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Hypertension. 2001;38:1150-1157
doi: 10.1161/hy1101.096109
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(Hypertension. 2001;38:1150.)
© 2001 American Heart Association, Inc.

Fourth Workshop on Structure and Function
of Large Arteries: Part II

Physiological and Pathophysiological Functions of the AT2 Subtype Receptor of Angiotensin II

From Large Arteries to the Microcirculation

Daniel Henrion; Nathalie Kubis; Bernard I. Lévy

From Institut National de la Santé et de la Recherche Médicale (INSERM) U 541, IFR Circulation-Paris VII, Université Paris VII (D.H., B.I.L.); and Department of Physiology, AP-HP-Hôpital Lariboisière (N.K., B.I.L.), Paris, France.

Correspondence to Bernard I. Levy, INSERM U541, 41 Bd de la Chapelle, 75475 Paris, France. E-mail levy{at}infobiogen.fr

Abstract

Abstract—— Angiotensin II exerts a potent role in the control of hemodynamic and renal homeostasis. Angiotensin II is also a local and biologically active mediator involved in both endothelial and smooth muscle cell function acting on 2 receptor subtypes: type 1 (AT1R) and type 2 (AT2R). Whereas the key role of AT2R in the development of the embryo has been extensively studied, the role of AT2R in the adult remains more questionable, especially in humans. In vitro studies in cultured cells and in isolated segments of aorta have shown that AT2R stimulation could lead to the production of vasoactive substances, among which NO is certainly the most cited, suggesting that acute AT2R stimulation will produce vasodilation. However, in different organs or in small arteries isolated from different type of tissues, other vasoactive substances may also mediate AT2R-dependent dilation. Sometimes, such as in large renal arteries, AT2R stimulation may lead to vasoconstriction, although it is not always seen. In isolated arteries submitted to physiological conditions of pressure and flow, AT2R stimulation may also have a role in shear stress–induced dilation through a endothelial production of NO. Thus, when acutely stimulated, the most probable response expected from AT2R stimulation will be a vasodilation. Therefore, in the perspective of a chronic AT1R blockade in patients, overstimulation of AT2R might be beneficial, given their potential vasodilator effect.

Concerning the possible role of AT2R in cardiovascular remodeling, the situation is more controversial. In vitro AT2R stimulation clearly inhibits cardiac and vascular smooth muscle growth and proliferation, stimulates apoptosis, and promotes extra cellular matrix synthesis. In vivo, the situation might be less beneficial if not deleterious; indeed, if chronic AT2R overstimulation would lead to cardiovascular hypertrophy and fibrosis, then the long-term consequences of chronic AT1R blockade, and thus AT2R overstimulation, require more in-depth analysis.


Key Words: blood pressure • growth • hypertrophy • vascular • endothelium • relaxation

Disorders of the renin-angiotensin system contribute largely to the pathophysiology of hypertension, renal diseases, and congestive heart failure. Angiotensin (Ang) II exerts hemodynamic and renal effects, but it is also a local biologically active mediator with direct effects on endothelial and smooth muscle cells.1 Two major subtypes of Ang II receptors, type 1 (AT1R) and type 2 (AT2R), have been identified; their roles have now been investigated in more depth in vivo and in vitro, although few data are available concerning the role of these receptors, especially AT2Rs, in the adult circulation in humans. These 2 subtypes, first distinguished on a pharmacological basis, have been identified by expression cloning from various species, including humans. They both share a seven-transmembrane domain topology. However, they display striking differences in many aspects.

The AT1R subtype is expressed ubiquitously and is involved in all the well-known biological functions of Ang II, although it is mostly studied at concentrations that are extraordinarily high compared with physiological concentrations (µmoles versus picomoles). The intracellular signal transduction events triggered by AT1R (with Ang II in the µmolar range) are well characterized and include G protein coupling, as well as activation of several tyrosine kinases.

In contrast to AT1Rs, the physiological role of AT2Rs has long remained an enigma.1 It is highly expressed in fetal tissues, although its expression is dramatically decreased after birth, being restricted to a few organs, including the cardiovascular system. The AT2R is re-expressed in the adult animal after cardiac and vascular injury and during wound healing, suggesting a role for this receptor in tissue remodeling, growth, and/or development. A major step toward the understanding of AT2R functions has recently been provided by the generation of genetically engineered animals either lacking or overexpressing the gene encoding for the AT2R.

The role of the AT2R is important to determine as it may possibly be involved in hypertensive patients receiving a chronic treatment of AT1R antagonists. Besides their effect on blood pressure, long-term administration of AT1R blockers results in a several-fold increase in plasma Ang II and thus in a possible overstimulation of AT2Rs.2 Therefore, the effect of the stimulation of the AT2R is becoming increasingly important in both physiological and pathological situations. Furthermore, a cross-talk between the 2 receptor subtypes (AT1R and AT2R) has been described,3,4 and AT1R blockade might also unmask potential effects of AT2Rs that were inhibited by AT1R stimulation.

In the present review, we focused on the cardiovascular role of the Ang II AT2R subtype in adult animals and humans and thus excluded its role during growth and development. We report the possible roles of the AT2R in the control of the vasomotor tone and the more speculative role of the AT2R in the Ang II–induced cardiovascular remodeling.

Location of AT2R in the Adult
The AT2R gene expression is high during fetal life and decreases rapidly after birth. In adults, the AT2R seems restricted to some vascular territories, and this location may change in situations such as pregnancy or in pathological situations such as hypertension, heart failure, or vascular injury (see review articles5–8).

In animals, AT2Rs were found in many vessel types. Briefly, AT2Rs are present in the uterus,9,10 the kidney,11,12 rat (Wistar-Kyoto rats and spontaneously hypertensive rats [SHR]) mesentery,13–15 the portal circulation,16 the heart,17 and the brain.18 Whereas the aorta has been the most commonly used model in the investigation of AT2R functions (see below), in small resistance arteries AT2Rs are also present in the endothelial and/or smooth muscle cells, depending on the vessel type and species. Using immunofluorescence, AT2Rs were localized in endothelial and smooth muscle cells in rat mesenteric arteries and skeletal muscle arterioles.14,19 (Figure 1).



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  		Figure 1. Immunolocalization of AT2Rs in endothelial (the arrow shows the endothelial size of the vascular wall) and smooth muscle cells in a mesenteric resistance artery (technique described in Matrougui et al14).

In humans, the presence of AT2Rs in the adult vasculature remains to be further demonstrated, as only scarce information is available. Although no AT2R was detected in vascular smooth muscle cells from renal arteries using the radio-labeled AT2R ligand CGP-42112,20 in the human kidney AT2R expression was localized using in situ hybridization to the medial layer of the interlobular arteries.6 In human kidney arteries, AT2Rs are mainly located to the adventitia and only detected with a low level in the endothelium.21 In coronary vessels, AT2Rs were detected and remained unchanged or upregulated in the failing heart.6 In primary cell cultures, AT2R transcripts are found in coronary endothelial cells22 and in human umbilical vein endothelial cells (HUVECs).23 Human uterine arteries also express a large number of AT2Rs.24 Thus, although the AT2R is present in the adult vasculature, its distribution is not homogenous and is subject to changes according to age, species, vessel type, and pathophysiological state.

Role of AT2R in the Control of Vascular Tone and Arterial Pressure
A role for the AT2R in the control of vascular tone can be deduced from both in vivo and in vitro experiments. During the past decade, the role of the acute stimulation of the AT2R has been investigated in several vascular territories and especially in the kidney, uterus, and mesentery. These studies have been performed in isolated arteries, in vitro, or in perfused organs (hindlimb, mesenteric bed, or kidney); the experimental conditions were quite often different, making it difficult to have a clear view on the exact role of the AT2R. Finally, most of these studies have been performed in animals, and the effect of acute stimulation of AT2R remains to be determined in humans.

Experimental Evidence Obtained In Vivo or In Situ
In anesthetized rats, a bolus injection of Ang II induces a biphasic response with an initial rise in blood pressure due to AT1R activation and a latter slow decrease in pressure that has been attributed to AT2Rs.25 In rats submitted to a high-salt diet, Ang II infusion produces a higher rise in blood pressure when co-infused with the AT2R blocker PD 123,319,26 suggesting that AT2Rs have a vasodilator effect in these experimental conditions. However, in similar Ang II perfusion conditions, Macari et al27 reported that PD 123,319 did not affect blood pressure, whereas high doses of CGP-42112, an AT2R agonist, increased blood pressure, suggesting that CGP-42112 behaves as a nonspecific AT1R agonist when used at a high concentration.

Experimental protocols involving local injections of Ang II allow appreciation of the diversity of the involvement of AT2R in the control of vasomotor tone in different regional networks. Intra-mesenteric injection of Ang II induces a rise in pressure, sensitive28 or insensitive to AT2R blockade.29 The AT2R does not seem involved in Ang II–induced increase in vascular resistance in the isolated rat heart17 and in the rat hindquarter.30 In the control of cerebral blood flow, as assessed by measurements performed using laser Doppler flow probes in anesthetized rats, the AT2R does not seem to play a major role in baseline conditions.31,32 Similarly, AT2R blockade has no effect on the decrease in cerebral blood flow caused by Ang II when injected into the carotid artery.33 In contrast, in the in situ perfused kidney, AT2R blockade decreases Ang II–dependent vasoconstriction when NO synthesis is inhibited.34 From these in vivo or in situ perfused organs experiments, it can be deduced that AT2Rs play a weak role in the control of systemic blood pressure under normal physiological conditions. However, the AT2R likely plays a role in the local control of blood flow in several organs. The great diversity of the possible responses to AT2R stimulation, depending on the location, may explain the near absence of in vivo effect of AT2R blockade, although in some situations AT2R activity might be revealed after AT1R blockade (possible cross-talk between AT1R and AT2R) or NO synthesis inhibition (see below).

A role for AT2R in the control of blood pressure can also be deduced from the studies in AT2R knockout mice that have high blood pressure.35 These mice also exhibit a higher increase in blood pressure and a higher increase in total peripheral vascular resistance following a low-dose infusion of Ang II.36,37 In addition, mice overexpressing AT2R in vascular smooth muscle lose their ability to raise blood pressure after Ang II infusion, whereas they become responsive to Ang II after NO synthesis blockade or AT2R blockade.38 Therefore, data from transgenic mice for the AT2R suggest that the AT2R plays a vasodilator role, lowering blood pressure. Thus, according to these results, selective stimulation of AT2R in the presence of AT1R antagonists is predicted to have a beneficial clinical effect in controlling blood pressure. Recently, this effect has been demonstrated in SHR.39

Role of AT2R in the Control of Vasomotor Tone and Blood Flow In Vitro
In Renal Circulation
In the renal circulation, AT2R stimulation seems to have a vasoconstrictor effect in mid-size and large arterioles in the rat as AT2R blockade with PD 123,319 reduces Ang II–induced contraction of intralobular renal arteries in the perfused hydronephrotic kidney.40 Nevertheless, PD 123,319 failed to affect Ang II–dependent vasoconstriction in isolated rabbit renal arteries.12 Dual effect of AT2R stimulation on large and small arteries has been reported: on larger arterioles AT2R stimulation might result in vasoconstriction,40 whereas on small arterioles AT2R activation produces vasodilation. Indeed, in isolated and perfused afferent arterioles, AT2R stimulation mediates an endothelium-dependent dilation sensitive to cytochrome P 450 (CyP450) blockade. The mediators involved might be epoxy-eicosatrienoic acids.11,41 This vasodilatory effect of AT2R may antagonize AT1R-dependent contraction in these arterioles in normotensive but not young hypertensive (SHR) rats.42 This defect in AT2R-dependent dilation in arterioles from young SHR might play a role in the pathogenesis of hypertension.42 Finally, in mice lacking the gene for AT2R, ACE activity is doubled in the kidney,43 suggesting that AT2R stimulation might downregulate the activity of the enzyme.

In the Uterus
In the uterus, AT2R are widely expressed in the myometrium.24,44,45 In the uterine artery, AT2R are also expressed in ewes and rats,24,44–46 and their number increases tremendously during pregnancy.45,46 In rat uterine arteries, isolated in a small vessels myograph, Ang II–induced contraction is attenuated by AT2R stimulation with CGP-42112 and is increased after AT2R blockade with PD 123,319, whereas phenylephrine-induced tone is unaffected. This effect of AT2R is less pronounced during pregnancy,46 which fits with a downregulation of myometrial AT2R.44

In the Cerebral Circulation
In the cerebral circulation, Ang II has been shown to dilate arteries when applied topically on a cranial window in anesthetized rats.47 This relaxation is mediated by cyclooxygenase derivatives (the relaxation was sensitive to indomethacin) produced by the endothelium. On the other hand, in isolated rat, bovine, or canine cerebral arteries (>=150 to 200 µm ID), Ang II induces a contraction.48–51 The role of AT2R in this contraction is not yet understood. Nevertheless, in vivo measurements (detailed above in Experimental Evidence Obtained In Vivo or In Situ) failed to show a role for AT2Rs in cerebral blood flow.31–33 This might reflect the heterogeneity of the responses to AT2R stimulation in cerebral vessels from different size and location.

In the Mesenteric Circulation
In perfused and pressurized isolated mesenteric resistance arteries, Ang II–induced contraction is independent of AT2R in adult normotensive rats and SHR, but in young prehypertensive SHR Ang II–induced contraction involves both AT1R and AT2R. This double involvement of AT1R and AT2R in Ang II–induced contraction was not found in age-matched young normotensive rats.13 Thus, in young SHR, the involvement of the 2 types of receptor might explain the hyperreactivity of the arteries in SHR and contribute to the development of hypertension.13 In mesenteric isolated vessels, AT2R are also involved in the Ang IV–dependent dilation.52

In mesenteric arteries, AT2Rs also have a role in the control of the vascular tone by flow (shear stress). In resistance arteries, pressure induces an active vasoconstrictor (myogenic) tone53 that is opposed by flow-induced dilation.54,55 Flow (shear stress)-induced dilation depends mainly on the release of endothelium-derived relaxing factors,55–58 and the local tissue renin-angiotensin59,60 has the ability to interact with flow-induced dilation. Although locally produced Ang II is a potent amplifier of vascular tone,60 Ang II is also able to interact with flow-dependent dilation. AT2R blockade (PD 123,319) reduces the amplitude of flow (shear stress)-induced dilation in rat mesenteric arteries.14 Blockade of AT1R had no affect on arterial diameter changes due to flow, but the nonselective inhibitor saralasin (blocking both AT1R and AT2R) produced an effect similar to that of PD 123,319, confirming the role AT2R in flow-dependent dilation. This effect represents 20% of the flow-dependent dilation observed in these arteries (150 µm diameter) and depends on the release of NO by the endothelium.14 The involvement of AT2R in flow-induced dilation was not found in hypertensive rats.15 Thus, as illustrated in Figure 2, in mesenteric resistance arteries from normotensive rats, flow-induced dilation involves the production of NO, in part through the stimulation of AT2R.



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  		Figure 2. Possible role of AT1Rs and AT2Rs in the response of mesenteric resistance arteries to flow (shear stress). In normotensive Wistar-Kyoto rats, flow-induced dilation involves AT2R-dependent dilation through the NO pathway. In SHR, shear stress–induced AT2R-dependent dilation is absent, and AT1R-dependent contraction antagonizes flow-dependent dilation.

In Other Vascular Territories
In other vascular territories, it remains somewhat difficult to describe definitively the role of an acute stimulation of the AT2R. In coronary arteries, Ang II increases vascular resistance in the isolated rat heart exclusively through the AT1R, whereas in coronary microvessels NO production can be elicited through both AT1Rs and AT2Rs.61 The rat tail artery is very responsive to sympathetic stimulation and contains a high density of Ang II receptors. The AT2R reduces the Ang II–dependent enhancement of the stimulation-induced norepinephrine release, whereas the direct contractile effect of Ang II was only sensitive to AT1R blockade.62 In skeletal muscle arterioles, AT2Rs have been localized in both endothelial and smooth muscle cells;19 however, in the perfused rat hindquarter, Ang II–induced contraction was insensitive to AT2R blockade.63

Thus, a role for AT2Rs is clear in the kidney, where AT2Rs may mediate either a contraction in large arteries or a dilation in small afferent arterioles. In the uterus, AT2Rs unequivocally mediate a dilation. In the mesenteric circulation, AT2Rs are also involved in endothelium-dependent dilation when stimulated by shear stress, although in young SHR AT2R may also contribute to Ang II–induced contraction. In other vascular territories, AT2Rs may also be involved in different types of responses or, more often, may not be involved in the control of vascular tone. In brief, AT2Rs cannot be associated with a single type of vascular response. The vascular response to AT2R-stimulation is vessel type and species dependent. The diversity of the possible responses to AT2R stimulation involves that different types of mediators are involved in these responses (see sections on mediators involved in AT2R-mediated contraction and AT2R-mediated dilation below). It is also important to note that a cross-talk between AT1R and AT2R may have a key importance during chronic AT1R blockade. In such a condition AT2R-dependent functions may be revealed or increased.

In hypertension, a dysregulation of AT2R-mediated tone might have a role in the pathogenesis of the disease. Indeed, a defect in AT2R-mediated dilation in response to shear stress in mesenteric resistance arteries15 has been observed. In addition, in young prehypertensive SHR, the AT2R has a direct vasoconstrictor effect in mesenteric resistance arteries. Thus, together with the high blood pressure found in AT2R knockout mice, these data support a role for the AT2R in hypertension. The quantitative importance of this role in the establishment and the gravity of arterial hypertension are not yet well defined and need further investigation.

Mediators Involved in the Acute Vascular Response to AT2R Stimulation
Mediators Involved in the AT2R-Mediated Contraction
In mesenteric arteries, the mediators involved in AT2R-dependent contraction in hypertensive rats are not known.13 In the kidney, AT2R-dependent contraction is proposed to involve CyP450 metabolites such as 20-HETE.34,64

Mediators Involved in the AT2R-Mediated Dilation
Although the aorta is not, per se, involved in the local control of blood flow, it is the most commonly used experimental model in the study of receptor function. Ang II increases cGMP content in the aorta from rabbits and rats. In the rat aorta, this increase in cGMP content is exclusively dependent on the AT1R,59 although both AT1Rs and AT2Rs are expressed in the rabbit aorta.65 In rings of the rat aorta, the inhibitory affect of AT2Rs on phenylephrine-induced contraction depends on the production of NO.3 Ang II–induced cGMP production depends on AT2Rs in SHR and in stroke-prone hypertensive rats, in which AT2R stimulation increases NO synthesis and cGMP production through the activation of the bradykinin B2 receptor.66 In SHR, the inhibition of Ang II–induced contraction by losartan is attenuated by AT2R blockade.3 This latter study also suggests a downregulation of AT2R function by AT1Rs.3 Contractions induced by another vasoconstrictor such as the thromboxane A2/PGH2 receptor agonist U46619 were not affected by AT2R blockade, although they were sensitive to AT1R blockade.67 Finally, AT2R knockout in mice induces a decrease in aortic cGMP content, together with an overexpression of the AT1R.68 On the contrary, AT2R transgenic mice overexpressing the AT2R have a high aortic cGMP content normalized by either NO-synthesis blockade or bradykinin B2 receptor blockade.38 This AT2R-dependent bradykinin production might be mediated by an intracellular acidosis, which would activate an acid-optimum kininogenase.38

A clear relation between AT2R-stimulation and the NO-cGMP pathway has been shown in several conditions and in different types of arteries. In mesenteric resistance arteries, AT2R-dependent flow-mediated dilation is lost after NO-synthesis blockade or endothelium disruption.14 Thus, AT2Rs located on endothelial cells could trigger a release of NO after shear stress stimulation in these vessels.

In coronary microvessels, NO production depends on both AT1Rs and AT2Rs.61 The involvement of bradykinin as a mediator between AT2R stimulation and NO production is supported by experiments performed in transgenic mice overexpressing the AT2R and also in stroke-prone SHR. In these rats, a 4-hour infusion of Ang II increases the aortic cGMP content. This effect was inhibited by either AT2R blockade, NO-synthesis inhibition, or bradykinin B2 receptor blockade.66 The relation between AT2R, bradykinin, and NO has been evidenced in vascular smooth muscle cells but remains to be explored in endothelial cells.

Other mechanisms may be involved in AT2R-mediated dilation. In isolated afferent arterioles from the rabbit kidney, AT2R blockade with PD 123,319 suppresses the facilitatory effect of miconazole on Ang II–induced contraction without affecting the effect of nitro-L-arginine methyl ester, suggesting that in this vessel the AT2R mediates a dilation, probably through the release of epoxy-eicosatrienoic acids.11 In quiescent HUVECs, AT2R blockade increases Ang II–induced superoxide formation,23 which could reduce the Ang II–induced contraction in blood vessels. The AT2R-dependent inhibition of AT1R-mediated superoxide formation involves tyrosine phosphates.23 Indeed, AT2Rs have previously been shown to activate phosphotyrosine phosphate activity in different cell types.7,69–71 Similarly, Ang II–dependent contraction might be reduced in situ thanks to a possible inhibitory effect of the AT2R on ACE activity in different organs. Indeed, in AT2R knockout mice, circulating and tissue (heart, lung, and kidney) ACE activity is doubled.43 This increased ACE in AT2R knockout mice leads to a higher vasoconstrictor effect of Ang I and to a lower vasodilatory effect of bradykinin.43 This AT2R-dependent inhibition of ACE activity was also observed, by the same authors, in wild-type mice after an acute inhibition of the AT2R with PD 123,319.43

Regulation of AT2R
As described above, as a possible mechanism for the vasodilatory effect of AT2R stimulation, the AT2R-mediated attenuation of AT1R-dependent contraction is a way by which AT2Rs can downregulate AT1R-dependent function. On the other hand, a downregulation of AT2Rs by AT1Rs has also been reported. In aortic rings from SHR, AT1R blockade with losartan reduces phenylephrine-induced contraction; this reduction is inhibited by either NO-synthesis blockade (nitro-L-arginine methyl ester) or AT2R blockade with PD 132,319.3 Furthermore, the AT2R-dependent NO production can only be observed after AT1R blockade, suggesting an inhibitory effect of AT1Rs on AT2Rs. AT2Rs may also be regulated by other endocrine systems, as insulin increases the expression of AT2Rs in rat aortic smooth muscle cells72 and adrenocorticotropic hormone decreases the density of AT2Rs in the uterine arteries of ewes.9

Effect of AT2Rs in the Control of Cardiovascular Structure
Recent clinical trials of ACE inhibitors have consistently documented the salutary effects of this class of agents in treating and preventing cardiovascular disease, with impressive reductions in coronary and cerebral vascular events despite a modest effect on blood pressure lowering.73–75 These data suggest that ACE inhibitors may also exert direct actions on blood vessels beyond their hemodynamic effects. ACE inhibitors have also demonstrated marked effects on the cardiovascular remodeling associated with hypertension, mainly hypertrophy and fibrosis. Therefore, the effect of Ang II and its receptor subtypes on vascular remodeling deserves to be examined. In vitro, Ang II triggers vascular smooth muscle cell hypertrophy and/or hyperplasia,76,77 this effect being mediated by the AT1R. In organ culture of isolated segments of rabbit aorta maintained under physiological pressure and flow, Bardy et al78,79 have reported that mechanical factors stimulated a local synthesis of Ang II, which in turn induces an increase in the synthesis of extracellular matrix proteins, such as fibronectin and collagen, via the AT1R. In the same way, van Kleef et al80 reported that AT1Rs, but not AT2Rs, mediate the progression of neointimal thickening induced by delayed application of Ang II in the injured carotid artery in the rat.81 Mifune and coworkers82 aimed to examine the effects of stimulation of AT2Rs on collagen synthesis in vascular smooth muscle cells. Because in vitro cultured vascular smooth muscle loses the AT2R subtype, retroviral gene transfer was used to supplement adult vascular smooth muscle cells with AT2Rs to mimic the vasculature in vivo. The treatment of these cells with the AT2R agonist CGP-42212A alone did not cause a significant change in p42/p44 mitogen-activated protein kinase activity but caused a 30% to 50% decrease in protein tyrosine phosphatase activity. Treatment with CGP-42112A also caused a dose- and time-dependent increase in collagen synthesis, which was completely inhibited by the AT2R antagonist PD 123,319, unaffected by the AT1R antagonist losartan, and attenuated by a treatment with pertussis toxin or Gi antisense oligonucleotides. Interestingly, studies in other cell lines demonstrated that CGP-42112A caused similar results in transfected mesangial cells but had essentially opposite effects in fibroblasts (NIH-3T3-AT2). These results suggest that AT2R stimulation can increase collagen synthesis in vascular smooth muscle cells via a Gi-mediated mechanism and provide evidence for heterogeneity in the effects of AT2R stimulation in different tissues.82

The effect of the AT2R on extracellular matrix synthesis in cardiac tissues was studied in cardiomyopathic hamsters.83 AT2R density increases by 153% during heart failure, whereas AT1R density increases in the hypertrophy stage and then returns to control level during heart failure. Such differential regulation of AT2Rs and AT1Rs during heart failure is consistent with changes in the respective mRNA levels.83 Cardiac fibroblasts isolated from cardiomyopathic hearts from hamsters during heart failure, but not from controls, expressed AT2R. Using the cardiac fibroblasts expressing AT2Rs, Ohkubo et al83 found that Ang II stimulates net collagen protein production. Pretreatment with an AT2R antagonist (PD 123,319) evokes a further elevation in collagen and fibronectin synthesis.

In vivo, Ang II is involved in the increase in cardiovascular fibrosis, which is a pathological feature associated with hypertension.84–86 In the myocardium, the progressive interstitial and perivascular fibrosis contribute to increase the stiffness of the cardiac muscle and to develop diastolic dysfunction.87 Indeed, Ang II is involved in the development of cardiomyocyte hypertrophy and cardiac fibrosis and in the modulation of cardiac fibroblast growth and collagen synthesis in human and animal models.87,88 Clearly, 1 major role of the AT2R lies in developmental processes as well as in vascular cardiac remodeling. Most of the reports indicate antigrowth, antifibrotic, and proapoptotic effects of the AT2R in the fetus and in damaged tissues. Being first reported to inhibit neointima formation after vascular injury, AT2R has more recently been shown to contribute to growth inhibition in fetal vascular smooth muscle cells and in hypertrophied hearts.89 AT2R stimulation was also reported to reduce interstitial fibrosis in failing cardiomyopathic hearts.83

However, several recent reports of in vivo and in vitro studies using receptor subtype specific blockers and antisense DNA suggest a possible role of the AT2R in medial hypertrophy and fibrosis in the aorta and cultured cells. In rats receiving hypertensive doses of Ang II, chronic blockade of the AT2R did not affect the plasma level of Ang II and the vascular reactivity to Ang II mediated by the AT1R. Chronic blockade of the AT1R in rats receiving Ang II resulted in normal arterial pressure but induced a significant aortic hypertrophy and fibrosis. Chronic blockade of the AT2R in Ang II–induced hypertensive rats had no effect on arterial pressure but antagonized the effect of Ang II on arterial hypertrophy and fibrosis, suggesting that in vivo vascular trophic effects of Ang II are at least partially mediated via AT2R in adult normotensive rats.86 Nevertheless, in another study conducted in similar conditions, this profibrosis effect of AT2Rs was not found.90

Dzau and coworkers,91 used mice lacking AT2 gene (Agtr2-/Y) to test the in vivo roles of the AT2R; they reported that cardiac hypertrophy was induced by suprarenal abdominal aortic banding in 10- to 12-week-old Agtr2- and wild-type (Agtr2+) mice. Carotid arterial pressure was not different between the strains, although aortic banding increased arterial pressure by {approx}40 mm Hg. Aortic banding increased the heart-weight/body-weight ratio and the cross-sectional area of cardiomyocytes by 15%, resulting in comparable cardiomyocyte hypertrophy in the 2 strains. In contrast, coronary arterial thickening and perivascular fibrosis, determined by the media/lumen-area ratio and the collagen/vessel-area ratio, respectively, were 50% greater in Agtr2- than in Agtr2+ mice after banding. These parameters were similar in sham-operated mice. Radioligand binding studies using the whole heart and immunohistochemistry showed that AT2R expression was limited and localized in the coronary artery and perivascular region. These results suggested that the AT2R mediates an inhibitory effect on coronary arterial remodeling, such as medial hypertrophy and perivascular fibrosis in response to pressure overload, and an activation of the renin-angiotensin system.91 In contrast, Inagami et al35 developed another strain of mice lacking the AT2R gene (Agtr2-/Y) to test the in vivo roles of the AT2R. Pressure overload by surgical aortic banding failed to induce left ventricular hypertrophy and fibrosis in Agtr2-/Y mice, suggesting that AT2R may be responsible for cardiac hypertrophy and perivascular myocardial fibrosis.92 The opposite results obtained by these 2 groups are likely in relation with the different genetic background of Agtr2- mice used in these studies: Dzau’s group reported coronary arterial remodeling in response to pressure overload in Agtr2-/Y mice; these mice were back-crossed 6 times into the FVB/N (related to the 129 strain) background36 whereas Inagami’s Agrt2- mice were back-crossed 9 times on a C57B6 background.35

Conclusion

Most in vitro studies in cultured cells and in isolated segments of aorta have shown that AT2R stimulation could lead to the production of vasodilating substances, among which NO is the most cited. However, in different organs or in small arteries isolated from different type of tissues, other vasoactive substances may also mediate AT2R-dependent dilation, and sometimes, such as in large renal arteries, AT2R stimulation may lead to a vasoconstriction. Nevertheless, when acutely stimulated, the most probable response expected from AT2R stimulation will be a vasodilation. Thus, in the perspective of a chronic AT1R blockade in patients, overstimulation of AT2Rs might be beneficial, regarding their potential vasodilator effect. Concerning the possible role of AT2Rs in cardiovascular remodeling, the situation is more controversial. In vitro, AT2R stimulation clearly inhibits cardiac and vascular smooth muscle growth and proliferation, stimulates apoptosis, and promotes extra cellular matrix synthesis. In vivo, the situation might be less beneficial if not deleterious; indeed, if chronic AT2R overstimulation would lead to cardiovascular hypertrophy and fibrosis, then the long-term consequences of chronic AT1R blockade and thus AT2R overstimulation require more in-depth analysis.

Received April 28, 2001; first decision June 18, 2001; accepted June 29, 2001.

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