Elsevier

Peptides

Volume 32, Issue 10, October 2011, Pages 2141-2150
Peptides

Review
A new look at the renin–angiotensin system—Focusing on the vascular system

https://doi.org/10.1016/j.peptides.2011.09.010Get rights and content

Abstract

The renin–angiotensin system (RAS), critically involved in the control of blood pressure and volume homeostasis, is a dual system comprising a circulating component and a local tissue component. The rate 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, renal and vascular cells. The tissue RAS can operate independently of the circulating RAS and may be activated even when the circulating RAS is suppressed or normal. A functional tissue RAS has been identified in brain, kidney, heart, adipose tissue, hematopoietic tissue, gastrointestinal tract, liver, endocrine system and blood vessels. Whereas angiotensinsinogen, angiotensin converting enzyme (ACE), Ang I and Ang II are synthesized within these tissues, there is still controversy as to whether renin is produced locally or whether it is taken up from the circulation, possibly by the (pro)renin receptor. This is particularly true in the vascular wall, where expression of renin is very low. The exact function of the vascular RAS remains elusive, but may contribute to fine-tuning of vascular tone and arterial structure and may amplify vascular 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 elucidated including: (1) the presence of functionally active Ang-(1-7)-Mas axis in the vascular system, (2) the importance of the RAS in perivascular adipose tissue and cross talk with vessels, and (3) the contribution to vascular RAS of Ang II derived from immune and inflammatory cells within the vascular wall. The present review highlights recent progress in the RAS field, focusing on the tissue system and particularly on the vascular RAS.

Highlights

► All the elements of the RAS are present in the vasculature, indicating that the vascular system may act independently from the systemic RAS to generate Ang II. ► Vascular renin probably derives primarily from circulating kidney-derived renin. ► New components of the RAS have been identified in the vascular wall, including (P)RR, Ang-(1-7), Ang III, Ang IV, ACE2 and ProAng-12. ► Ang II generated from immune and inflammatory cells contributes to Ang II levels in the vascular wall. ► Activation of the RAS in perivascular adipose tissue contributes to the vascular RAS and influences vascular function. ► Functionally the vascular RAS may amplify vascular effects of the circulating RAS.

Introduction

The renin–angiotensin system (RAS) is critically involved in the physiological regulation of blood pressure and volume homeostasis and in the pathogenesis of hypertension and other cardiovascular diseases [43], [137]. Pharmacological inhibition of the RAS is a major therapeutic strategy currently used to manage hypertension and to reduce the risks of cardiovascular events [6]. Since its discovery in the 1890s the RAS was identified as an endocrine system whereby circulating kidney-derived renin regulates cardiovascular function through Ang II binding to its receptors on target tissues [149]. Until recently this system was accepted as the conventional RAS. However it is now clear that the kidney is not the only source of renin production and that angiotensin (Ang) peptides may be formed in tissues and organs that have a blood pressure-independent function.

Genes coding for enzymes and peptides of the RAS are expressed in many tissues beyond the kidney, including the brain, adrenal gland, pituitary gland, reproductive tissues, gastrointestinal tract, hematopoietic tissue, heart and vessels, suggesting the presence of a functionally active local or tissue RAS [10], [24], [142]. Functions of the local RAS remain elusive, but are probably tissue-specific. The exact role of tissue RAS in human (patho)physiology is still unclear. The present review provides an update of the classical RAS and highlights some new concepts, focusing on the tissue RAS and specifically the vascular RAS.

Section snippets

The classical RAS

Activation of the classical RAS originates with the synthesis of renin, a glycoprotein, by the juxtaglomerular (JG) cells of the renal afferent arteriole [57]. In JG cells, preprorenin is processed to prorenin and then to active renin, which is secreted into the circulation [95]. Renal renin release is stimulated by low volume states, high salt content in the distal tubules, renal sympathetic nerve activity and reduced renal perfusion [70], [150]. In the blood, renin, an aspartyl protease,

Beyond the classical RAS

Until recently, the RAS was considered a linear process (Fig. 1) and Ang II was accepted as the major effector peptide [143]. However the conventional view of the RAS has undergone significant change at four main levels: (1) identification of renin/prorenin receptor, (2) recognition of functionally active Ang II-derived peptides, (3) intracellular RAS and (4) existence of a tissue RAS. The present review highlights some of these new paradigms focusing on the tissue system, specifically the

The vascular RAS

All the elements of the RAS are present in the vasculature, indicating that the vascular system may act independently from the systemic RAS to generate Ang II (Fig. 3). Expression of renin, angiotensinogen, ACE, Ang I and Ang II has been demonstrated at the mRNA and/or protein levels in veins (saphenous and umbilical), large conduit arteries (aorta) and small resistance arteries, primarily within the endothelium [4], [104], [109], [145]. Because regulation of tissue RAS occurs locally, the

Ang-derived peptides in the vascular wall

In addition to classical RAS components being identified in vessels, new members of the RAS have been detected, including ACE2, Ang-(1-7) and Mas. Vascular ACE2 is functionally active and generates Ang-(1-7) from Ang II. Ang-(1-7) is found in the endothelium and vascular wall [32], [136], [161] and immunohistochemical staining shows abundant presence in aortic perivascular adventitial tissue (PVAT) [78], [79]. Ang-(1-7), by binding to receptor Mas on endothelial cells, opposes Ang II actions by

The RAS in perivascular adventitial tissue (PVAT)

Increasing evidence shows a paracrine role of PVAT in the regulation of vascular function mediated, in part, through adipocyte-derived vasoactive agents and pro-inflammatory cytokines [38], [45], [56], [83]. Of the many adipocyte-generated factors is Ang II [47], [56]. Other members of the RAS have been identified in adipose tissue and PVAT, including angiotensinogen, ACE, (pro)renin receptor, Ang II receptors and mineralocorticoid receptors [2], [14], [17], [18], [21], [22], [37], [58], [131] (

Functional evidence of vascular tissue RAS

Vascular actions of circulating-derived and tissue-generated Ang II are mediated via AT1 and AT2 receptors, located on endothelial cells, vascular smooth muscle cells and adventitial fibroblasts [64], [91]. Ang II mediates effects via complex signaling pathways that are stimulated following to its cell-surface receptors [82]. Both receptors regulate VSMC function, although they differ in their actions. Whereas the AT1R is associated with growth, inflammation and vasoconstriction, the AT2R is

The vascular RAS and hypertension

The potential role of a non-circulating RAS in the pathogenesis of hypertension was suggested when it was reported that inhibitors of the RAS can lower blood pressure in hypertensive patients whose plasma renin levels are normal or even low [36]. This was further observed in experimental studies, which demonstrated that chronic administration of ACE inhibitors or angiotensin II receptor blockers lower the blood pressure in various hypertensive animal models where activity of plasma renin is not

The (patho)physiological significance of the vascular RAS – further considerations

Despite extensive data supporting a functional vascular RAS there are a number of issues that warrant further consideration. Firstly, many studies identifying the tissue RAS were performed in in vitro conditions, where the RAS was investigated in isolated vessels or vascular beds ex vivo or in cultured endothelial and vascular smooth muscle cells. Cultured cells, and particularly immortalized cell lines, may differ phenotypically from cells in intact vessels in vivo. In many of those studies,

Conclusions

The global RAS comprises a dual system: circulating RAS and tissue RAS [69], [108], [116]. The vascular autocrine/paracrine RAS may function primarily in controlling vascular tone, whereas the endocrine circulating RAS may be more important in regulating short-term cardiovascular-renal homeostasis. All tissues important in cardiovascular regulation, as well as tissues unrelated to blood pressure control, e.g. pancreas and gut, possess a local RAS. Exact functions of the local RAS are unclear

Conflicts of interest

None.

Acknowledgements

Work from the author's laboratory was supported by grants 44018 and 57886, both from the Canadian Institutes of Health Research (CIHR). RMT is supported through a Canada Research Chair/Canadian Foundation for Innovation award. CAN is supported through a fellowship from the CIHR.

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