical initiating 2009 smooth muscle cells, which the authors suggested event in the pathogenesis of various vascular Blackwell Publishing Ltd may be of importance in atherosclerosis and diseases. Large amounts of ATP are released from

66 G. BURNSTOCK

Autonomic & Autacoid Pharmacology 2009, 29, 63–72

Figure 2 Schematic diagram of long-term (trophic) actions of purines released from nerves, platelets and endothelial cells [which also release uridine 5¢-triphosphate (UTP)] acting on P2 receptors to stimulate or inhibit cell proliferation. Adenosine 5¢-triphosphate (ATP) released as a cotransmitter from sympathetic nerves and sensory-motor nerves (during axon reflex activity) stimulates smooth muscle

cell proliferation via P2Y2 and ⁄ or P2Y4 receptors via a mitogen-activated protein kinase (MAPK) cascade, whereas adenosine resulting

from enzymatic breakdown of ATP acts on P1 (A2) receptors to inhibit cell proliferation [via elevation of cyclic adenosine monophosphate (cAMP)]. ATP and UTP released from endothelial cells stimulate endothelial and smooth muscle cell proliferation via

P2Y1, P2Y2 and P2Y4 receptors. Adenosine resulting from ATP breakdown acts on P1 (A2) receptors to stimulate endothelial cell proliferation and regulate the release of platelet-derived growth factor (PDGF) from platelets. NA, noradrenaline; CGRP, calcitonin gene-related peptide; SP, substance P (reproduced from Burnstock (2002) with permission from Lippincott, Williams and Wilkins).

injured cells and, as described above, ATP and hypercholesteraemic patients (Duarte et al., 2007). adenosine have potent actions on smooth muscle The authors suggest that this might be beneficial in and endothelial cell growth, migration, prolifera- reducing formation, but may also con- tion and death. Atherosclerotic damage modifies tribute to future fatal events such as unstable -dependent responses to ATP (Burn- angina and myocardial infarction. ATP releases stock, 2006d). Clinical trials with and from mast cells and releases inflamma- (P2Y12 receptor antagonists) in patients tory cytokines such as interleukin-1 from immune with atherosclerotic disease have shown significant cells via P2X7 receptors. In addition, occupation of benefit compared with aspirin (Gachet, 2005). P2Y receptors leads to prostaglandin and cyclo- Natural killer cells represent the main source of oxygenase-2 (COX-2) synthesis, both involved in interferon-c that contributes to atherosclerotic inflammatory processes. ATP-induced COX-2 plaque progression and instability. ATP and UTP expression is via p42 ⁄ p44, MAPK, p38 and NF- released from endothelial cells during changes in jB in vascular smooth muscle cells and the authors blood flow resulting in shear stress is enhanced in suggest that nucleotides may promote atheroscle- inflammatory states (Bodin & Burnstock, 1998; rosis via these mechanisms (Wang & Yang, 2006). Burnstock, 1999) and might represent a protective The pattern of vascular connexins is altered mechanism for killer cell-mediated plaque forma- during atherosclerotic plaque formation and in tion (Gorini et al., 2007). Apoptotic cell death is restenosis affecting gap-junctional communication recognized to occur in atherosclerosis and resteno- between smooth muscle cells and genetically mod- sis (Mallat & Tedgui, 2000). ified connexin expression alters the course of Atherosclerosis is an inflammatory disease in- atherosclerosis and restenosis (Chadjichristos duced by hypercholesteraemia and increase in et al., 2006). Connexin hemichannel formation 2009 NTPDase (CD39, apyrase) and subsequent ATP has been shown to be regulated by ATP (Jiang Blackwell Publishing Ltd and ADP hydrolysis has been shown in platelets of et al., 2005; Lurtz & Louis, 2007).

67 PURINERGIC REGULATION OF VASCULAR TONE AND REMODELLING

Autonomic & Autacoid In restenosis following balloon angioplasty, lease, modulation and altered NTP- Pharmacology there is a peak in the proliferation and apoptosis Dase expression (Goepfert et al., 2001). In 2009, 29, 63–72 of vascular smooth muscle at about 14 days (Han , new capillary blood vessels et al., 1995). Saphenous vein, internal mammary invade the joint leading to destruction of the and radial arteries have been used as grafts for cartilage. In diabetes, new capillaries in the retina coronary bypass surgery; the level of endothelial invade the vitreous body, bleed and cause blind- P2Y2 receptors is comparable in all three vessels, ness, and tumour growth and metastasis are but endothelial P2X4 receptors vary from high in angiogenesis-dependent (Folkman & Shing, saphenous vein to significantly lower in the other 1992). Anginal patients treated chronically with two vessels. It has been suggested that P2X4 to increase adenosine levels showed receptors play a more significant role in intense an increase in coronary angiogenesis (Picano & proliferation in arteriosclerosis and restenosis than Michelassi, 1997). P2Y2 receptors, as reflected by the susceptibility of saphenous vein grafts to atherosclerosis compared Hypertension with internal mammary arteries (Ray et al., 2002). In another study, P2X1 and P2Y6 receptors med- Adenosine 5¢-triphosphate plays a significant co- iated more prominent contractions in the saphe- transmitter role in sympathetic nerves supplying nous vein compared with the internal mammary hypertensive blood vessels. The purinergic compo- artery; it has been suggested that selective antag- nent is increased in spontaneously hypertensive rats onists to these receptors may prevent vasospasm (SHR) (Vidal et al., 1986; Brock & Van Helden, and restenosis in the saphenous vein during and 1995). The increase in sympathetic nerve activity in after revascularization surgery (Borna et al., 2003). hypertension is well established and there is an A study has shown that P2 receptors play an associated hyperplasia and hypertrophy of arterial important role in homocysteine-induced athero- walls (Julius & Nesbitt, 1996). Also, sympathetic sclerosis (Sharma et al., 2007). innervating the vasculature are dependent In conclusion, the long-term (trophic) roles of on nerve growth factor (NGF) in development, and purinergic signalling in vascular smooth muscle an increase in NGF gene expression and protein has and endothelial cell proliferation and death have been described in SHR (Zettler & Rush, 1993). been implicated in atherosclerosis and restenosis a,b-Methylene ATP has been shown to increase and there is exploration of novel therapeutic NGF secretion by vascular smooth muscle cells in strategies in relation to these events (Ralevic & SHR (Spitsbergen et al., 1995). ATP is a rapidly Burnstock, 2003; Burnstock, 2006d; Erlinge & acting hypotensive agent that compares favourably Burnstock, 2008). with sodium nitroprusside (Kien et al., 1987). ATP-MgCl2 is a safe, effective and preferential pulmonary vasodilator in children with pulmonary Angiogenesis hypertension secondary to congenital defects; The growth of new blood vessels takes place in it has also been used for treating pulmonary pathological events such as tumour growth, wound hypertension after cardiac surgery (Brook et al., healing, psoriasis and the ischaemic retinopathies 1994). ATP exerts mitogenic actions on human that occur in diabetes and sickle cell disease. In the pulmonary artery smooth muscle cells, which may adult, the development of new blood vessels, or be relevant to the pathophysiological basis of neovascularization, occurs by budding from exist- severe pulmonary hypertension (Ka¨a¨pa¨ et al., ing blood vessels and is referred to as angiogenesis 1997; Zhang et al., 2004). Eicosapentaenoic acid, (as distinct from vasculogenesis, which occurs in one of the active components in fish oil that has embryogenic development by vessel formation antihypertensive effects, increases the release of from mesenchyme precursor cells or angioblasts). ATP from vascular endothelial cells, leading to Peptide growth factors such as fibroblast growth reduction of the blood pressure rise characteristic factor, transforming growth factor-a and VEGF are of ageing (Hashimoto et al., 1998). P2X4 receptors clearly involved in angiogenesis, but purines and are localized in the syncytiotrophoblast, stroma pyrimidines also contribute to this process (Satter- and foetal capillary endothelial cells of human white et al., 1999). Newly developing vascular placenta. Placental P2X4 receptors are significantly endothelia express very high levels of the ectonu- up-regulated in mild preeclampsia (Roberts et al., cleotidase, NTPDase1, also seen under hypoxic 2007). conditions (Eltzschig et al., 2003). Angiogenesis requires the dynamic interaction of endothelial cell Vascular pain proliferation and differentiation with orchestrated interactions between extracellular matrix and sur- P2X3 receptors are found on nociceptive sensory rounding cells (such as vascular smooth muscle nerve fibres and local release of ATP activates these 2009 and ⁄ or pericytes). Such interactions could be fibres sending messages to the pain centres in the Blackwell Publishing Ltd coordinated by interplay between re- brain (see Burnstock, 2001). Burnstock speculated

68 G. BURNSTOCK

Autonomic & Autacoid in 1996 (Burnstock, 1996) that vascular pain, such BROCK, J.A. & VAN HELDEN, D.F. (1995). Enhanced excit- Pharmacology as angina, migraine, ischaemic muscle pain, lumbar atory junction potentials in mesenteric arteries from 2009, 29, 63–72 pain and pelvic pain, may involve purinergic spontaneously hypertensive rats. Pflu¨ gers Arch. Eur. J. Physiol., 430, 901–908. signalling. It was suggested that following local BROOK, M.M., FINEMAN, J.R., BOLINGER, A.M., WONG, A.F., vasospasm, ATP released from microvessel endo- HEYMANN, M.A. & SOIFER, S.J. (1994). Use of ATP- thelial cells during the reactive hyperaemia that MgCl2 in the evaluation and treatment of children with follows and is known to be associated with pain, pulmonary hypertension secondary to congenital heart reaches P2X3 receptors on the nociceptive sensory defects. Circulation, 90, 1287–1293. fibres in the adventitia to initiate pain. This concept BUCHHEISER, A., EMDE, B., FISCHER, J.W. & SCHRADER, J. was first proposed for the pain occurring in (2007). Role of Cd73-derived adenosine in atheroscle- migraine (Burnstock, 1981, 1989a). In anginal rosis. Circulation, 116, 114. pain, cardiac myocytes as well as coronary micro- BURNSTOCK, G. (1972). Purinergic nerves. Pharmacol. vessel endothelial cells may be the source of ATP Rev., 24, 509–581. BURNSTOCK, G. (1976). Do some nerve cells release more and adenosine reaching purinergic nociceptors than one transmitter? Neuroscience, 1, 239–248. (Crea et al., 1990; Sylve´n, 1993). BURNSTOCK, G. (1978). A basis for distinguishing two types of . In: Cell Membrane Diabetes Receptors for Drugs and Hormones: A Multidisciplin- ary Approach (Eds R.W. STRAUB & L. BOLIS), pp. 107– Along with its stimulating effect on bovine retinal 118. Raven Press, New York. capillary endothelial cells, adenosine has been BURNSTOCK, G. (1981). Pathophysiology of migraine: a shown to have an inhibitory effect on retinal new hypothesis. Lancet, 317, 1397–1399. pericytes, and it has been hypothesized that this BURNSTOCK, G. (1988). Local purinergic regulation of dual function plays a role in the pathological blood pressure. (The First John T. Shepherd Lecture). In: Vasodilatation: Vascular Smooth Muscle, Peptides, neovascularization process that takes place in Autonomic Nerves, and Endothelium (Ed. P.M. VAN- diabetes (Jackson & Carlson, 1992). Diabetic HOUTTE), pp. 1–14. Raven Press, New York. microangiopathy has been implicated as a funda- BURNSTOCK, G. (1989a). The role of adenosine triphos- mental feature of the pathological complications of phate in migraine. Biomed. Pharmacother., 43, 727– diabetes, including retinopathy, neuropathy and 736. foot ulceration (Kamal et al., 1998). BURNSTOCK, G. (1989b). Vascular control by purines with emphasis on the coronary system. Eur. Heart J., 10 (Suppl. F), 15–21. References BURNSTOCK, G. (1990a). Dual control of local blood flow by purines. Ann. NY Acad. Sci., 603, 31–44. ABBRACCHIO, M.P. & BURNSTOCK, G. (1998). Purinergic signalling: pathophysiological roles. Jpn. J. Pharmacol., BURNSTOCK, G. (1990b). Noradrenaline and ATP as 78, 113–145. cotransmitters in sympathetic nerves. Neurochem. Int., 17, 357–368. ADAIR, T.H. (2005). Growth regulation of the vascular system: an emerging role for adenosine. Am. J. Physiol. BURNSTOCK, G. (1996). A unifying purinergic hypothesis Regul. Integr. Comp. Physiol., 289, R283–R296. for the initiation of pain. Lancet, 347, 1604–1605. BURNSTOCK, G. (1999). Release of vasoactive substances VON ALBERTINI, M., PALMETSHOFER, A., KACZMAREK, E., from endothelial cells by shear stress and purinergic KOZIAK, K., STROKA, D., GREY, S.T., STUHLMEIER, K.M. & mechanosensory transduction. J. Anat., 194, 335–342. ROBSON, S.C. (1998). Extracellular ATP and ADP activate transcription factor NF-jB and induce endo- BURNSTOCK, G. (2001). -mediated signalling in pain thelial cell apoptosis. Biochem. Biophys. Res. Com- and visceral perception. Trends Pharmacol. Sci., 22, mun., 248, 822–829. 182–188. BURNSTOCK, G. (2002). Purinergic signalling and vascular BEVAN, R.D. (1989). Influence of adrenergic innervation on vascular growth and mature characteristics. Am. Rev. cell proliferation and death. Arterioscler. Thromb. Respir. Dis., 140, 1478–1482. Vasc. Biol., 22, 364–373. BURNSTOCK, G. (2006a). Purinergic signalling. Br. J. BOARDER, M.R. & HOURANI, S.M.O. (1998). The regulation of vascular function by P2 receptors: multiple sites and Pharmacol., 147, S172–S181. multiple receptors. Trends Pharmacol. Sci., 19, 99–107. BURNSTOCK, G. (2006b). Historical review: ATP as a neurotransmitter. Trends Pharmacol. Sci., 27, 166– BODIN, P. & BURNSTOCK, G. (1996). ATP-stimulated release of ATP by human endothelial cells. J. Cardiovasc. 176. Pharmacol., 27, 872–875. BURNSTOCK, G. (2006c). Vessel tone and remodeling. Nat. Med., 12, 16–17. BODIN, P. & BURNSTOCK, G. (1998). Increased release of ATP from endothelial cells during acute inflammation. BURNSTOCK, G. (2006d). Pathophysiology and therapeutic Inflamm. Res., 47, 351–354. potential of purinergic signaling. Pharmacol. Rev., 58, 58–86. BODIN, P. & BURNSTOCK, G. (2001). Purinergic signalling: ATP release. Neurochem. Res., 26, 959–969. BURNSTOCK, G. (2007a). and pathophysiology of purinergic neurotransmission. Physiol. Rev., 87, BORNA, C., WANG, L., GUDBJARTSSON, T., KARLSSON, L., 659–797. JERN, S., MALMSJO, M. & ERLINGE, D. (2003). Contrac- tions in human coronary bypass vessels stimulated by BURNSTOCK, G. (2007b). Purine and pyrimidine receptors. 2009 extracellular nucleotides. Ann. Thorac. Surg., 76, 50–57. Cell. Mol. Life Sci., 64, 1471–1483. Blackwell Publishing Ltd

69 PURINERGIC REGULATION OF VASCULAR TONE AND REMODELLING

Autonomic & Autacoid BURNSTOCK, G. (2008). Purinergic signalling in athero- GACHET, C. (2005). The platelet P2 receptors as molecular Pharmacology sclerosis and restenosis, IAS website June (http:// targets for old and new antiplatelet drugs. Pharmacol. 2009, 29, 63–72 www.athero.org/commentaries/comm770.pdf). Therap., 108, 180–192. BURNSTOCK, G. & KNIGHT, G.E. (2004). Cellular distribu- GLASS, R., LOESCH, A., BODIN, P. & BURNSTOCK, G. (2002).

tion and functions of P2 receptor subtypes in different P2X4 and P2X6 receptors associate with VE-cadherin in systems. Int. Rev. Cytol., 240, 31–304. human endothelial cells. Cell. Mol. Life Sci., 59, 870– BURNSTOCK, G. & RALEVIC, V. (1994). New insights into 881. the local regulation of blood flow by perivascular GOEPFERT, C., SUNDBERG, C., SEVIGNY, J., ENJYOJI, K., nerves and endothelium. Br. J. Plastic Surg., 47, 527– HOSHI, T., CSIZMADIA, E. & ROBSON, S. (2001). Disor- 543. dered cellular migration and angiogenesis in cd39-null CHA, S.H., HAHN, T.W., SEKINE, T., LEE, K.H. & ENDOU, H. mice. Circulation, 104, 3109–3115. (2000). Purinoceptor-mediated mobilization GORINI, S., MAMMI, C., FERRARI, D. et al. (2007). Extra- and cellular proliferation in cultured bovine corneal cellular ATP inhibits natural killer cell recruitment in endothelial cells. Jpn. J. Pharmacol., 82, 181–187. inflamed tissues and protects endothelial cells from NK- CHADJICHRISTOS, C.E., DEROUETTE, J.P. & KWAK, B.R. (2006). mediated vascular injury. Circulation, 116, 4-b. Connexins in atherosclerosis. Adv. Cardiol., 42, 255– GRANT, M.B., TARNUZZER, R.W., CABALLERO, S., OZECK, M.J., 267. DAVIS, M.I., SPOERRI, P.E., FEOKTISTOV, I., BIAGGIONI, I., CREA, F., PUPITA, G., GALASSI, A.R., EL TAMIMI, H., KASKI, J.C., SHRYOCK, J.C. & BELARDINELLI, L. (1999). Adenosine DAVIES, G. & MASERI, A. (1990). Role of adenosine in receptor activation induces vascular endothelial growth pathogenesis of anginal pain. Circulation, 81, 164– factor in human retinal endothelial cells. Circ. Res., 85, 172. 699–706. CROWLEY, S.T., DEMPSEY, E.C., HORWITZ, K.B. & HORWITZ, GRANT, M.B., DAVIS, M.I., CABALLERO, S., FEOKTISTOV, I., L.D. (1994). Platelet-induced vascular smooth muscle BIAGGIONI, I. & BELARDINELLI, L. (2001). Proliferation, cell proliferation is modulated by the growth amplifi- migration, and ERK activation in human retinal endo-

cation factors serotonin and adenosine diphosphate. thelial cells through A2B stimula- Circulation, 90, 1908–1918. tion. Invest. Ophthalmol. Vis. Sci., 42, 2068–2073. DAWICKI, D.D., CHATTERJEE, D., WYCHE, J. & ROUNDS, S. HAN, D.K., HAUDENSCHILD, C.C., HONG, M.K., TINKLE, B.T., (1997). Extracellular ATP and adenosine cause apop- LEON, M.B. & LIAU, G. (1995). Evidence for apoptosis in tosis of pulmonary artery endothelial cells. Am. J. human atherogenesis and in a rat vascular injury Physiol., 273, L485–L494. model. Am. J. Pathol., 147, 267–277. DI VIRGILIO, F. (2000). Dr. Jekyll ⁄ Mr. Hyde: the dual role HARRINGTON, L.S. & MITCHELL, J.A. (2004). Novel role for of extracellular ATP. J. Auton. Nerv. Syst., 81, 59– P2X receptor activation in endothelium-dependent 63. vasodilation. Br. J. Pharmacol., 143, 611–617. DI VIRGILIO, F. & SOLINI, A. (2002). P2 receptors: new HASHIMOTO, M., SHINOZUKA, K., SHAHDAT, H.M., KWON, potential players in atherosclerosis. Br. J. Pharmacol., Y.M., TANABE, Y., KUNITOMO, M. & MASUMURA, S. 135, 831–842. (1998). Antihypertensive effect of all-cis-5,8,11,14,17- DUARTE, M.M., LORO, V.L., ROCHA, J.B., LEAL, D.B., BEM, A.F., icosapentaenoate of aged rats is associated with an DORNELES, A., MORSCH, V.M. & SCHETINGER, M.R. increase in the release of ATP from the caudal artery. J. (2007). that hydrolyze adenine nucleotides of Vasc. Res., 35, 55–62. patients with hypercholesterolemia and inflammatory HOU, M., MOLLER, S., EDVINSSON, L. & ERLINGE, D. (1999). processes. FEBS J., 274, 2707–2714. MAPKK-dependent growth factor-induced upregula-

ELMALEH, D.R., NARULA, J., BABICH, J.W., PETROV, A., FIS- tion of P2Y2 receptors in vascular smooth muscle cells. CHMAN, A.J., KHAW, B.A., RAPAPORT, E. & ZAMECNIK, P.C. Biochem. Biophys. Res. Commun., 258, 648–652. (1998). Rapid noninvasive detection of experimental HOU, M., MOLLER, S., EDVINSSON, L. & ERLINGE, D. (2000).

atherosclerotic lesions with novel 99mTc-labeled diad- Cytokines induce upregulation of vascular P2Y2 recep- enosine tetraphosphates. Proc. Natl Acad. Sci. USA, tors and increased mitogenic responses to UTP and ATP. 95, 691–695. Arterioscler. Thromb. Vasc. Biol., 20, 2064–2069. ELTZSCHIG, H.K., IBLA, J.C., FURUTA, G.T., LEONARD, M.O., JACKSON, J.A. & CARLSON, E.C. (1992). Inhibition of bovine JACOBSON, K.A., ENJYOJI, K., ROBSON, S.C. & COLGAN, S.P. retinal microvascular pericyte proliferation in vitro by (2003). Coordinated adenine nucleotide phosphohy- adenosine. Am. J. Physiol., 263, H634–H640. drolysis and signaling in posthypoxic endo- JIANG, L., BARDINI, M., KEOGH, A., DOS REMEDIOS, C.G. &

thelium: role of and adenosine A2B BURNSTOCK, G. (2005). P2X1 receptors are closely receptors. J. Exp. Med., 198, 783–796. associated with connexin 43 in human ventricular ERLINGE, D. (1998). Extracellular ATP: a growth factor for myocardium. Int. J. Cardiol., 98, 291–297. vascular smooth muscle cells. Gen. Pharmacol., 31,1– JONZON, B., NILSSON, J. & FREDHOLM, B.B. (1985). Aden- 8. osine receptor-mediated changes in cyclic AMP pro- ERLINGE, D. & BURNSTOCK, G. (2008). P2 receptors in duction and DNA synthesis in cultured arterial smooth cardiovascular physiology and disease. Purinergic Sig- muscle cells. J. Cell. Physiol., 124, 451–456. nal., 4, 1–20. JULIUS, S. & NESBITT, S. (1996). Sympathetic overactivity in ERLINGE, D., HOU, M., WEBB, T.E., BARNARD, E.A. & MOLLER, hypertension. A moving target. Am. J. Hypertens., 9, S. (1998). Phenotype changes of the vascular smooth 113S–120S. muscle cell regulate P2 receptor expression as measured KA¨ A¨ PA¨ , P., JAHNUKAINEN, T., GRONLUND, J., RAUTANEN, M., by quantitative RT-PCR. Biochem. Biophys. Res. HALKOLA, L. & VALIMAKI, I. (1997). Adenosine triphos- Comm., 248, 864–870. phate treatment for meconium aspiration-induced pul- 2009 FOLKMAN, J. & SHING, Y. (1992). Angiogenesis. J. Biol. monary hypertension in pigs. Acta Physiol. Scand., Blackwell Publishing Ltd Chem., 267, 10931–10934. 160, 283–289.

70 G. BURNSTOCK

Autonomic & Autacoid KAMAL, K., DU, W., MILLS, I. & SUMPIO, B.E. (1998). RAY, F.R., HUANG, W., SLATER, M. & BARDEN, J.A. (2002). Pharmacology Antiproliferative effect of elevated glucose in human Purinergic receptor distribution in endothelial cells in 2009, 29, 63–72 microvascular endothelial cells. J. Cell. Biochem., 71, blood vessels: a basis for selection of coronary artery 491–501. grafts. Atherosclerosis, 162, 55–61. KIEN, N.D., WHITE, D.A., REITAN, J.A. & EISELE, J.H. JR ROBERTS, V.H., WEBSTER, R.P., BROCKMAN, D.E., PITZER, B.A. (1987). Cardiovascular function during controlled & MYATT, L. (2007). Post-translational modifications of

hypotension induced by or the P2X4 purinergic receptor subtype in the human sodium nitroprusside in the anesthetized dog. Anaes- placenta are altered in preeclampsia. Placenta, 28, 270– thes. Analges., 66, 103–110. 277. LURTZ, M.M. & LOUIS, C.F. (2007). Purinergic receptor- ROUNDS, S., YEE, W.L., DAWICKI, D.D., HARRINGTON, E., mediated regulation of lens connexin43. Invest. Oph- PARKS, N. & CUTAIA, M.V. (1998). Mechanism of thalmol. Vis. Sci., 48, 4177–4186. extracellular ATP- and adenosine-induced apoptosis of LUTTY, G.A., MATHEWS, M.K., MERGES, C. & MCLEOD, D.S. cultured pulmonary artery endothelial cells. Am. J. (1998). Adenosine stimulates canine retinal microvas- Physiol., 275, L379–L388. cular endothelial cell migration and tube formation. SAI¨AG, B., BODIN, P., SHACOORI, V., CATHELINE, M., RAULT, Curr. Eye Res., 17, 594–607. B. & BURNSTOCK, G. (1995). Uptake and flow-induced MALAM-SOULEY, R., SEYE, C., GADEAU, A.P., LOIRAND, G., release of uridine nucleotides from isolated vascular PILLOIS, X., CAMPAN, M., PACAUD, P. & DESGRANGES, C. endothelial cells. Endothelium, 2, 279–285. (1996). Nucleotide receptor P2u partially mediates SATTERWHITE, C.M., FARRELLY, A.M. & BRADLEY, M.E. ATP-induced cell cycle progression of aortic smooth (1999). Chemotactic, mitogenic, and angiogenic ac- muscle cells. J. Cell. Physiol., 166, 57–65. tions of UTP on vascular endothelial cells. Am. J. MALLAT, Z. & TEDGUI, A. (2000). Apoptosis in the Physiol., 276, H1091–H1097. vasculature: mechanisms and functional importance. SEYE, C.I., YU, N., JAIN, R., KONG, Q., MINOR, T., NEWTON, J., Br. J. Pharmacol., 130, 947–962. ERB, L., GONZALEZ, F.A. & WEISMAN, G.A. (2003). The

MCAUSLAN, B.R., REILLY, W.G., HANNAN, G.N. & GOLE, G.A. P2Y2 nucleotide receptor mediates UTP-induced vas- (1983). Angiogenic factors and their assay: activity of cular cell adhesion molecule-1 expression in coronary formyl methionyl leucyl phenylalanine, adenosine artery endothelial cells. J. Biol. Chem., 278, 24960– diphosphate, heparin, , and bovine endothelium 24965. stimulating factor. Microvasc. Res., 26, 323–338. SEYE, C.I., KONG, Q., YU, N., GONZALEZ, F.A., ERB, L. & MIYAGI, Y., KOBAYASHI, S., AHMED, A., NISHIMURA, J., FUKUI, WEISMAN, G.A. (2006). P2 receptors in atherosclerosis

M. & KANAIDE, H. (1996). P2U purinergic activation and postangioplasty restenosis. Purinergic Signal., 2, leads to the cell cycle progression from the G1 to the S 471–480. and M phases but not from the G0 to G1 phase in SHARMA, M., RAI, S.K., TIWARI, M. & CHANDRA, R. (2007). vascular smooth muscle cells in primary culture. Effect of hyperhomocysteinemia on cardiovascular risk Biochem. Biophys. Res. Commun., 222, 652–658. factors and initiation of atherosclerosis in Wistar rats. MOTTE, S., COMMUNI, D., PIROTTON, S. & BOEYNAEMS, J.M. Eur. J. Pharmacol., 574, 49–60. (1995). Involvement of multiple receptors in the actions SOUTHWELL, B.R., CHAMLEY-CAMPBELL, J.H. & CAMPBELL, of extracellular ATP: the example of vascular endo- G.R. (1985). Tropic interactions between sympathetic thelial cells. Int. J. Biochem. Cell Biol., 27, 1–7. nerves and vascular smooth muscle. J. Auton. Nerv. NEARY, J.T. (1997). MAPK cascades in cell growth and Syst., 13, 343–354. death. News Physiol. Sci., 12, 286–293. SPITSBERGEN, J.M., STEWART, J.S. & TUTTLE, J.B. (1995). NEARY, J.T. & ABBRACCHIO, M.P. (2001). Trophic roles of Altered regulation of nerve growth factor secretion by purines and pyrimidines. In: Handbook of Pharmacol- cultured VSMCs from hypertensive rats. Am. J. Phys- ogy: Purinergic and Pyrimidinergic Signalling (Eds M.P. iol., 269, H621–H628. ABBRACCHIO & M. WILLIAMS), pp. 305–338. Springer, SPRAGUE, R.S., ELLSWORTH, M.L. & DETRICH, H.H. (2003). Berlin. Nucleotide release and purinergic signaling in the NEARY, J.T., RATHBONE, M.P., CATTABENI, F., ABBRACCHIO, vasculature driven by the . Curr. Top. M.P. & BURNSTOCK, G. (1996). Trophic actions of Membr., 54, 243–268. extracellular nucleotides and nucleosides on glial and SYLVE´ N, C. (1993). Mechanisms of pain in angina pectoris neuronal cells. Trends Neurosci., 19, 13–18. – a critical review of the adenosine hypothesis. PICANO, E. & MICHELASSI, C. (1997). Chronic oral dipyri- Cardiovasc. Drugs Ther., 7, 745–759. damole as a Ônovel’ antianginal drug: the collateral TAKIGUCHI, Y., NAGANO, M., IKEDA, Y. & NAKASHIMA, M. hypothesis. Cardiovasc. Res., 33, 666–670. (1995). Early administration of YT-146, an adenosine RALEVIC, V. (2001). Roles of purines and pyrimidines in A2 receptor agonist, inhibits neointimal thickening endothelium. In: Handbook of Experimental Pharma- after rat femoral artery endothelium injury. Eur. J. cology, Volume 151 ⁄ II. Purinergic and Pyrimidinergic Pharmacol., 281, 205–207. Signalling II – Cardiovascular, Respiratory, Immune, TEUSCHER, E. & WEIDLICH, V. (1985). Adenosine nucleo- Metabolic and Gastrointestinal Tract Function (Eds tides, adenosine and adenine as angiogenesis factors. M.P. ABBRACCHIO & M. WILLIAMS), pp. 101–120. Berlin, Biomed. Biochim. Acta, 44, 493–495. Springer. VAN COEVORDEN, A., ROGER, P. & BOEYNAEMS, J.-M. (1989). RALEVIC, V. & BURNSTOCK, G. (1998). Receptors for purines Mitogenic action of adenine nucleotides and nucleo- and pyrimidines. Pharmacol. Rev., 50, 413–492. sides on aortic endothelial cells. Thromb. Haemost., RALEVIC, V. & BURNSTOCK, G. (2003). Involvement of 62, 190. purinergic signalling in cardiovascular diseases. Drug VIDAL, M., HICKS, P.E. & LANGER, S.Z. (1986). Differential 2009 News Perspect., 16, 133–140. effects of a,b-methylene ATP on responses to nerve Blackwell Publishing Ltd

71 PURINERGIC REGULATION OF VASCULAR TONE AND REMODELLING

Autonomic & Autacoid stimulation in SHR and WKY tail arteries. Naunyn- YAMAMOTO, K., SOKABE, T., MATSUMOTO, T. et al. (2006). Pharmacology Schmiedebergs Arch. Pharmacol., 332, 384–390. Impaired flow-dependent control of vascular tone and 2009, 29, 63–72 WANG, W.-J. & YANG, C.-M. (2006). ATP-induced COX-2 remodeling in P2X4-deficient mice. Nat. Med., 12, expression via p42 ⁄ p44 MAPK, p38, and NF-jBin 133–137. vascular smooth muscle cells. FASEB J., 20, A229. YU, S.M., CHEN, S.F., LAU, Y.T., YANG, C.M. & CHEN, J.C. WANG, D.J., HUANG, N.N. & HEPPEL, L.A. (1992). Extracel- (1996). Mechanism of extracellular ATP-induced pro- lular ATP and ADP stimulate proliferation of porcine liferation of vascular smooth muscle cells. Mol. Phar- aortic smooth muscle cells. J. Cell. Physiol., 153, 221– macol., 50, 1000–1009. 233. ZETTLER, C. & RUSH, R.A. (1993). Elevated concentrations WANG, L., KARLSSON, L., MOSES, S., HULTGARDH-NILSSON, of nerve growth factor in heart and mesenteric arteries A., ANDERSSON, M., BORNA, C., GUDBJARTSSON, T., JERN, of spontaneously hypertensive rats. Brain Res., 614, S. & ERLINGE, D. (2002). P2 receptor expression profiles 15–20. in human vascular smooth muscle and endothelial cells. ZHANG, S., REMILLARD, C.V., FANTOZZI, I. & YUAN, J.X. J. Cardiovasc. Pharmacol., 40, 841–853. (2004). ATP-induced mitogenesis is mediated by cyclic WILDEN, P.A., AGAZIE, Y.M., KAUFMAN, R. & HALENDA, S.P. AMP response element-binding protein-enhanced (1998). ATP-stimulated smooth muscle cell prolifera- TRPC4 expression and activity in human pulmonary tion requires independent ERK and PI3K signaling artery smooth muscle cells. Am. J. Physiol. Cell pathways. Am. J. Physiol., 275, H1209–H1215. Physiol., 287, C1192–C1201.

2009 Blackwell Publishing Ltd

72