Angiotensin Receptor Expression and Vascular Endothelial Dysfunction in Obstructive Sleep Apnea

Abstract

Background: Obstructive sleep apnea (OSA) is associated with vascular endothelial dysfunction (VED) in otherwise healthy patients. The role of renin-angiotensin system (RAS) in the OSA induced VED is not well understood.

Methods: Recently diagnosed OSA patients with very low cardiovascular disease (CVD) risk (Framingham score <5%) were studied at diagnosis and after 12 weeks of verified continuous positive airway pressure (CPAP) therapy. Participants underwent biopsy of gluteal subcutaneous tissue at baseline and after CPAP. Microcirculatory endothelial expression of angiotensin receptors type-1 (AT-1) and type-2 (AT-2) was measured in the subcutaneous tissue using quantitative confocal microscopy techniques. The ex-vivo effect of AT-1 receptor blockade (ARB) on endothelial superoxide production was also measured before and after CPAP treatment.

Results: In OSA patients (n = 11), microcirculatory endothelial AT1 expression decreased from 873 (200) (fluorescence units) at baseline to 393 (59) units after 12 weeks of CPAP (P = 0.02). AT2 expression did not decrease significantly in these patients (479 (75) to 329 (58) post CPAP (P = 0.08)). The ex-vivo addition of the losartan to the microcirculatory endothelium resulted in decreased superoxide expression in the vascular walls from 14.2 (2.2) units to 4.2 (0.8) P < 0.001; while it had no effect on post-CPAP patient tissue (P = 0.64).

Conclusions: In OSA patients with no to minimal CVD risk, VED is associated with upregulation of AT-1 expression that is reversible with CPAP. Endothelial oxidative stress was reversible with ARB. RAS activation may play an important role in the development of early CVD risk in OSA patients.

Keywords: blood pressure; endothelial dysfunction; hypertension; nitric oxide; obstructive sleep apnea.

© American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Figures

Figure 1.

Detection of angiotensin receptors type 1 and 2 (AT-1 and AT-2) expression in the microcirculatory endothelium. Top: Representative confocal microscopy images of AT-1 fluorescence (red) in the frozen sections (8 µm) from one control and one OSA patient before and after treatment with CPAP. Bottom AT-2 fluorescence (green) in the same control and OSA patient. Magnification, ×20. Insets show higher magnifications of the endothelium/cells within squares. Bars: 100 µm. Abbreviations: AT, angiotensin receptors type; CPAP, continuous positive airway pressure; OSA, obstructive sleep apnea.

Figure 2.

Representative fluorescence photomicrographs of confocal optical sections of gluteal tissue biopsies from OSA patient before (pre) and after (post) CPAP and non-OSA volunteer (control), labeled with DHE with/without incubation of losartan. Each panel shows microvascular endothelial cell regions. Original magnification: ×20; bar, 100 µm, for all images. The intensity of DHE fluorescence measured from the corresponding sections (endothelium) of OSA patient (pre and post) CPAP and control tisuse samples, and after pretreatment of sections with the angiotensin inhibitor losartan (50 µM). Abbreviations: AT, angiotensin receptors type; CPAP, continuous positive airway pressure; DHE, dihydroethidium; OSA, obstructive sleep apnea.

Figure 3.

Microvascular angiotensin receptors (type 1 and 2) expression in OSA patients and controls. (a) AT1 expression. (b) AT2 expression. Abbreviations: AT, angiotensin receptors type; CPAP, continuous positive airway pressure.

Figure 4.

Ex-vivo effect of losartan on endothelial superoxide expression in OSA patients before and after CPAP therapy. Abbreviations: CPAP, continuous positive airway pressure; OSA, obstructive sleep apnea.