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Review
. 2020 Jun 16;21(12):4268.
doi: 10.3390/ijms21124268.

Impact of the Renin-Angiotensin System on the Endothelium in Vascular Dementia: Unresolved Issues and Future Perspectives

Fatima Y Noureddine  1 , Raffaele Altara  2 , Fan Fan  3 , Andriy Yabluchanskiy  4 , George W Booz  3 , Fouad A Zouein  1
Affiliations
Review

Impact of the Renin-Angiotensin System on the Endothelium in Vascular Dementia: Unresolved Issues and Future Perspectives

Fatima Y Noureddine et al. Int J Mol Sci. .

Erratum in

Abstract

The effects of the renin-angiotensin system (RAS) surpass the renal and cardiovascular systems to encompass other body tissues and organs, including the brain. Angiotensin II (Ang II), the most potent mediator of RAS in the brain, contributes to vascular dementia via different mechanisms, including neuronal homeostasis disruption, vascular remodeling, and endothelial dysfunction caused by increased inflammation and oxidative stress. Other RAS components of emerging significance at the level of the blood-brain barrier include angiotensin-converting enzyme 2 (ACE2), Ang(1-7), and the AT2, Mas, and AT4 receptors. The various angiotensin hormones perform complex actions on brain endothelial cells and pericytes through specific receptors that have either detrimental or beneficial actions. Increasing evidence indicates that the ACE2/Ang(1-7)/Mas axis constitutes a protective arm of RAS on the blood-brain barrier. This review provides an update of studies assessing the different effects of angiotensins on cerebral endothelial cells. The involved signaling pathways are presented and help highlight the potential pharmacological targets for the management of cognitive and behavioral dysfunctions associated with vascular dementia.

Keywords: ACE1; ACE2; AT2 receptor; Ang(1–7); Mas receptor; blood–brain barrier.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Key components of the angiotensin (Ang) system relevant to the blood–brain barrier. The traditional arm of the system (shown in yellow) consists of the sequential processing of Ang I, Ang II, and Ang III. The latter two act upon the AT1 receptor to cause a number of physiological actions, including (for the most part) vasoconstriction, increased oxidative stress, and inflammation. The AT2 receptor may contribute as well to oxidative and inflammatory signaling, but may oppose vasoconstriction. In recent years, evidence has been found for a parallel arm (shown in green) that largely opposes the traditional actions of Ang II/Ang III. The primary effector of this system is Ang(1–7), which acts through the Mas receptor. Both Ang(1–9) and Ang(1–7) may also act through AT2R. Abbreviations: ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; AP, aminopeptidase; CP, carboxypeptidase; NEP, neutral endopeptidase.
Figure 2
Figure 2
Angiotensin signaling in the endothelium of the blood–brain barrier. Traditional and novel components of the renin–angiotensin system (RAS) converge at the level of the endothelium to modulate blood flow, vascular remodeling, and brain permeability. Ang II formed by the actions of ACE on Ang I may act on the AT1 receptor to induce either vasodilation, via production of EDHF, or vasoconstriction by stimulating ROS production via Nox2 and attenuating eNOS-induced NO production. Inhibition of PPARα/γ may exacerbate ROS production. Ang II-induced ROS and inhibition of PPARα/γ may act synergistically to increase blood–brain barrier permeability by impeding the expression or functioning of tight junction proteins. ROS contributes as well to adverse vascular remodeling and vessel rarefaction that impedes blood flow and occurs with hypertension and aging. Through AT2R, Ang II may induce vasodilation via EDHF production. AT2R is also linked to cardioprotective effects via vascular endothelial growth factor (VEGF) expression, as well as strengthening of interendothelial junctions via inhibition of β-catenin. However, VEGF is also implicated in the disruption of the blood–brain barrier. NO may also increase AT2R expression, which in turn may reduce ACE levels (not shown). Ang(1–9), Ang(1–7), and Ang III may activate AT2R as well, with Ang III also acting on AT1R. Ang(1–7), formed from Ang II by ACE2, acts upon the Mas receptor to constitute a protective arm of RAS through inhibition of Nox2 and activation of eNOS. In pericytes, AT1R activation may induce oxidative stress by increasing Nox4, thereby triggering pericyte loss and compromising the blood–brain barrier. Based on recent research in the heart, brain pericytes may also express ACE2. Not shown are the RAS components associated with astrocytes and neurons. See text for additional details. Abbreviations: ACE, angiotensin converting enzyme; AP, aminopeptidase; AT1, angiotensin II type 1 receptor; AT2, angiotensin II type 2 receptor; CP, carboxypeptidase; EDHF, endothelium-derived hyperpolarizing factor; eNOS, endothelial nitric oxide synthase; mTOR, mammalian target of rapamycin; NO, nitric oxide; NOX, NADPH oxidase; PI3K, phosphoinositide 3-kinase; PPARα/γ, peroxisome proliferator-activated receptor alpha/gamma; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor. Some images are from Servier Medical Art (https://smart.servier.com/).
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