Angiotensin II Induces Oxidative Stress and Endothelial Dysfunction in Mouse Ophthalmic Arteries via Involvement of AT1 Receptors and NOX2.

Michael Birk,Adrian Gericke,Marin Kuntic,Sebastian Steven,Jenia Kouchek Zadeh,Andreas Patzak,Andreas Daiber,Caroline Manicam,Johanna Helmstädter,Ewa Baum,Norbert Pfeiffer

doi:10.3390/antiox10081238

Abstract

Angiotensin II (Ang II) has been implicated in the pathophysiology of various age-dependent ocular diseases. The purpose of this study was to test the hypothesis that Ang II induces endothelial dysfunction in mouse ophthalmic arteries and to identify the underlying mechanisms. Ophthalmic arteries were exposed to Ang II in vivo and in vitro to determine vascular function by video microscopy. Moreover, the formation of reactive oxygen species (ROS) was quantified and the expression of prooxidant redox genes and proteins was determined. The endothelium-dependent artery responses were blunted after both in vivo and in vitro exposure to Ang II. The Ang II type 1 receptor (AT1R) blocker, candesartan, and the ROS scavenger, Tiron, prevented Ang II-induced endothelial dysfunction. ROS levels and NOX2 expression were increased following Ang II incubation. Remarkably, Ang II failed to induce endothelial dysfunction in ophthalmic arteries from NOX2-deficient mice. Following Ang II incubation, endothelium-dependent vasodilation was mainly mediated by cytochrome P450 oxygenase (CYP450) metabolites, while the contribution of nitric oxide synthase (NOS) and 12/15-lipoxygenase (12/15-LOX) pathways became negligible. These findings provide evidence that Ang II induces endothelial dysfunction in mouse ophthalmic arteries via AT1R activation and NOX2-dependent ROS formation. From a clinical point of view, the blockade of AT1R signaling and/or NOX2 may be helpful to retain or restore endothelial function in ocular blood vessels in certain ocular diseases.

Highlights

The renin-angiotensin system (RAS) plays a critical role in blood pressure regulation [1]
It was shown in mice that angiotensin II (Ang II) induces a pro-inflammatory phenotype that is characterized by the infiltration of monocytes into the vascular wall as well as higher levels of reactive oxygen species
U46619 (10−11 M–10−6 M) elicited concentration-dependent vasoconstriction that did not differ between ophthalmic arteries from mice subjected to Ang II

Summary

Introduction

The renin-angiotensin system (RAS) plays a critical role in blood pressure regulation [1]. Since it was shown that endothelial and vascular dysfunction both progress with age as well as with the burden of oxidative stress, e.g., by genetic deletion of antioxidant enzymes, such as manganese superoxide dismutase or glutathione peroxidase-1, the aging process and accumulation of oxidative damage may impair ophthalmic endothelial and vascular function [7,8]. Per se, is associated with higher ROS formation rates, especially from mitochondria, these “oxidative stress aging conditions” can be mimicked by a deficiency in antioxidant enzymes, e.g., manganese superoxide dismutase, leading to more pronounced eNOS uncoupling, endothelial dysfunction, and higher blood pressure in Ang II-treated manganese superoxide dismutase deficient mice [9]

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