Review
Role of the renin–angiotensin system in vascular inflammation

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Angiotensin (Ang) II, the main effector of the renin–angiotensin system (RAS), is one of the major mediators of vascular remodeling in hypertension. Besides being a potent vasoactive peptide, Ang II exerts proinflammatory effects on the vasculature by inducing integrins, adhesion molecules, cytokines and growth and profibrotic mediators through activation of redox-sensitive pathways and transcription factors. Clinical findings suggest that inflammation participates in the mechanisms involved in the pathophysiology of hypertension and its complications. Antagonists of the RAS have been shown to exert cardiovascular protection, in part through their vascular anti-inflammatory effects. However, further studies are needed to better understand whether inflammatory biomarkers might be clinically useful for cardiovascular risk stratification and whether targeting inflammation pharmacologically will improve cardiovascular outcomes beyond blood pressure reduction. The present review addresses recent findings regarding the pathophysiology of vascular inflammation in hypertension, focusing specifically on the role of Ang II.

Introduction

The renin–angiotensin system (RAS) plays a key role in the development and pathophysiology of hypertension and cardiovascular disease (CVD). In hypertension small and large arteries undergo structural, mechanical and functional changes that contribute to vascular complications and increased cardiovascular risk. Growing evidence indicates that hypertension-induced vascular injury involves a low-grade inflammatory process and that inflammation plays a significant role in the pathophysiology of high blood pressure (BP) and its complications [1]. Inflammation is a complex process that can arise in tissues in response to pathogenic stimuli. Usually, inflammation leads to recovery and restoration of tissue integrity, but if repair is imperfectly controlled the inflammatory process could result in persistent tissue damage. Angiotensin (Ang) II, a potent vasoactive peptide and the main effector of the RAS, induces vascular remodeling and endothelial dysfunction in association with increases in levels of BP. However, Ang II is able to induce vascular injury independently of its haemodynamic effects [2]. BP-independent vascular injury induced by Ang II can be explained, at least in part, by its proinflammatory properties (Figure 1). The present review discusses recent findings regarding the pathophysiology of vascular inflammation in hypertension, focusing specifically on the role of Ang II and the clinical implications and new therapeutic possibilities for CVDs thereof.

Section snippets

RAS and vascular inflammation

Independently of the etiology of the primary stimulus and the tissue involved, inflammation classically follows three stages: increased vascular permeability, leukocyte recruitment and activation of tissue-repair processes. Ang II influences all the stages of the inflammatory response (Figure 2).

Molecular mechanisms involved in RAS-induced vascular inflammation

Among the intracellular signaling pathways involved in Ang-II-induced vascular remodeling and inflammation, the production of ROS and the activation of proinflammatory transcription factors such as nuclear factor (NF)-κB play a key role (Figure 3).

Molecular mechanisms that antagonize RAS-induced vascular inflammation

Effects of Ang II can be counteracted by some mechanisms, and among these we should mention peroxisome proliferator activated receptors (PPARs). PPARs are nuclear receptors that in the inactivated state are bound to corepressor proteins. Under the effect of PPAR activators, they dissociate from their corepressors and recruit coactivators, including a PPAR-binding protein and the steroid receptor coactivator-1, and then bind to a PPAR response element (PPRE) in target genes to modulate gene

Role of aldosterone and other components of the RAS in Ang-II-induced vascular inflammation

Aldosterone is a mineralocorticoid hormone produced by the adrenal glomerulosa whose secretion is regulated by different agents, the most important of which is Ang II. It plays a key role in hypertension and CVDs, beyond its effects on the kidney to retain salt and water, by contributing to vascular inflammation, oxidative stress, fibrosis and the vascular injury [64]. Aldosterone, through activation of the mineralocorticoid receptor (MR), caused vascular injury in brain, heart and kidneys by

Clinical implications of vascular inflammation in hypertension

Considering that, as described hitherto, inflammation plays a key role in the pathophysiology of Ang-II-induced vascular injury, it is relevant to consider the impact of these data on clinical practice. Biomarkers of systemic low-grade inflammation predict incident hypertension and cardiovascular risk 70, 71. Several mediators of inflammation, including C-reactive protein (CRP), myeloperoxidase (MPO), IL-1, IL-6, IL-18, TNF-α, soluble adhesion molecules (sICAM, sVCAM, sE-selectin, P-selectin),

Conclusions

Inflammation and the RAS are intricately interrelated and their association induces an amplification process that involves oxidative stress and proinflammatory transcription factors, leading to progressive vascular injury in hypertension. A growing body of evidence also suggests that inflammation through vascular remodeling participates in the mechanisms leading to the development and pathophysiology of hypertension and its complications, which could mean that inflammatory mediators could be

Acknowledgements

The work of the authors was supported by Canadian Institutes of Health Research grants 37917 and 82790, a Canada Research Chair on Hypertension and Vascular Research and the Canadian Fund for Innovation, all to E.L.S.

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