Peptides 32 (2011) 21412150

Contents lists available at SciVerse ScienceDirect

Peptides

j ourna l ho me pa ge: www.elsev ier .com/ locate /pept ides

Review

A new

Aurelie NKidney Researc

a r t i c l

Article history:Received 23 AAccepted 7 SepAvailable onlin

Keywords:Tissue RASReninCirculating RAVascular toneAng-(1-7)Vascular cells

remains elusive, but may contribute to ne-tuning of vascular tone and arterial structure and may amplifyvascular effects of the circulating RAS, particularly in pathological conditions, such as in hypertension,atherosclerosis and diabetes. New concepts relating to the vascular RAS have recently been elucidatedincluding: (1) the presence of functionally active Ang-(1-7)-Mas axis in the vascular system, (2) the

Contents

1. Introd2. The cl3. Beyon

3.1. 3.2. 3.3. 3.4.

4. The va5. Ang-d6. The R7. Funct8. The va9. The (p10. Concl

ConAcknoRefer

This is parWalmor C. De

CorresponE-mail add

0196-9781/$ doi:10.1016/j.importance of the RAS in perivascular adipose tissue and cross talk with vessels, and (3) the contributionto vascular RAS of Ang II derived from immune and inammatory cells within the vascular wall. Thepresent review highlights recent progress in the RAS eld, focusing on the tissue system and particularlyon the vascular RAS.

2011 Elsevier Inc. All rights reserved.

uction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2142assical RAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2142d the classical RAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2142Renin/prorenin receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2142ACE2, Ang-(1-7), Ang III, Ang IV and other Ang-derived peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2142Intracellular RAS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2143Tissue-based RAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2143scular RAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2144erived peptides in the vascular wall . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2144AS in perivascular adventitial tissue (PVAT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2145ional evidence of vascular tissue RAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2146scular RAS and hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2146atho)physiological signicance of the vascular RAS further considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2147usions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2147icts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2147wledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2147

ences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2147

t of a series of reviews on local reninangiotensin systems edited byMello.ding author. Tel.: +1 613 562 5800x8241; fax: +1 613 562 5487.ress: rtouyz@uottawa.ca (R.M. Touyz).

see front matter 2011 Elsevier Inc. All rights reserved.peptides.2011.09.010look at the reninangiotensin systemFocusing on the vascular system

guyen Dinh Cat, Rhian M. Touyz

h Centre, Ottawa Hospital Research Institute, University of Ottawa, 451 Smyth Rd, Ottawa, ON KIH 8M5, Canada

e i n f o

ugust 2011tember 2011e 16 September 2011

S

a b s t r a c t

The reninangiotensin system (RAS), critically involved in the control of blood pressure and volumehomeostasis, is a dual system comprising a circulating component and a local tissue component. Therate limiting enzyme is renin, which in the circulating RAS derives from the kidney to generate Ang II,which in turn regulates cardiovascular function by binding to AT1 and AT2 receptors on cardiac, renaland vascular cells. The tissue RAS can operate independently of the circulating RAS and may be activatedeven when the circulating RAS is suppressed or normal. A functional tissue RAS has been identied inbrain, kidney, heart, adipose tissue, hematopoietic tissue, gastrointestinal tract, liver, endocrine systemand blood vessels. Whereas angiotensinsinogen, angiotensin converting enzyme (ACE), Ang I and Ang IIare synthesized within these tissues, there is still controversy as to whether renin is produced locallyor whether it is taken up from the circulation, possibly by the (pro)renin receptor. This is particularlytrue in the vascular wall, where expression of renin is very low. The exact function of the vascular RAS

2142 A. Nguyen Dinh Cat, R.M. Touyz / Peptides 32 (2011) 21412150

1. Introduction

The reninangiotensin system (RAS) is critically involved in thephysiological regulation of blood pressure and volume homeostasisand in the pdiseases [43therapeuticreduce the the 1890s tcirculating through Anrecently thiever it is noproductiontissues andtion.

Genes coin many tisgland, pituihematopoieof a functioof the localThe exact runclear. Theand highligspecically

2. The clas

Activatioof renin, a renal affereto prorenincirculation states, highnerve activrenin, an asto form the verting enzactive octap(especially Ang I, ACE BK-(1-7) [2promotes thdegrading B

Vascularated via tw1 (AT1) recgeneral, in multiple hegers, such and ROS [6non-receptp70S6K, Akcyclase [15are mediataldosteronevation of thchronotropphy and b

The AT2AT1 recepto[55]. It is exglomeruli athe AT1 rec

protein tyrosine phosphatase activation, NO generation and sig-naling through sphingolipids to stimulate vasodilation, natriuresis,anti-inammatory and anti-brotic actions and inhibition of cellgrowth [77,128]. Increased AT2R expression occurs in pathological

ions , renrespoRs ins, teted wgativd kinothclingted w

as mindinn of ologyed [9

ond

il recg II we co

at or, (23) int rev

tissu

nin/p

in woducer i

speignal, proted pting diomascu)phygh it

(P)R thecces-RASr vacase pting ig to en V-reninproliveloous p

E2, As

omohe Aathogenesis of hypertension and other cardiovascular,137]. Pharmacological inhibition of the RAS is a major

strategy currently used to manage hypertension and torisks of cardiovascular events [6]. Since its discovery inhe RAS was identied as an endocrine system wherebykidney-derived renin regulates cardiovascular functiong II binding to its receptors on target tissues [149]. Untils system was accepted as the conventional RAS. How-w clear that the kidney is not the only source of renin

and that angiotensin (Ang) peptides may be formed in organs that have a blood pressure-independent func-

ding for enzymes and peptides of the RAS are expressedsues beyond the kidney, including the brain, adrenaltary gland, reproductive tissues, gastrointestinal tract,tic tissue, heart and vessels, suggesting the presencenally active local or tissue RAS [10,24,142]. Functions

RAS remain elusive, but are probably tissue-specic.ole of tissue RAS in human (patho)physiology is still

present review provides an update of the classical RAShts some new concepts, focusing on the tissue RAS and

the vascular RAS.

sical RAS

n of the classical RAS originates with the synthesisglycoprotein, by the juxtaglomerular (JG) cells of thent arteriole [57]. In JG cells, preprorenin is processed

and then to active renin, which is secreted into the[95]. Renal renin release is stimulated by low volume

salt content in the distal tubules, renal sympatheticity and reduced renal perfusion [70,150]. In the blood,partyl protease, cleaves liver-derived angiotensinogendecapeptide angiotensin I (Ang I) [53]. Angiotensin con-yme (ACE) hydrolyzes inactive Ang I into the biologicallyeptide Ang II. ACE is found primarily in endothelial cellspulmonary endothelium) [63]. In addition to cleavingmetabolizes bradykinin (BK), a vasodilator, to inactive0]. Hence ACE has a dual role in the vasculature in that ite production of Ang II, a potent vasoconstrictor whileK, a vasodilator., cardiac, renal and adrenal effects of Ang II are medi-o G protein-coupled receptors (GPCR), the Ang typeeptor and the Ang type 2 (AT2) receptor that act, inopposite directions. The AT1 receptor interacts withterotrimeric G-proteins and produces second messen-as inositol trisphosphate (IP3), diacylglycerol (DAG)4]. Ang II/AT1 receptor coupling activates receptor andor tyrosine kinases, serine/threonine kinases, MAPKs,t/PKB and PKC [64,91] and couples negatively to adenyl1]. Most of the (patho)physiological effects of Ang IIed through AT1 receptors including vasoconstriction,

secretion, renal tubular Na+ reabsorption, thirst, acti-e sympathetic nervous system, cardiac ionotropic andic actions and cardiovascular inammation, hypertro-rosis [97,127,155].receptor shares partial amino acid homology (34%) tors and is the predominant Ang II receptor in the fetuspressed at low levels in the adult vasculature, JG cells,nd tubules and it elicits effects to counteract those ofeptor [66]. The AT2 receptor mediates actions through

conditfailurestress

GPCproteinassociaas a nelung antion. Ain recyassociaknownAT2R btivatioThe bireview

3. Bey

Untand Anever thchangerecepttides, (presenon the

3.1. Re

Renfor prHowevbind tovate s(PLZF)activatpromoin carcells, v(pathoalthou

Thebeyondbe an ain nontial foV-ATPregulabindinbetwea (pro)in cell onic dein vari

3.2. ACpeptide

A herate tincluding: hypertension, myocardial infarction, cardiacal failure, cerebral ischemia and diabetes, possibly as anse where fetal genes are re-expressed [1,129,134].teract not only with G proteins but also with accessoryrmed GPCR interacting proteins (GIP). GIP specicallyith AT1R, called AT1R-associated protein (ATRAP), acts

e regulator of AT1R [5] and is expressed in aorta, heart,dney. Overexpression leads to decreased cell prolifera-er GIP, ARAP1 (AT1R-associated protein 1), is involved

of the AT1 receptor [92,146]. GPCR interacting proteinsith AT2R, include AT2R-interacting protein (ATIP) (alsoitochondrial tumor suppressor gene 1 (MTUS1) andg protein of 50 kDa (ATBP50)) is involved in transinac-

receptor tyrosine kinases and growth inhibition [105]. and regulation of Ang receptors has been extensively0,101].

the classical RAS

ently, the RAS was considered a linear process (Fig. 1)as accepted as the major effector peptide [143]. How-

nventional view of the RAS has undergone signicantfour main levels: (1) identication of renin/prorenin) recognition of functionally active Ang II-derived pep-tracellular RAS and (4) existence of a tissue RAS. Theiew highlights some of these new paradigms focusinge system, specically the vascular RAS.

rorenin receptor

as considered to be a protease enzyme responsibletion of Ang I without any direct biological actions.t has now been shown that prorenin and renincic (pro)renin receptors ((P)RR) [98,99], which acti-ing molecules, including promyelocytic zinc ngersein-phosphatidylinositol-3-kinase (PI3K) and mitogen-rotein (MAP) kinases (ERK1/2 and p38MAP kinase),cell growth and brosis, independently of Ang II,yocytes, mesangial cells, podocytes, distal tubularlar endothelial cells and VSMCs [27,119]. The exactsiological signicance of the (P)RR remains unclear

may act as an amplier of tissue RAS.R is a multifunctional receptor that mediates effects

RAS [65]. A truncated form of the receptor (M8.9), maysory protein of vacuolar H+-ATPase (V-ATPase) involved-related functions [86]. The (P)RR/ATP6AP2 is essen-uolar H+-ATPase assembly in cardiomyocytes [3,71].lays a role in physiological and biochemical processes byntracellular pH, an effect that is enhanced by (pro)renin(P)RR [23]. The (P)RR also acts as an adaptor proteinATPase and Wnt receptors and signals through Wnt in-independent manner [23]. Wnt signaling is involved

feration, polarity, and fate determination during embry-pment and tissue homeostasis and has been implicatedathologies including cancer.

ng-(1-7), Ang III, Ang IV and other Ang-derived

logue of ACE, ACE2 catalyzes Ang I and Ang II to gen-ng peptides Ang-(1-9) and Ang-(1-7), which mediate,

A. Nguyen Dinh Cat, R.M. Touyz / Peptides 32 (2011) 21412150 2143

Angiotensinogen

E2

V

m

Fig. 1. The clais hydrolyzed Ang II to Ang-(Mas and induc

in general, 7) is metabthe circulatreproductivreceptor Ma

Other smIV. Ang III, cally activeIII infusion promotes v[107]. In vitmediators aAng III bindAng III by amd-aminopepvasodilationa wide ranlearning anproperties aactions are to a specienzyme insanism(s) ofunclear andbe elucidate

Other Anand kidney production,cated in carRenin

Angiotensin I

ACE

Bradykinin

Angiotensin II

AC

dilAT1R AT2R

asodilatition

Vasoconstriction

Fibrosis

Hypertrophy

Inflammation

Inactive

etabolitesssical reninangiotensin system. Kidney-derived renin is secreted into the circulation wto angiotensin II (Ang II) by angiotensin converting enzyme (ACE). ACE metabolizes brad1-7). Ang II binds to Ang II type 1 receptors (AT1R) and Ang II type 2 receptors (AT2R) on es effects similar to those mediated by AT2R.

opposite effects to those of Ang II [28,42]. Ang-(1-olized by ACE to Ang-(1-5). Ang-(1-7) is present inion and in tissues (brain, heart, kidneys, vessels, liver,e organs) [52,125], and binds to its G protein-coupleds [126].all peptides derived from Ang II include Ang III and Ang

formed from Ang II by aminopeptidase A, is a biologi- peptide with actions similar to those of Ang II [8]. Angin experimental models and in humans increases BP,asoconstriction and stimulates aldosterone productionro, it stimulates growth, production of proinammatorynd deposition of extracellular matrix proteins [158].s to AT1R, as well as to AT2R. Ang IV is generated frominopeptidase N and directly from Ang II by the enzymetidase. Ang IV increases renal blood ow, it induces

and improves cardiac function [165]. Ang IV also exertsge of neural effects including the ability to enhanced memory recall, anticonvulsant and anti-epileptogenicnd protection against cerebral ischemia. Some of thesemediated via the AT1R, but others are due to bindingc binding site, AT4R, identied as the transmembraneulin-regulated aminopeptidase (IRAP) [80]. Exact mech-

action whereby Ang IV induces effects via IRAP are the biological signicance of Ang IV/IRAP remains tod.g peptides include Ang-(3-7), important in the brain

[44], Ang-(1-9), which enhances bradykinin actions, NO and platelet regulation [100] and Ang-(1-12), impli-diac function [25].

3.3. Intrace

The intrcomponentsize Ang IIsites [75]. of Ang II antypes [30] renin, angiothe cytosolangiotensinlar and secenzymes (cgest a putatAng and AnRAS [59,60]or alternatiney, brain anovel uoreBP and kidnrole of the e

3.4. Tissue-

The circtissue RASsThe tissue sponents, inAng II recepAngiotensin-(1-7) Mas

Vasodila tio n

Anti-fib rotic

Anti-growth

Anti-in flamma tor yhere it cleaves liver-derived angiotensinogen to angiotensin I, whichykinin to inactive metabolites. A homologue of ACE, ACE2, catalyzesvascular cells, mediating vascular effects. Ang-(1-7) binds to receptor

llular RAS

acellular RAS is characterized by the presence of RASs within the cell and the ability of cells to synthe-, which elicits biological effects through intracellularAlthough the intracellular presence and/or synthesisd its receptors have been demonstrated in many cell

there is less evidence that the other RAS components,tensinogen and ACE are located within cells. Howeveric presence of differentially glycosylated isoforms ofogen, alternatively spliced forms of renin, intracellu-reted forms of ACE and alternative Ang II-generatingathepsins and chymase) and intracellular (P)RR, sug-ive cytosolic RAS [74,121]. The demonstration of nuclearg-(1-7) receptors further supports a functional cytosolic. The intracellular RAS, which is probably an extensionve form of tissue RAS, has been identied in the kid-nd heart. Overexpression of intracellular Ang II, using ascent fusion protein of Ang II, correlates with elevatedey pathology [81]. However the (patho)physiologicalndogenous system remains unclear.

based RAS

ulating RAS is only one entity of the overall RAS and can function independently of the circulating system.ystem is characterized by the presence of all RAS com-cluding renin, angiotensinogen, ACE, Ang I, Ang II, andtors and is found in the heart, vessels, kidney, adrenal

2144 A. Nguyen Dinh Cat, R.M. Touyz / Peptides 32 (2011) 21412150

Adipose

tissue

Heart Vessels

Fig. 2. Tissue ressedin cardiovascu cardiosystem).

gland, panctissue [11,1been identiin maintainlopathies as[41,164]. Alproduced frto whethertake up kidnsecreted locheart and v

The locaendocrine fin cardiovaatherosclerkidney disethose in threviewed [9

4. The vasc

All the indicating tthe systemangiotensinthe mRNA ical), large primarily wlation of tisits active min microves

Whereaswithin the renin is synderived rencapable of the 1970s wrat hindquapresent in vtic smooth secrete renfrom SHRspmented An

t thenditeninsing rm

has nin hkidnCE inll is e vaVasce froutioe bictab

-der

dditiw m-7) ag-(1sculaKidney

Immune cellsTissueRAS

Hematopoietic

Reproductive

tissue

Livertissue

reninangiotensin systems. Components of the reninangiotensin system are explar regulation (e.g. heart, vessels and kidneys) and others which are unrelated to

reas, CNS, reproductive system, lymphatic and adipose10,138,147] (Fig. 2). Elements of the RAS have alsoed in the eye, which may be important physiologicallying ocular pressure [41] and pathologically in vascu-sociated with retinopathy of hypertension and diabetesthough it is fairly well established that tissue Ang II isom locally derived Ang I, there is still uncertainty as

tissue renin is synthesized locally or whether tissuesey-generated renin from the circulation. Renin may beally in the kidney, adrenal glands and brain, but in theessels, it seems to be primarily kidney-derived.l RAS acts in an autocrine/intracrine, paracrine andashion. Elevated tissue levels of RAS components occurscular diseases independently of BP elevation, such as,osis, myocardial infarction, cardiac failure, diabetes andase [114]. The best characterized tissue RASs includee brain, kidney and heart, and have recently been,31,165,166].

ular RAS

elements of the RAS are present in the vasculature,hat the vascular system may act independently fromic RAS to generate Ang II (Fig. 3). Expression of renin,

supporvitro colife of rexpres

Conditionsand reoping with Asel wathat threnin. enzymcontribbecausundete

5. Ang

In asels, neAng-(1ates Anand vaogen, ACE, Ang I and Ang II has been demonstrated atand/or protein levels in veins (saphenous and umbil-conduit arteries (aorta) and small resistance arteries,ithin the endothelium [4,104,109,145]. Because regu-sue RAS occurs locally, the concentration of Ang II andetabolites may vary between tissues and may be highersels than that in the plasma [26].

there is general agreement that Ang II is synthesizedvessel wall, there is still controversy as to whetherthesized locally or whether it is taken up as kidney-in from the circulation. The concept that vessels aresynthesizing and releasing renin was rst reported inhere it was shown that renin is released from isolatedrters and splanchnic vessels and that renin activity isascular extracts [48,54]. Cultured canine and rat aor-muscle cells and human arterial cells synthesize andin [76,115,144]. Renin activity is greater in aortic cells

compared with WKY and has been implicated in aug-g II vascular effects in hypertension [148]. To further

ing shows tissue (PVAendothelialgrowth-inhgenic and aNO producreduced MAgeneration sion of ACE2endothelial[117]. Ang-inhibiting Asidered as ain the vascAng-(1-7) mconditions

ProAng-gen, is the It might seBrain

Gastrointestinal

tract

Endocrine

TissuePancreas,

Adrenal, pituitary

in multiple organs and tissues, some of which are directly involvedvascular control (e.g. Reproductive tissue, pancreas, gastrointestinal

presence of a functional vascular renin system in inions, aliskiren (direct renin inhibitor) increases the half

and prorenin in rat vascular smooth muscle cells over-human (P)RR [13].ing the presence of vascular renin in physiological con-been more challenging than in in vitro studies. Proreninave been demonstrated in microvessels of the devel-ey [19] and in renal arteries from adult rats treatedhibitors [112]. However renin expression in the ves-hardly detectable and there is still a strong notionsculature itself is likely not a major source of localular (P)RR probably plays a role in the uptake of them the circulation into the vessel wall. Moreover, then of vascular/tissue renin to circulating levels is unclearnephrectomized animals and anephric patients havele circulating renin [112].

ived peptides in the vascular wall

on to classical RAS components being identied in ves-embers of the RAS have been detected, including ACE2,nd Mas. Vascular ACE2 is functionally active and gener--7) from Ang II. Ang-(1-7) is found in the endotheliumr wall [32,136,161] and immunohistochemical stain-

abundant presence in aortic perivascular adventitialT) [78,79]. Ang-(1-7), by binding to receptor Mas on

cells, opposes Ang II actions by mediating vasodilation,ibition, anti-inammatory responses, antiarrhythmo-ntithrombotic effects [123,124] through NOS-derivedtion, activation of protein tyrosine phosphatases,PK activation and inhibition of NADPH oxidase-derivedof reactive oxygen species (ROS) [123,124]. Overexpres-

in the vascular wall of SHR is associated with improved function and attenuated development of hypertension(1-7)-Mas can hetero-oligomerize with AT1R, therebyng II actions. The ACE2-Ang-(1-7)-Mas axis is now con-

counter-regulatory system to the ACE-Ang II-AT1R axisulature [113], although some evidence indicates thatay also promote brosis and inammation in certain

[40,156].12, a recently characterized metabolite of angiotensino-newest functional peptide of the RAS to be identied.rve as an alternate substrate for local Ang production

A. Nguyen Dinh Cat, R.M. Touyz / Peptides 32 (2011) 21412150 2145

Fig. 3. Vascular reninangiotensin system. All components of the RAS are present in vascular cells. The expression of vascular renin is very low and probably derives primarilyfrom circulating renin, which is taken up from the circulation through (pro)renin receptors. Membrane-associated angiotensin converting enzyme (ACE) hydrolyzes Ang Ito Ang II, both in the extracellular and in the intracellular milieu. Vascular ACE2 catalyzes Ang II to Ang-(1-7). Ang II and Ang-(1-7) bind to their respective receptors. Ang IImay also be generated from renin-independent processes involving ProAng-12.

by circumventing the classical renin-dependent conversion ofangiotensinogen to Ang I [16]. ProAng-12 is produced in rat aortaand may contribute to Ang I production independently of reninin the vascular wall [111]. Functionally proAng-12 induces vaso-constriction through ACE1- and chymase-dependent mechanisms[16]. However the (patho)physiological signicance of vascularproAng-12 requires further clarication.

6. The RAS

Increasinregulation adipocyte-dcytokines [3is Ang II [4tied in adACE, (pro)r

receptors [2,14,17,18,21,22,37,58,131] (Fig. 4). A comprehensivestudy examining the RAS in perivascular adipose tissue of the aortaand mesenteric arteries from WKY rats demonstrated the presenceof angiotensinogen, ACE, ACE2, Ang I and Ang II [47]. In addition,(P)RR, chymase, AT1a and AT2 receptors were expressed [47].However renin was undetectable, both at the mRNA and proteinlevels, and the AT1b receptor was barely detectable in PVAT. Levels

ressirom es hnic

PVATar behan ncespocyversudent

Fig. 4. The adsystem. Adipoadipocytokineof Ang II withi in perivascular adventitial tissue (PVAT)

g evidence shows a paracrine role of PVAT in theof vascular function mediated, in part, througherived vasoactive agents and pro-inammatory8,45,56,83]. Of the many adipocyte-generated factors7,56]. Other members of the RAS have been iden-ipose tissue and PVAT, including angiotensinogen,

enin receptor, Ang II receptors and mineralocorticoid

of expPVAT fve timwas sigartery vasculPVAT tdiffereto aditissue been iipocyte reninangiotensin system in perivascular adventitial tissue (PVAT) inuences vcyte-derived Ang II, Ang-(1-7) and aldosterone inuence vascular function through sps in response to locally generated Ang II may also impact vascular function. Adipocyte-den vascular cells. AT1R, Ang II type 1 receptor; MR, mineralocorticoid receptor.on of angiotensinogen, ACE and ACE2 were similar inaorta and mesenteric arteries. Expression of (P)RR wasigher and that of chymase and AT1a and AT2 receptorsantly lower in aortic PVAT compared with mesenteric. Whereas levels of adipose Ang I were similar betweends, Ang II levels were higher in mesenteric arteryaortic PVAT [104]. The functional signicance of these

is unclear, but may contribute to differential responseste-derived factors emanating from brown adiposes white adipose tissue. Periaortic adipose tissue has

ied as brown adipose tissue expressing uncouplingascular function and contributes to the vascular reninangiotensinecic vascular smooth muscle cell (VSMC) receptors. Production ofrived renin may be taken up by vascular cells to stimulate production

2146 A. Nguyen Dinh Cat, R.M. Touyz / Peptides 32 (2011) 21412150

protein-1 (UCP-1), whereas mesenteric artery adipose tissue isconsidered to be white adipose tissue [47].

Within PVAT, ACE2 activity promotes production of Ang-(1-7)from Ang II, both in arteries and in veins [79,84]. Ang-(1-7) releasedby PVAT inhyperpolarlaxation [5in vessels fimpaired va

We recepose tissuemanner [9responses. Ptant mechacells [96,14increase thexert autocvascular tisena may binsulin senshyperaldos

7. Functio

VascularAng II are mlial cells, va[64,91]. Anthat are stimreceptors ractions. Whtion and vaand vasodialso stimulamay play an

The conrole of vasccell Ang II staldosteroneences vascuactivates vacular tone. Vand reuptaautocrine/pRAS.

IdentifyiresponsiblechallengingII can direintravasculdependent whereas locIn hypertenhigher thantone. Someof tissue retrols [157] hypertensioatherosclerthe pro-inassociated w

Recent sious T-cell key role in age [12,61]

decient in monocytes/macrophages [29], fail to develop hyper-tension, endothelial dysfunction, vascular remodeling or vascularinammation following Ang II infusion. Since macrophages and Tlymphocytes express components of the RAS, it is possible that

e/invessed ATroph

implatiolarlyamm. It s

xperr.

vasc

potertenAS c

renserv

c admrs lows whode

sculad sugwall

pathrougpertactivt incr

exae of ar RAne cting,pressensio[122

(pal hypgiot

ts wious vascuensivicanin SHensioar wr), ex2,133s, bere to2,133ted ws [13d regtogelocal

hypduces production of endothelial NO, which acts as aizing factor through K(Ca) channels to induce vasore-0]. These PVAT-derived Ang-(1-7) effects are alteredrom SHR contributing to endothelial dysfunction andsodilation in hypertension [50].ntly demonstrated that mouse and human visceral adi-

and PVAT produce aldosterone in an Ang II-dependent6], processes that inuence vascular inammatoryVAT-derived components of the RAS provide an impor-nism for cross talk between adipocytes and vascular0]. Adipocyte RAS components may contribute toe local synthesis of Ang II [85], which in turn mayrine/paracrine effects on adipocytes and on adjacentsue [15,39,46,49,51,56,68,88,89,102]. These phenom-e particularly important in vascular dysfunction anditivity associated with obesity, metabolic syndrome andteronism [38,67,83].

nal evidence of vascular tissue RAS

actions of circulating-derived and tissue-generatedediated via AT1 and AT2 receptors, located on endothe-scular smooth muscle cells and adventitial broblastsg II mediates effects via complex signaling pathwaysulated following to its cell-surface receptors [82]. Both

egulate VSMC function, although they differ in theirereas the AT1R is associated with growth, inamma-soconstriction, the AT2R is associated with apoptosislation [82,141]. In pathological conditions, AT2R mayte hypertrophy and inammation [160]. Vascular RAS

important role in the ne-tuning of vascular tone.cept of the vascular RAS and the autocrine/paracrineular Ang II was suggested in the 1980s [33]. Vascularimulates synthesis of prostaglandins, endothelin-1 and

in the endothelium and vessel wall, which in turn inu-lar function [33,97,127,155]. Endothelial-derived Ang IIscular smooth muscle Ang receptors and controls vas-ascular Ang II may also inuence catecholamine release

ke by noradrenergic nerve endings [33]. The intrinsicaracrine RAS may contribute little to the circulating

ng the source (systemic versus vascular) of Ang II for vascular regulation in physiological conditions is. However, there is evidence that intravascular Angctly inuence vascular function. In pig pial arteries,ar Ang II induces AT1receptor-mediated, endothelium-vasodilation that is blocked by COX and NOS inhibition,al Ang II induces vasoconstriction or vasodilation [72].sion, the concentration of Ang II within microvessels is

in plasma, and may contribute to increased vascular studies have shown an increase in the concentrationnin in vessels from SHR versus normotensive con-and may reect an overactive local vascular RAS inn. Similar ndings have been reported in models ofosis, suggesting a role for vascular RAS activation inammatory, pro-thrombotic and atherogenic processesith atherosclerosis [73,139].

tudies have demonstrated that macrophages and var-lymphocyte subtypes within the vascular wall play athe regulation of blood pressure and target organ dam-. Mice decient in T-lymphocytes [93,159] and mice

immunin the ACE anin macare anUpreguparticuand intensionfrom eunclea

8. The

Theof hypeof the Rplasmather obchroniblockemodelsuch mthe vamentevessel to thetone thand hythetic exhibi

Thetenancvasculney, ocirculablood hypertAng II

Theclinicaand anpatienexogentured hypertis signthose hypertone yeblocke[87,13changepressu[87,13associaarterietion anTaken tional humanammatory cells may contribute to local Ang II levelsl wall. Expression (mainly mRNA) of angiotensinogen,1 receptors and Ang II protein has been demonstratedages, mast cells and lymphocytes [62,94]. Macrophagesortant source of thymic renin and Ang II in rats [163].n of the RAS in macrophages and immune cells may be

important in conditions associated with vascular injuryation, such as in diabetes, atherosclerosis and hyper-

hould be stressed that these data derive predominantlyimental models and the signicance in humans remains

ular RAS and hypertension

ntial role of a non-circulating RAS in the pathogenesission was suggested when it was reported that inhibitorsan lower blood pressure in hypertensive patients whosein levels are normal or even low [36]. This was fur-ed in experimental studies, which demonstrated thatinistration of ACE inhibitors or angiotensin II receptorer the blood pressure in various hypertensive animal

ere activity of plasma renin is not elevated [103]. Inls with normal/low PRA, ACE activity is increased inture and vasoconstrictor responses to Ang I are aug-gesting that increased Ang II levels are present in the. Hyperactivation of the vascular RAS may contributeophysiology of hypertension by increasing vascularh direct vasoconstrictor, pro-inammatory, pro-broticrophic effects of Ang II and by increased local sympa-ity, independently of circulating Ang II [34,35,120]. SHReased vascular renin activity [7].ct role of circulating versus vascular RAS in the main-blood pressure is unclear. Some studies showed thatS is critically involved in maintaining chronic two kid-lip hypertension [103], whereas others showed that

but not extra-renal RAS, is important in maintainingure in Goldblatt hypertension [122]. In this model ofn, vascular RAS regulation is independent of circulating

].tho)physiological signicance of the vascular RAS inertension is unclear and little is known about reninensinogen status in human intact vessels. However,th hypertension have increased vascular responses toAng II [106,135] and we demonstrated that in cul-lar smooth muscle cells from resistance arteries ofe patients, signaling by Ang II through AT1 receptorstly enhanced [152154]. These ndings are similar toR indicating hyperactivation of the vascular RAS inn [103]. Moreover, hypertensive patients treated forith ACE inhibitors or ARBs, but not with atenolol (betahibited signicant regression of vascular remodeling]. These processes were independent of hemodynamiccause ACE inhibitors, ARBs and atenolol reduced blood

similar levels, suggesting a local effect of RAS inhibition]. Chronic ARB treatment in hypertensive patients wasith increased expression of AT2 receptors in resistance

0], which could contribute to improved vascular func-ression of vascular remodeling in these patients [130].

ther, these clinical data, albeit indirect, suggest a func- RAS, which may be important in vascular regulation inertension.

A. Nguyen Dinh Cat, R.M. Touyz / Peptides 32 (2011) 21412150 2147

9. The (patho)physiological signicance of the vascular RAS further considerations

Despite extensive data supporting a functional vascular RASthere are aFirstly, manin in vitro lated vesseand vasculaimmortalizintact vessetion was evup- or dowtion. SeconRAS was pegen was ovdifcult to RAS enzymof the majowhole animthe local tisgant novel recently bethe eld bythe precisemanner. Focontrol elemin the exprAng II (or ittein engineelucidate threstricted mdemonstratit participahas yet to ies where arenin altholow concen[162].

10. Conclu

The globtissue RAS may functioendocrine cshort-term in cardiovapressure cofunctions oregional tisactions of cing angiotevascular syrenin is synkidney-derimajor devebe highlighcomponentpresent in tsystem mayvation of thto the vascutargeting bomore comp

might provide better therapeutic outcomes in patients with AngII-dependent cardiovascular diseases.

Conicts of interest

e.

wled

rk fr andch (Canadh a f

nces

badir Podulaon proes 201chard press07;29

dvani ceptoe kidngoudem com05;12

naka YTRAP BS Le

RB Triesartaypertesaad Mts: pofect oxelban

scrutsolate

ader Mlogica

ader M08;86

altatu ainaarhoury lymjury. Hatenbuliskirelar sm

oustanctivatiiet-indl 2004randeses va07;15

ujak-Gt R.

roangiampbepressnger r87;12

aprio le of ts. FASarey Ae devarey ninagulatiassis Lep 200assis Lgulatirs in a number of issues that warrant further consideration.y studies identifying the tissue RAS were performedconditions, where the RAS was investigated in iso-ls or vascular beds ex vivo or in cultured endothelialr smooth muscle cells. Cultured cells, and particularlyed cell lines, may differ phenotypically from cells inls in vivo. In many of those studies, Ang II produc-aluated in conditions in which the RAS enzymes weren-regulated by genetic or pharmacological manipula-dly, in many animal studies, activation of the vascularrformed in mice in which renin and/or angiotensino-erexpressed in a vascular-specic manner, making itinterpret the physiological signicance of endogenouses and peptides at the local vascular level. Thirdly, oner challenges in studying the role of vascular RAS inals is being able to differentiate, in an intact system,sue system from the circulating/systemic system. Ele-approaches to study tissue RAS in whole animals haveen developed. Reudelhuber [118] has revolutionized

creating a peptide-releasing protein that facilitates targeting of peptide production in a tissue-specicr example, linking the fusion protein to specic geneents (promoters) that target vascular genes results

ession of the transgene in vessels and the release ofs peptides) into the vessel wall. Using this fusion pro-ered to release peptides from specic cell-types wille (patho)physiological role of Ang peptides in a tissue-anner in whole animals over the long-term. Finally,

ion that the vascular/tissue RAS is activated and thattes in the regulation of vascular function in humansbe demonstrated. This is highlighted in clinical stud-nephric patients failed to demonstrate any circulatingugh Ang I, Ang II, and Ang III were detectable in verytrations indicating a non-specic extra-renal source

sions

al RAS comprises a dual system: circulating RAS and[69,108,116]. The vascular autocrine/paracrine RASn primarily in controlling vascular tone, whereas theirculating RAS may be more important in regulatingcardiovascular-renal homeostasis. All tissues importantscular regulation, as well as tissues unrelated to bloodntrol, e.g. pancreas and gut, possess a local RAS. Exactf the local RAS are unclear but probably contribute tosue control. Functionally tissue-based RAS may amplifyirculating Ang II. Most components of the RAS, includ-nsinogen, ACE, Ang I and Ang II are expressed in thestem. However it still remains elusive as to whetherthesized in the vessel wall or whether it is taken up asved renin from the circulation. There have been threelopments in the eld of the vascular RAS that need toted: (1) the ndings that in addition to the classicals of the RAS, (P)RR, novel Ang peptides and ACE2 arehe vessel wall, (2) cells of the immune/inammatory

contribute to Ang II in the vessel wall, and (3) acti-e RAS in perivascular adipose tissue may contributelar RAS and inuence vascular function. Interventionsth the systemic and the vascular RAS should facilitatelete inhibition of the RAS, which in the clinical setting

Non

Ackno

Wo44018ResearChair/Cthroug

Refere

[1] AmtiR

[2] Aex20

[3] Areth

[4] Ate20

[5] AAFE

[6] AdH

[7] Araef

[8] AAba

[9] Bco

[10] B20

[11] Bbr

[12] Btoin

[13] BAcu

[14] BAdio

[15] Bat20

[16] Bbup

[17] Cexse19

[18] Crosi

[19] Cth

[20] Crere

[21] CR

[22] Cretogements

om the authors laboratory was supported by grants 57886, both from the Canadian Institutes of HealthIHR). RMT is supported through a Canada Researchian Foundation for Innovation award. CAN is supported

ellowship from the CIHR.

M, Walston JD, Carey RM, Siragy HM. Angiotensin II type-2 receptorste inammation through signal transducer and activator of transcrip-teins 3 phosphorylation and TNF production. J Interferon Cytokine1;31(6):4714.V, Boullu-Ciocca S, Desbriere R, Nguyen G, Grino M. Renin receptorion in human adipose tissue. Am J Physiol Regul Integr Comp Physiol2:27482.A, Kelly DJ, Cox AJ, White KE, Advani SL, Thai K, et al. The (pro)reninr: site-specic and functional linkage to the vacuolar H+-ATPase iney. Hypertension 2009;54:2619.mos MM, Greene AS. Localization of the reninangiotensin sys-ponents to the skeletal muscle microcirculation. Microcirculation(8):62736.. The novel angiotensin II type 1 receptor (AT1R)-associated proteindownregulates AT1R and ameliorates cardiomyocyte hypertrophy.tt 2005;579(7):157986.alists Collaboration. Effects of telmisartan, irbesartan, valsartan, can-n, and losartan on cancers in 15 trials enrolling 138,769 individuals. Jns 2011;29(4):62335.M, Antonaccio MJ. Vascular wall renin in spontaneously hypertensivetential relevance to hypertension maintenance and antihypertensivef captopril. Hypertension 1982;4:48793.d F, Dias J, Miranda F, Ferro FM, Barros NM, Carmona AK, et al.iny of the biochemical pathways from Ang II to Ang-(3-4) in renalral membranes. Regul Pept 2009;158(13):4756.. Tissue reninangiotensinaldosterone systems: targets for pharma-l therapy. Annu Rev Pharmacol Toxicol 2010;50:43965., Ganten D. Update on tissue reninangiotensin systems. J Mol Med(6):61521.OC, Campos LA, Bader M. Local reninangiotensin system and the

continuous quest for knowledge. Peptides 2011;32(5):10836.mi T, Kasal DA, Li MW, Shbat L, Laurant P, Neves MF, et al. T regula-phocytes prevent angiotensin II-induced hypertension and vascularypertension 2011;57(3):46976.rg WW, de Bruin RJ, van Gool JM, Mller DN, Bader M, Nguyen G, et al.n-binding increases the half life of renin and prorenin in rat aortic vas-ooth muscle cells. Arterioscler Thromb Vasc Biol 2008;28(6):11517.y CM, Bharadwaj K, Daugherty A, Brown DR, Randall DC, Cassis LA.on of the systemic and adipose reninangiotensin system in rats withuced obesity and hypertension. Am J Physiol Regul Integr Comp Phys-;287:R9439.

RP. The fatter the better? Perivascular adipose tissue attenu-scular contraction through different mechanisms. Br J Pharmacol1:3034.izycka B, Olszanecki R, Suski M, Madek J, Stachowicz A, Kor-Angiotensinogen metabolism in rat aorta: robust formation ofotensin-12. J Physiol Pharmacol 2010;61(December (6)):67982.ll DJ, Habener JF. Cellular localization of angiotensinogen geneion in brown adipose tissue and mesentery: quantication of mes-ibonucleic acid abundance using hybridization in situ. Endocrinology1:161626.

M, Fve B, Clas A, Viengchareun S, Lombs M, Zennaro MC. Pivotalhe mineralocorticoid receptor in corticosteroid-induced adipogene-EB J 2007;21:218594.V, Carey RM, Gomez RA. Expression of alpha-smooth muscle actin ineloping kidney vasculature. Hypertension 1992;19:II16875.RM, Siragy HM. Newly recognized components of thengiotensin system: potential roles in cardiovascular and renalon. Endocr Rev 2003;24(3):26171.A. Fat cell metabolism: insulin, fatty acids, and renin. Curr Hypertens0;2:1328.A, Fettinger MJ, Roe AL, Shenoy UR, Howard G. Characterization andon of angiotensin II receptors in rat adipose tissue. angiotensin recep-dipose tissue. Adv Exp Med Biol 1996;396:3947.

2148 A. Nguyen Dinh Cat, R.M. Touyz / Peptides 32 (2011) 21412150

[23] Cruciat CM, Ohkawara B, Acebron SP, Karaulanov E, Reinhard C, IngelngerD, et al. Requirement of prorenin receptor and vacuolar H+-ATPase-mediatedacidication for Wnt signaling. Science 2010;327:45963.

[24] Cuadra AE, et al. A current view of brain reninangiotensin sys-tem: is the (pro)renin receptor the missing link? Clin Pharmacol Ther2010;12

[25] CummiproAng

[26] Danser J Bioche

[27] Danser ing of re

[28] Dantas insightsAm J Ph

[29] De CiucReducedresistanfactor-dinduced

[30] Deliu E,activate

[31] De MelBasic an

[32] Dzau VJphysiolCardiov

[33] Dzau VJsion 198

[34] Dzau VJtion: a h

[35] Dzau VJin contr

[36] Dzau VJdiovasc

[37] Engeli expressHyperte

[38] Engeli Sadiposesyndrom

[39] Eringa Eulation perivasc

[40] EstebanWang Ykey play

[41] Fletcherreninarons, gl

[42] FerrarioHyperte

[43] Ferrariotem frometabo

[44] Ferreira(3-7) p2007;14

[45] Galic S,Cell End

[46] Galvez Perivascneously

[47] Glvez-et al. Coponents2008;19

[48] Ganten or prod

[49] Gao YJ, perivascBr J Pha

[50] Gao YJ, Ttissue pRes 200

[51] Gao YJ, Zadiposeartery. J

[52] Gava E,RA, et aglucose2009;24

[53] Gomez during d

[54] Gould Awalls. J

[55] Grady EF. Expression of AT2 receptors in the developing rat fetus. J Clin Invest1991;88:92133.

[56] Greenstein AS, Khavandi K, Withers SB, Sonoyama K, Clancy O, JeziorskaM, et al. Local inammation and hypoxia abolish the protective anti-contractile properties of perivascular fat in obese patients. Circulation009;11riendlninaupte M

al. ACm J Phwathm

al. Nuitric owathmgiote

xide. Aarrisoationaznednina010;11eenemsculaiguchiansduathophitom Hlls frooriuchpe 2999;33sueh Wypertecobellay a rhnstostem hayat ensioninouchr in asnecht gioteaywo

oh KKent otherosumar nthesumar e hearrue red h35.mari

iseasee RModulauly).e RM,

y perivw RA

gandsase (IR

XC, C intrabules

011;30uis SFationeart C

C, Sud fun

C, Zhipose

H, Bipose

007;29dwigtion a

rotein998;27alik Rgioteith ty5(1):2738.ns PM. A new addition to the reninangiotensin peptide family:iotensin-12 (PA12). Cardiovasc Res 2009;82(1):78.AH. Local reninangiotensin systems: the unanswered questions. Intm Cell Biol 2003;35(6):75968.AJ, Nguyen G. The Renin Academy Summit: advancing the understand-nin science. J Renin Angiotensin Aldosterone Syst 2008;9(2):11923.AP, Sandberg K. Regulation of ACE2 and ANG-(1-7) in the aorta: new

into the reninangiotensin system in the control of vascular function.ysiol Heart Circ Physiol 2005;289(3):H9801.eis C, Amiri F, Brassard P, Endemann DH, Touyz RM, Schiffrin EL.

vascular remodeling, endothelial dysfunction, and oxidative stress ince arteries of angiotensin II-infused macrophage colony-stimulatingecient mice: evidence for a role in inammation in angiotensin-

vascular injury. Arterioscler Thromb Vasc Biol 2005;25(10):210613. Tica AA, Motoc D, Brailoiu GC, Brailoiu E. Intracellular angiotensin IIs rat myometrium. Am J Physiol Cell Physiol 2011;(May).lo WC, Frohlich ED. On the local cardiac reninangiotensin system.d clinical implications. Peptides 2011;32(8):17749., Bernstein K, Celermajer D, Cohen J, Dahlof B, Deaneld J, et al. Patho-ogic and therapeutic importance of tissue ACE: a consensus report.asc Drugs Ther 2002;16(2):14960.. Signicance of the vascular reninangiotensin pathway. Hyperten-6;8:5539.. Vascular wall reninangiotensin pathway in control of the circula-ypothesis. Am J Med 1984;77(4A):316.. Vascular reninangiotensin: a possible autocrine or paracrine systemol. J Cardiovasc Pharmacol 1984;6:S37782.. Vascular reninangiotensin system and vascular protection. J Car-

Pharmacol 1993;22(Suppl. 5):S19.S, Gorzelniak K, Kreutz R, Runkel N, Distler A, Sharma AM. Co-ion of reninangiotensin system genes in human adipose tissue. Jns 1999;17:55560., Schling P, Gorzelniak K, Boschmann M, Janke J, Ailhaud G, et al. The-tissue reninangiotensinaldosterone system: role in the metabolice? Int J Biochem Cell Biol 2003;35(6):80725.C, Bakker W, Smulders YM, Serne EH, Yudkin JS, Stehouwer CD. Reg-of vascular function and insulin sensitivity by adipose tissue: focus onular adipose tissue. Microcirculation 2007;14:389402.

V, Heringer-Walther S, Sterner-Kock A, de Bruin R, van den Engel S,, et al. Angiotensin-(1-7) and the g protein-coupled receptor MAS areers in renal inammation. PLoS One 2009;4(4):e5406.

EL, Phipps JA, Ward MM, Vessey KA, Wilkinson-Berka JL. Thengiotensin system in retinal health and disease: its inuence on neu-ia and the vasculature. Prog Retin Eye Res 2010;29(4):284311.

CM. ACE2: more of Ang-(1-7) or less Ang II? Curr Opin Nephrolns 2011;20(1):16.

CM. New physiological concepts of the reninangiotensin sys-m the investigation of precursors and products of angiotensin Ilism. Hypertension 2010;55(2):44552.

PM, Souza Dos Santos RA, Campagnole-Santos MJ. Angiotensin-ressor effect at the rostral ventrolateral medulla. Regul Pept1(13):16874.

Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ. Molocrinol 2010;316:12939.B, de Castro J, Herold D, Dubrovska G, Arribas S, Gonzalez MC, et al.ular adipose tissue and mesenteric vascular function in sponta-

hypertensive rats. Arterioscler Thromb Vasc Biol 2006;26:1297302.Prieto B, Bolbrinker J, Stucchi P, de Las Heras AI, Merino B, Arribas S,mparative expression analysis of the reninangiotensin system com-

between white and brown perivascular adipose tissue. J Endocrinol7(1):5564.D, Hayduk K, Brecht HM, Boucher R, Genest J. Evidence of renin releaseuction in splanchnic territory. Nature (London) 1970;226:5512.Lu C, Su LY, Sharma AM, Lee RM. Modulation of vascular function byular adipose tissue: the role of endothelium and hydrogen peroxide.rmacol 2007;151:32331.akemori K, Su LY, An WS, Lu C, Sharma AM, et al. Perivascular adiposeromotes vasoconstriction: the role of superoxide anion. Cardiovasc6;71(2):36373.eng ZH, Teoh K, Sharma AM, Abouzahr L, Cybulsky I, et al. Perivascular

tissue modulates vascular function in the human internal thoracic Thorac Cardiovasc Surg 2005;130:11306.

Samad-Zadeh A, Zimpelmann J, Bahramifarid N, Kitten GT, Santosl. Angiotensin-(1-7) activates a tyrosine phosphatase and inhibits-induced signalling in proximal tubular cells. Nephrol Dial Transplant(6):176673.

RA. Molecular biology of components of the reninangiotensin systemevelopment. Pediatr Nephrol 1990;4(4):4213.B, Skeggs LT, Kahn JR. The presence of renin activity in blood vesselExp Med 1964;119:389400.

2[57] G

re[58] G

etA

[59] Getn

[60] Gano

[61] Hm

[62] Hre2

[63] Hva

[64] Htrp

[65] Hce

[66] Hty1

[67] Hh

[68] Iap

[69] Josy

[70] Kp

[71] Kto

[72] Kan(M

[73] KmA

[74] Ksy

[75] Kth

[76] LatuS4

[77] Led

[78] Lem(J

[79] Leb

[80] Lelid

[81] Liantu2

[82] LoerH

[83] Luan

[84] Luad

[85] Luad2

[86] Lucap1

[87] Manw9(12):166170.ing KK, Murphy TJ, Alexander RW. Molecular biology of thengiotensin system. Circulation 1993;87(6):181628.N, Boustany-Kari CM, Bharadwaj K, Police S, Thatcher S, Gong MC,E2 is expressed in mouse adipocytes and regulated by a high fat diet.ysiol Regul Integr Comp Physiol 2008;295:R7818.ey TM, Shaltout HA, Pendergrass KD, Pirro NT, Figueroa JP, Rose JC,clear angiotensin II type 2 (AT2) receptors are functionally linked to

xide production. Am J Physiol Renal Physiol 2009;296:F148493.ey TM, Westwood BM, Pirro NT, Tang L, Rose JC, Diz DI, et al. Nuclear

nsin-(1-7) receptor is functionally coupled to the formation of nitricm J Physiol Renal Physiol 2010;299(5):F98390.n DG, Guzik TJ, Lob HE, Madhur MS, Marvar PJ, Thabet SR, et al. Inam-, immunity, and hypertension. Hypertension 2011;57(2):13240.aroglu IC, Beyazit Y. Pathobiological aspects of the local bone marrowngiotensin system: a review. J Renin Angiotensin Aldosterone Syst(4):20513.an S, Sluimer JC, Daemen MJ. Angiotensin-converting enzyme and

r remodeling. Circ Res 2007;101(5):44154. S, Ohtsu H, Suzuki H, Shirai H, Frank GD, Eguchi S. Angiotensin II signalction through the AT1 receptor: novel insights into mechanisms andysiology. Clin Sci (Lond) 2007;112(8):41728., Liu G, Nishiyama A. Role of (pro)renin receptor in cardiovascular

m the aspect of signaling. Front Biosci 2010;2:2461249.i M, Akishita M, Dzau VJ. Recent progress in angiotensin II

receptor research in the cardiovascular system. Hypertension:61321.A, Wyne K. Reninangiotensinaldosterone system in diabetes and

nsion. J Clin Hypertens 2011;13:22437.lis G, Gao YJ, Sharma AM. Do cardiac and perivascular adipose tissueole in atherosclerosis? Curr Diab Rep 2008;8:204.n CI, Franz VL. Reninangiotensin system: a dual tissue and hormonalfor cardiovascular control. J Hypertens Suppl 1992;10(7):S1326.A, Gonda S, Sen S, Smeby RR. Responses of juxtaglomerular cell sus-s to various stimuli. Hypertension 1981;3(2):15767.i K, Ichihara A, Itoh H. Functional characterization of (pro)renin recep-sociation with V-ATPase. Front Biosci 2011;17:321623.KR, Lefer CW. Distinct effects of intravascular and extravascularnsin II on cerebrovascular circulation of newborn pigs. Exp Biol Medod) 2010;235(12):147988., Han SH, Oh PC, Shin EK, Quon MJ. Combination therapy for treat-r prevention of atherosclerosis: focus on the lipid-RAAS interaction.clerosis 2010;209(2):30713.R, Boim MA. Diversity of pathways for intracellular angiotensin IIis. Curr Opin Nephrol Hypertens 2009;18(1):339.R, Singh VP, Baker KM. The intracellular reninangiotensin system inrt. Curr Hypertens Rep 2009;11(2):10410.J, Demond-Henri J, Daret D. Reninangiotensin system in cul-uman arterial smooth muscle cells. J Cardiovasc Pharmacol 1989;4:

CA, Schiffrin EL. The angiotensin II type 2 receptor in cardiovascular. J Renin Angiotensin Aldosterone Syst 2010;11(1):1931., Bader M, Alenina N, Santos RA, Gao YJ, Lu C. Mas receptors inting relaxation induced by perivascular adipose tissue. Life Sci 2011;

Lu C, Su LY, Gao YJ. Endothelium-dependent relaxation factor releasedascular adipose tissue. J Hypertens 2009;27(4):78290., Mustafa T, Ye S, McDowall SG, Chai SY, Albiston AL. Angiotensin AT4

are potent, competitive inhibitors of insulin regulated aminopepti-AP). J Neurochem 2003;86(2):34450.ook JL, Rubera I, Tauc M, Zhang F, Zhuo JL. Intrarenal transfer ofcellular uorescent fusion of angiotensin II selectively in proximal

increases blood pressure in rats and mice. Am J Physiol Renal Physiol0(5):F107688., Saward L, Zahradka P. Both AT1 and AT2 receptors mediate prolif-

and migration of porcine vascular smooth muscle cells. Am J Physiolirc Physiol 2011;(May).

LY, Lee RM, Gao YJ. Alterations in perivascular adipose tissue structurection in hypertension. Eur J Pharmacol 2011;656(13):6873.ao AX, Gao YJ, Lee RM. Modulation of vein function by perivascular

tissue. Eur J Pharmacol 2011;657(13):1116.oustany-Kari CM, Daugherty A, Cassis LA. Angiotensin II increases

angiotensinogen expression. Am J Physiol Endocrinol Metab2:E12807.

J, Kerscher S, Brandt U, Pfeiffer K, Getlawi F, Apps DK, et al. Identi-nd characterization of a novel 9.2-kDa membrane sector-associated

of vacuolar proton-ATPase from chromafn granules. J Biol Chem3:1093947.A, Schoeld IJ, Izzard A, Austin C, Bermann G, Heagerty AM. Effects ofnsin type-1 receptor antagonism on small artery function in patientspe 2 diabetes mellitus. Hypertension 2005;45(2):2649.

A. Nguyen Dinh Cat, R.M. Touyz / Peptides 32 (2011) 21412150 2149

[88] Malinowski M, Deja MA, Golba KS, Roleder T, Biernat J, Wos S. Perivasculartissue of internal thoracic artery releases potent nitric oxide and prostacyclin-independent anticontractile factor. Eur J Cardiothorac Surg 2008;33:22531.

[89] Mathai ML, Chen N, Cornall L, Weisinger RS. The role of angiotensin in obe-sity and metabolic disease. Endocr Metab Immune Disord Drug Targets 2011[Epub a

[90] Mederomechan

[91] Mehta patholo2007;29

[92] Mogi Mrecepto

[93] Muller target-o

[94] NahmodImpaireJ Pharm

[95] Naruse evidencjuxtaglo

[96] NguyenAdipocymineral

[97] Nguyentone: no

[98] NguyenHyperte

[99] Nguyen2010;21

[100] OcaranzAngiotetens 201

[101] Ohtsu HAngiotemechan2006;48

[102] Okada SAdiposein obesi

[103] Okamurtem in t

[104] Oliver nism o1984;74

[105] Oppermvolume

[106] rneskoresponsJ Cardio

[107] Padia SHConversmediate

[108] Paul M,Physiol

[109] Paul M,in humaClin Inv

[110] Prez-DHiriart and non2011;40

[111] Prosser responstides 20

[112] Pupilli of renin1992;26

[113] Rabelo Ltive stre

[114] RaizadareninaJ Investi

[115] Re R, Fasmooth

[116] Re RN2004;88

[117] Rentzscgenic anrats red2008;52

[118] Reudelhwhole a

[119] Reudelhtension

[120] Rosenthal JH, Pfeie B, Michailov ML, Pschorr J, Jacob ICM, Dahlheim H.Investigations of components of the reninangiotensin system in rat vasculartissue. Hypertension 1984;6:38390.

[121] Sakoda M, Ichihara A, Kurauchi-Mito A, Narita T, Kinouchi K, Murohashi-Bokuda K, et al. Aliskiren inhibits intracellular angiotensin II levels without

fectin10;23maniRNA impai

M. Andothempaihiffrindotheypertentos giote08;93ntos Rngioteas. Prvoia Ce vascvoia C

/AT2 rnsiveypertevoia

hoA/Rlls: ro

eouslyvoia sistan07;49ye JA,rming

hiffrinre angiote

hiffrinnina

hypehinza

functd vasoback

efect sentialva DMS. Evidraguengh Mnsionragy Hstem tia S,

al. F10;9(ltis Eootharks

er CN,lls do11;57eckeliV diselin Phaegbauom blo

Y, Wesized92;7(ales

:S36naka

TRAP BS Leatcheninadocriurstod blohead of print].s Y, Schnitzler M, Storch U, Gudermann T. AT1 receptors asosensors. Curr Opin Pharmacol 2011;11(2):1126.PK, Griendling KK. Angiotensin II cell signaling: physiological andgical effects in the cardiovascular system. Am J Physiol Cell Physiol2(1):C8297., Iwai M, Horiuchi M. New insights into the regulation of angiotensinrs. Curr Opin Nephrol Hypertens 2009;18(2):13843.DN, Kvakan H, Luft FC. Immune-related effects in hypertension andrgan damage. Curr Opin Nephrol Hypertens 2011;20(2):1137.

K, Gentilini C, Vermeulen M, Uharek L, Wang Y, Zhang J, et al.d function of dendritic cells decient in angiotensin II type 1 receptors.acol Exp Ther 2010;334(3):85462.K, Inagami T, Celio MR, Workman RJ, Takii Y. Immunohistochemicale that angiotensins I and II are formed by intracellular mechanism inmerular cells. Hypertension 1982;4(3 Pt 2):704.

Dinh Cat A, Briones AM, Callera GE, Yogi A, He Y, Montezano AC, et al.te-derived factors regulate vascular smooth muscle cells throughocorticoid and glucocorticoid receptors. Hypertension 2011;(July).

Dinh Cat A, Touyz RM. Cell signaling of angiotensin II on vascularvel mechanisms. Curr Hypertens Rep 2011;13(2):1228.

G. Renin and prorenin receptor in hypertension: whats new? Currns Rep 2011;13(1):7985.

G, Muller DN. The biology of the (pro)renin receptor. J Am Soc Nephrol(1):1823.a MP, Lavandero S, Jalil JE, Moya J, Pinto M, Novoa U, et al.nsin-(1-9) regulates cardiac hypertrophy in vivo and in vitro. J Hyper-0;28(5):105464., Suzuki H, Nakashima H, Dhobale S, Frank GD, Motley ED, et al.nsin II signal transduction through small GTP-binding proteins:ism and signicance in vascular smooth muscle cells. Hypertension(4):53440., Kozuka C, Masuzaki H, Yasue S, Ishii-Yonemoto T, Tanaka T, et al.

tissue-specic dysregulation of angiotensinogen by oxidative stressty. Metabolism 2010;59(September):124151.a T, Miyazaki M, Inagami T, Toda N. Vascular reninangiotensin sys-wo-kidney, one clip hypertensive rats. Hypertension 1986;8:5605.JA, Sciacca RR. Local generation of angiotensin II as a mecha-f regulation of peripheral vascular tone in the rat. J Clin Invest(4):124751.ann M. Atrap deciency increases arterial blood pressure and plasma. J Am Soc Nephrol 2010;21(3):46877.g G, Kahan T, Ekholm M, Brijersn A, Walln NH. Altered vasculares to circulating angiotensin II in familial combined hyperlipidemia.vasc Med 2008;9(10):103744., Kemp BA, Howell NL, Fournie-Zaluski MC, Roques BP, Carey RM.

ion of renal angiotensin II to angiotensin III is critical for AT2 receptor-d natriuresis in rats. Hypertension 2008;51(2):4605.

Mehr AP, Kreutz R. Physiology of local reninangiotensin systems.Rev 2006;86:747803.

Wagner J, Dzau VJ. Gene expression of the reninangiotensin systemn tissues. Quantitative analysis by the polymerase chain reaction. Jest 1993;91(5):205864.az I, Guzmn C, Olivares-Reyes JA, Ramrez T, Gutierrz-Reyes G,M, et al. Evidence of an intracellular angiotensin-generating system-AT1, non-AT2 binding site in a human pancreatic cell line. Pancreas(5):7017.HC, Richards AM, Forster ME, Pemberton CJ. Regional vasculare to ProAngiotensin-12 (PA12) through the rat arterial system. Pep-10;31(8):15405.C, Chevalier RL, Carey RM, Gomez RA. Distribution and content

and renin mRNA in remnant kidney of adult rat. Am J Physiol3:F7315.A, Alenina N, Bader M. ACE2-angiotensin-(1-7)-Mas axis and oxida-ss in cardiovascular disease. Hypertens Res 2011;34(2):15460.

V, Skipper B, Luo W, Grifth J. Intracardiac and intrarenalngiotensin systems: mechanisms of cardiovascular and renal effects.g Med 2007;55(7):34159.llon JT, Dzau V, Quay SC, Haber E. Renin synthesis by canine aortic

muscle cells in culture. Life Sci 1982;30:99106.. Tissue reninangiotensin systems. Med Clin North Am(1):1938.h B, Todiras M, Iliescu R, Popova E, Campos LA, Oliveira ML, et al. Trans-giotensin-converting enzyme 2 overexpression in vessels of SHRSP

uces blood pressure and improves endothelial function. Hypertension(5):96773.uber TL. Deciphering the roles of tissue reninangiotensin systems innimals. Hypertension 2011;57(3):5327.uber TL. Prorenin, renin, and their receptor: moving targets. Hyper-

2010;55(5):1071107.

af20

[122] Sam

[123] SaRen

[124] SaScenH

[125] Saan20

[126] SaAM

[127] Sath

[128] SaIIteH

[129] SaRcen

[130] Sare20

[131] Safo6.

[132] Sctuan9.

[133] Screin

[134] Scofan

[135] ShDes

[136] SiVSp

[137] Site

[138] Sisy

[139] Siet20

[140] Sosm

[141] Spnce20

[142] StCC

[143] Stfr

[144] Suth19

[145] Sw2)

[146] TaAFE

[147] ThreEn

[148] Thang (pro)renin receptor signals in human podocytes. Am J Hypertens(5):57580.

NJ, Brammar WJ, Swales JD. Renal and extra-renal levels of reninn experimental hypertension. Clin Sci (Lond) 1991;80(4):33944.o WO, Henrique de Castro C, Santos RA, Schiffrin EL, Touyzgiotensin-(1-7) counterregulates angiotensin II signaling in humanlial cells. Hypertension 2007;50(6):10938.

o WO, Souza dos Santos RA, Faria-Silva R, da Mata Machado LT, EL, Touyz RM. Angiotensin-(1-7) through receptor Mas mediateslial nitric oxide synthase activation via Akt-dependent pathways.nsion 2007;49(1):18592.RA, Ferreira AJ, Simes E, Silva AC. Recent advances in thensin-converting enzyme 2-angiotensin(1-7)-Mas axis. Exp Physiol(5):51927.A, Simoes e Silva AC, Maric C, Silva DM, Machado RP, de Buhr I, et al.nsin-(1-7) is an endogenous ligand for the G protein-coupled receptoroc Natl Acad Sci U S A 2003;100(14):825863., Burger D, Nishigaki N, Montezano A, Touyz RM. Angiotensin II andular phenotype in hypertension. Expert Rev Mol Med 2011;13:e11., Ebrahimian T, He Y, Gratton JP, Schiffrin EL, Touyz RM. Angiotensineceptor-induced vasodilation in stroke-prone spontaneously hyper-

rats involves nitric oxide and cGMP-dependent protein kinase. Jns 2006;24(12):241722.C, Tabet F, Yao G, Schiffrin EL, Touyz RM. Negative regulation ofho kinase by angiotensin II type 2 receptor in vascular smooth musclele in angiotensin II-induced vasodilation in stroke-prone sponta-

hypertensive rats. J Hypertens 2005;23(5):103745.C, Touyz RM, Volpe M, Schiffrin EL. Angiotensin type 2 receptor ince arteries of type 2 diabetic hypertensive patients. Hypertension(2):3416.

Ragsdale NV, Carey RM, Peach MJ. Localization of angiotensin peptide- enzymes of 3T3-F442A adipocytes. Am J Physiol 1993;264:C1570

EL, Park JB, Intengan HD, Touyz RM. Correction of arterial struc-d endothelial dysfunction in human essential hypertension by thensin receptor antagonist losartan. Circulation 2000;101(14):1653

EL, Touyz RM. From bedside to bench to bedside: role ofngiotensinaldosterone system in remodeling of resistance arteriesrtension. Am J Physiol Heart Circ Physiol 2004;287(2):H43546.ri F, Tesauro M, Rovella V, Adamo A, Mores N, Cardillo C. Coexistenceional angiotensin II type 2 receptors mediating both vasoconstrictionodilation in humans. J Hypertens 2011;29(9):17438.

DM, Williams GH, Moore TJ, Dluhy RG, Podolsky S, Hollenberg NK.in the sodium-modulated tissue responsiveness to angiotensin II inl hypertension. J Clin Invest 1983;72:211524., Vianna HR, Cortes SF, Campagnole-Santos MJ, Santos RA, Lemos

ence for a new angiotensin-(1-7) receptor subtype in the aorta of-Dawley rats. Peptides 2007;28(3):7027., Mensah GA, Bakris G. Pathogenesis and clinical physiology of hyper-. Cardiol Clin 2010;28(4):54559.M, Carey RM. Role of the intrarenal reninangiotensinaldosteronein chronic kidney disease. Am J Nephrol 2010;31(6):54150.

Tomasoni L, Atzeni F, Ambrosio G, Cordiano C, Catapano A,rom endothelial dysfunction to atherosclerosis. Autoimmun Rev12):8304.E, Cassis LA. Inuence of perivascular adipose tissue on rat aortic

muscle responsiveness. Clin Exp Hypertens A 1991;13:27796.MA, Parsons KK, Stegbauer J, Gurley SB, Vivekanandan-Giri A, Fort-

et al. Angiotensin II type 1A receptors in vascular smooth muscle not inuence aortic remodeling in hypertension. Hypertension(3):57785.ngs UM. The evolving story of the RAAS in hypertension, diabetes andase: moving from macrovascular to microvascular targets. Fundamrmacol 2009;23(6):693703.er J, Coffman TM. New insights into angiotensin receptor actions:od pressure to aging. Curr Opin Nephrol Hypertens 2011;20(1):848.ang H, Liao Y, Liu D, Ding J. Atrial natriuretic factor and renin syn-

in cultured aortic smooth muscle cells of rats. Chin Med Sci J2):1125.JD, Samani NJ. Vascular RAA system. J Hum Hypertens 1993;7(Suppl..Y. The novel angiotensin II type 1 receptor (AT1R)-associated proteindownregulates AT1R and ameliorates cardiomyocyte hypertrophy.tt 2005;579(7):157986.r S, Yiannikouris F, Gupte M, Cassis L. The adiposengiotensin system: role in cardiovascular disease. Mol Cellnol 2009;302(2):1117.n H, Swales JD, Bing RF, Hurst BC, Marks EJ. Vascular renin-like activityod pressure maintenance in the rat. Hypertension 1979;1:6439.

2150 A. Nguyen Dinh Cat, R.M. Touyz / Peptides 32 (2011) 21412150

[149] Tigerstedt R, Bergman PG. Niere und Kreislauf. Skand Arch Physiol1898;8:22371.

[150] Torretti J. Sympathetic control of renin release. Annu Rev Pharmacol Toxicol1982;22:16792.

[151] Touyz RM. Reactive oxygen species as mediators of calcium signaling byangiotensin II: implications in vascular physiology and pathophysiology.Antioxid Redox Signal 2005;7(910):130214.

[152] Touyz RM, Chen X, Tabet F, Yao G, He G, Quinn MT, et al. Expression ofa functionally active gp91phox-containing neutrophil-type NAD(P)H oxi-dase in smooth muscle cells from human resistance arteries: regulation byangiotensin II. Circ Res 2002;90(11):120513.

[153] Touyz RM, Schiffrin EL. Increased generation of superoxide by angiotensinII in smooth muscle cells from resistance arteries of hypertensive patients:role of phospholipase D-dependent NAD(P)H oxidase-sensitive pathways. JHypertens 2001;19(7):124554.

[154] Touyz RM, Wu XH, He G, Park JB, Chen X, Vacher J, et al. Role of c-Srcin the regulation of vascular contraction and Ca2+ signaling by angiotensinII in human vascular smooth muscle cells. J Hypertens 2001;19(3):4419.

[155] Ushio-Fukai M. Vascular signaling through G protein-coupled receptors: newconcepts. Curr Opin Nephrol Hypertens 2009;18(2):1539.

[156] Velkoska E, Dean RG, Griggs K, Burchill L, Burrell LM. Angiotensin-(1-7) infusion is associated with increased blood pressure and adversecardiac remodelling in rats with subtotal nephrectomy. Clin Sci (Lond)2011;120(8):33545.

[157] Vicaut E, Hou X. Local reninangiotensin system in the microcirculation ofspontaneously hypertensive rats. Hypertension 1994;24(1):706.

[158] Wang HX, Zhang QF, Zeng XJ, Wang W, Tang CS, Zhang LK. Effects ofangiotensin III on protein, DNA, and collagen synthesis of neonatal car-diomyocytes and cardiac broblasts in vitro. J Cardiovasc Pharmacol Ther2010;15(4):393402.

[159] Viel EC, Lemari CA, Benkirane K, Paradis P, Schiffrin EL. Immune regulationand vascular inammation in genetic hypertension. Am J Physiol Heart CircPhysiol 2010;298(3):H93844.

[160] Wassmann S, Nickenig G. Pathophysiological regulation of the AT1-receptorand implications for vascular disease. J Hypertens 2006;24(1):S1521.

[161] Weiss D, Bernstein KE, Fuchs S, Adams J, Synetos A, Taylor WR. Vascularwall ACE is not required for atherogenesis in ApoE/ mice. Atherosclerosis2010;209(2):3528.

[162] Wilkes BM, Mento PF, Pearl AR, Hollander AM, Mossey RT, Bellucci A,et al. Plasma angiotensins in anephric humans: evidence for an extrarenalangiotensin system. Cardiovasc Pharmacol 1991;17(3):41923.

[163] Wilkinson-Berka JL, Kelly DJ, Rong P, Campbell DJ, Skinner SL. Characterisationof a thymic reninangiotensin system in the transgenic m(Ren-2)27 rat. MolCell Endocrinol 2002;194(12):2019.

[164] Wilkinson-Berka JL, Miller AG, Binger KJ. Prorenin the (pro)renin receptor:recent advances and implications for retinal development and disease. CurrOpin Nephrol Hypertens 2011;20(1):6976.

[165] Yang R, Walther T, Gembardt F, Smolders I, Vanderheyden P, Albiston AL,et al. Renal vasoconstrictor and pressor responses to angiotensin IV in miceare AT1a-receptor mediated. J Hypertens 2010;28(3):48794.

[166] Zhuo JL, Li XC. New insights and perspectives on intrarenal reninangiotensinsystem: focus on intracrine/intracellular angiotensin II. Peptides2011;32(7):155165.

A new look at the reninangiotensin systemFocusing on the vascular system1 Introduction2 The classical RAS3 Beyond the classical RAS3.1 Renin/prorenin receptor3.2 ACE2, Ang-(1-7), Ang III, Ang IV and other Ang-derived peptides3.3 Intracellular RAS3.4 Tissue-based RAS

4 The vascular RAS5 Ang-derived peptides in the vascular wall6 The RAS in perivascular adventitial tissue (PVAT)7 Functional evidence of vascular tissue RAS8 The vascular RAS and hypertension9 The (patho)physiological significance of the vascular RAS further considerations10 ConclusionsConflicts of interestAcknowledgementsReferences